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Chan YL, Liao JC, Li TL, Wu CJ, Chiu YH. Bifidobacterium lactis ameliorates AOM/DSS-induced inflammation, dysbiosis, and colonic precancerous lesions. Appl Microbiol Biotechnol 2025; 109:69. [PMID: 40116950 PMCID: PMC11928396 DOI: 10.1007/s00253-025-13445-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 02/25/2025] [Accepted: 02/25/2025] [Indexed: 03/23/2025]
Abstract
Bowel cancer is the third most common malignancy of tumors and one of the major causes of cancer-related death. Bowel precancerous conditions can develop without any symptoms, which either makes it difficult for early diagnosis or poses a poor prognosis/gloomy relapse. This study aimed to investigate the effects of Bifidobacterium animalis subsp. lactis TCI604 (B. lactis) on inflammatory responses, gut microbiome, and protectiveness against azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colonic precancerous lesions. The AOM/DSS-induced colonic precancerous lesion murine model was studied with 24 female C57BL/6 J mice assigned to the control group, AOM/DSS-induced colonic precancerous lesion group (AOM/DSS), AOM/DSS treated with B. lactis probiotic group (B. lactis P), and AOM/DSS treated with B. lactis cell-free supernatant group (B. lactis S). The results showed that both B. lactis P and B. lactis S could attenuate AOM/DSS-induced body weight loss and intestine damage, reduce aberrant crypt foci (ACF) and the formation of colonic polyps, and significantly inhibit pro-inflammatory cytokines and the NF-κB signaling pathway, in which the B. lactis S group outperformed others. Further analysis using 16S rDNA sequencing suggested that both B. lactis P and B. lactis S optimize gut microbiota. Several bacteria, including Muribaculaceae, Prevotellaceae_UCG-001, Anaerostipes, Ruminococcaceae, Mucispirillum, Clostridia_UCG-014, and Clostridia_vadinBB60 that were known in close relation to colonic precancerous lesions, were sequenced at taxonomic level. Our results indicated that both B. lactis P and B. lactis S improved AOM/DSS-induced colonic precancerous lesions by regulating inflammation as well as optimizing gut microbiota, thereby establishing reciprocally cooperative net benefits between probiotics/postbiotics and mice with colonic precancerous lesions. KEY POINTS: • Prophylactic administration of probiotic and postbiotic of B. lactis is capable of alleviating the AOM/DSS-induced body weight loss and colon shortening, as well as diminishing the development of colonic precancerous lesions, such as the formation of ACF and colonic polyps, in an AOM/DSS mouse model • Either probiotic or postbiotic of B. lactis has a positive role in mediating immune imbalance and colonic inflammation via suppression of inflammatory immune cells, pro-inflammatory cytokines, and the NF-κB signaling pathway • AOM/DSS-induced dysbiosis can be reversed with the probiotic and postbiotic of B. lactis supplementation.
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Affiliation(s)
- Yi-Lin Chan
- Department of Chemistry, Chinese Culture University, Taipei, Taiwan, ROC
| | - Jun-Cheng Liao
- Department of Microbiology, Soochow University, 70, Linhsi Road, Taipei, Taiwan, ROC
| | - Tsung-Lin Li
- Genomics Research Center, Academia Sinica, Taipei, Taiwan, ROC
| | - Chang-Jer Wu
- Department of Food Science and Center of Excellence for the Oceans, National Taiwan Ocean University, 2, Pei Ning Road, Keelung, Taiwan, ROC.
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.
| | - Yi-Han Chiu
- Department of Microbiology, Soochow University, 70, Linhsi Road, Taipei, Taiwan, ROC.
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Al Sulais E, AlAmeel T, Alenzi M, Shehab M, AlMutairdi A, Al-Bawardy B. Colorectal Neoplasia in Inflammatory Bowel Disease. Cancers (Basel) 2025; 17:665. [PMID: 40002259 PMCID: PMC11853504 DOI: 10.3390/cancers17040665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/10/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
Patients with inflammatory bowel disease (IBD), including ulcerative colitis and colonic Crohn's disease, are at an increased risk of developing colonic dysplasia and neoplasia. Multiple risk factors have been identified that increase the risk of colonic neoplasia in IBD, including but not limited to underlying disease extent, severity, duration, and concomitant primary sclerosing cholangitis. The overall risk of colonic neoplasia in IBD is decreasing but surveillance is still warranted in patients with high-risk features. In this review, we will discuss the epidemiology, pathogenesis, risk factors, approach to surveillance, and management of colonic neoplasia in IBD.
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Affiliation(s)
- Eman Al Sulais
- Department of Medicine, King Fahad Specialist Hospital, Dammam 32253, Saudi Arabia; (E.A.S.)
| | - Turki AlAmeel
- Department of Medicine, King Fahad Specialist Hospital, Dammam 32253, Saudi Arabia; (E.A.S.)
| | - Maram Alenzi
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Mohammad Shehab
- Division of Gastroenterology, Department of Internal Medicine, Mubarak Alkabeer University Hospital, Kuwait University, Aljabreyah 47060, Kuwait
| | - Abdulelah AlMutairdi
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, King Faisal Specialist Hospital and Research Center, Riyadh 11121, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Badr Al-Bawardy
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, King Faisal Specialist Hospital and Research Center, Riyadh 11121, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT 06510, USA
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Jumaniyazova E, Lokhonina A, Dzhalilova D, Miroshnichenko E, Kosyreva A, Fatkhudinov T. The Role of Macrophages in Various Types of Tumors and the Possibility of Their Use as Targets for Antitumor Therapy. Cancers (Basel) 2025; 17:342. [PMID: 39941714 PMCID: PMC11815841 DOI: 10.3390/cancers17030342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/07/2025] [Accepted: 01/16/2025] [Indexed: 02/16/2025] Open
Abstract
In solid tumors, tumor-associated macrophages (TAMs) are one of the most numerous populations and play an important role in the processes of tumor cell invasion, metastasis, and angiogenesis. Therefore, TAMs are considered promising diagnostic and prognostic biomarkers of tumors, and many attempts have been made to influence these cells as part of antitumor therapy. There are several key principles of action on ТАМs: the inhibition of monocyte/macrophage transition; the destruction of macrophages; the reprogramming of macrophage phenotypes (polarization of M2 macrophages to M1); the stimulation of phagocytic activity of macrophages and CAR-M therapy. Despite the large number of studies in this area, to date, there are no adequate approaches using antitumor therapy based on alterations in TAM functioning that would show high efficacy when administered in a mono-regimen for the treatment of malignant neoplasms. Studies devoted to the evaluation of the efficacy of drugs acting on TAMs are characterized by a small sample and the large heterogeneity of patient groups; in addition, in such studies, chemotherapy or immunotherapy is used, which significantly complicates the evaluation of the effectiveness of the agent acting on TAMs. In this review, we attempted to systematize the evidence on attempts to influence TAMs in malignancies such as lung cancer, breast cancer, colorectal cancer, cervical cancer, prostate cancer, gastric cancer, head and neck squamous cell cancer, and soft tissue sarcomas.
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Affiliation(s)
- Enar Jumaniyazova
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
| | - Anastasiya Lokhonina
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
- Avtsyn Research Institute of Human Morphology, FSBSI Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov, Ministry of Healthcare of Russian Federation, 4 Oparina Street, 117997 Moscow, Russia
| | - Dzhuliia Dzhalilova
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
- Avtsyn Research Institute of Human Morphology, FSBSI Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
| | - Ekaterina Miroshnichenko
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
- Avtsyn Research Institute of Human Morphology, FSBSI Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
| | - Anna Kosyreva
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
- Avtsyn Research Institute of Human Morphology, FSBSI Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
| | - Timur Fatkhudinov
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
- Avtsyn Research Institute of Human Morphology, FSBSI Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov, Ministry of Healthcare of Russian Federation, 4 Oparina Street, 117997 Moscow, Russia
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Vermani L, Winnberg JS, Liu W, Soller V, Sjödin T, Lindblad M, Lindblom A. A Haplotype GWAS in Syndromic Familial Colorectal Cancer. Int J Mol Sci 2025; 26:817. [PMID: 39859530 PMCID: PMC11765965 DOI: 10.3390/ijms26020817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/14/2025] [Accepted: 01/16/2025] [Indexed: 01/27/2025] Open
Abstract
A previous genome-wide association study (GWAS) in colorectal cancer (CRC) patients with gastric and/or prostate cancer in their families suggested genetic loci with a shared risk for these three cancers. A second haplotype GWAS was undertaken in the same colorectal cancer patients and different controls with the aim of confirming the result and finding novel loci. The haplotype GWAS analysis involved 685 patients with colorectal cancer cases and 1642 healthy controls from Sweden. A logistic regression model was used with a sliding window haplotype approach. Whole-genome and exome sequencing datawere used to find candidate SNPs to be tested in a nested case-control study. In the analysis of 685 colorectal cancer cases and 1642 controls, all ten candidate loci from the previous study were confirmed. Fifty candidate loci were suggested with a p-value < 5 × 10-6 and odds ratios between 1.35-6.52. Two of the 50 loci, on 13q33.3 and 16q23.3, were the same as in the previous study. Whole-genome or exome data from 122 colorectal cancer patients was used to search for candidate variants in these 50 loci. A nested case-control study was performed to test genetic variants at 11 loci in a cohort of 827 familial colorectal cancer and a sub-cohort of 293 familial CRC cases with colorectal, gastric, and/or prostate cancer within their families and 1530 healthy controls. One SNP, rs115943733 on 10q11.21, reached statistical significance (OR = 3.26, p = 0.009). Seven SNPs in 4 loci had a higher OR in the smaller cohort compared to the larger study CRC cases. The results in this GWAS gave support for suggested loci with an increased shared risk of CRC, gastric, and/or prostate cancer. Further studies are needed to confirm the shared risk to be able to use this information in cancer prevention.
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Affiliation(s)
- Litika Vermani
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden; (W.L.); (V.S.); (T.S.)
| | - Johanna Samola Winnberg
- Division of Surgery, Department of Clinical Science Intervention and Technology (CLINTEC), Karolinska Institutet, 17177 Stockholm, Sweden; (J.S.W.); (M.L.)
- Department of Upper Abdominal Diseases, Karolinska University Hospital, 17177 Stockholm, Sweden
| | - Wen Liu
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden; (W.L.); (V.S.); (T.S.)
- Department of Neuroscience, Uppsala University, 75237 Uppsala, Sweden
| | - Veronika Soller
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden; (W.L.); (V.S.); (T.S.)
| | - Tilde Sjödin
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden; (W.L.); (V.S.); (T.S.)
| | - Mats Lindblad
- Division of Surgery, Department of Clinical Science Intervention and Technology (CLINTEC), Karolinska Institutet, 17177 Stockholm, Sweden; (J.S.W.); (M.L.)
- Department of Upper Abdominal Diseases, Karolinska University Hospital, 17177 Stockholm, Sweden
| | - Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden; (W.L.); (V.S.); (T.S.)
- Department of Clinical Genetics and Genomics, Karolinska University Hospital, 17176 Stockholm, Sweden
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Liu Q, Li R, Zhu W, Zheng P. Case report: Microsatellite instability-high pancreas adenosquamous carcinoma with postoperative liver metastasis recurrence treated with multimodality therapy achieving complete pathological response. Front Immunol 2024; 15:1456343. [PMID: 39726603 PMCID: PMC11669589 DOI: 10.3389/fimmu.2024.1456343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 11/26/2024] [Indexed: 12/28/2024] Open
Abstract
Pancreatic adenosquamous carcinoma (PASC) is a rare subtype of pancreatic cancer (PC), with no established consensus on the optimal treatment for postoperative liver metastasis recurrence. We report a case of a 48-year-old male patient who underwent radical surgery and was pathologically diagnosed with microsatellite instability-high (MSI-H) PASC. The patient experienced liver metastasis recurrence following single-agent gemcitabine adjuvant chemotherapy. After one session of transarterial chemoembolization (TACE) with oxaliplatin, fluorouracil, and epirubicin, followed by six cycles of adjuvant chemotherapy with gemcitabine and nab-paclitaxel combined with sintilimab immunotherapy and bevacizumab targeted therapy, complete pathological regression of the liver metastasis was achieved. The patient has now reached a 24-month survival period and continues to be monitored at our center. This case illustrates the promise of the proposed treatment regimen, highlighting the significant potential of multimodality strategies in managing metastatic recurrence of MSI-H PASC.
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Affiliation(s)
- Qinghua Liu
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Ruoyun Li
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Wei Zhu
- Department of Pathology, Lanzhou University Second Hospital, Lanzhou, China
| | - Pengfei Zheng
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, China
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Kanth P, Hazel MW, Schell JC, Rutter J, Yao R, Mills AP, Delker DA. Evaluation of EGFR and COX pathway inhibition in human colon organoids of serrated polyposis and other hereditary cancer syndromes. Fam Cancer 2024; 23:479-489. [PMID: 38609520 PMCID: PMC11512843 DOI: 10.1007/s10689-024-00370-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 03/05/2024] [Indexed: 04/14/2024]
Abstract
Serrated polyposis syndrome (SPS) presents with multiple sessile serrated lesions (SSL) in the large intestine and confers increased colorectal cancer (CRC) risk. However, the etiology of SPS is not known. SSL-derived organoids have not been previously studied but may help provide insights into SPS pathogenesis and identify novel biomarkers and chemopreventive strategies. This study examined effects of EGFR and COX pathway inhibition in organoid cultures derived from uninvolved colon and polyps of SPS patients. We also compared with organoids representing the hereditary gastrointestinal syndromes, Familial Adenomatous Polyposis (FAP) and Lynch syndrome (LS). Eighteen total organoid colon cultures were generated from uninvolved colon and polyps in SPS, FAP, LS, and non-syndromic screening colonoscopy patients. BRAF and KRAS mutation status was determined for each culture. Erlotinib (EGFR inhibitor) and sulindac (COX inhibitor) were applied individually and in combination. A 44-target gene custom mRNA panel (including WNT and COX pathway genes) and a 798-gene microRNA gene panel were used to quantitate organoid RNA expression by NanoString analysis. Erlotinib treatment significantly decreased levels of mRNAs associated with WNT and MAPK kinase signaling in organoids from uninvolved colon from all four patient categories and from all SSL and adenomatous polyps. Sulindac did not change the mRNA profile in any culture. Our findings suggest that EGFR inhibitors may contribute to the chemopreventive treatment of SSLs. These findings may also facilitate clinical trial design using these agents in SPS patients. Differentially expressed genes identified in our study (MYC, FOSL1, EGR1, IL33, LGR5 and FOXQ1) may be used to identify other new molecular targets for chemoprevention of SSLs.
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Affiliation(s)
- Priyanka Kanth
- MedStar Georgetown University Hospital, Washington, DC, 20007, USA
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, 84132, USA
| | - Mark W Hazel
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, 84132, USA
| | - John C Schell
- Department of Biochemistry, University of Utah, Salt Lake City, UT, 84132, USA
| | - Jared Rutter
- Department of Biochemistry, University of Utah, Salt Lake City, UT, 84132, USA
| | - Ruoxin Yao
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, 84132, USA
| | - Alyssa P Mills
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, 84132, USA
| | - Don A Delker
- Integrative Bioinformatics, National Institutes of Environmental Health Sciences, 111 TW Alexander Drive, Research Triangle Park, NC, 27709, USA.
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Ždralević M, Radović A, Raonić J, Popovic N, Klisic A, Vučković L. Advances in microRNAs as Emerging Biomarkers for Colorectal Cancer Early Detection and Diagnosis. Int J Mol Sci 2024; 25:11060. [PMID: 39456841 PMCID: PMC11507567 DOI: 10.3390/ijms252011060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 09/21/2024] [Accepted: 09/27/2024] [Indexed: 10/26/2024] Open
Abstract
Colorectal cancer (CRC) remains the second most common cause of cancer-related mortality worldwide, necessitating advancements in early detection and innovative treatment strategies. MicroRNAs (miRNAs), small non-coding RNAs involved in gene regulation, have emerged as crucial players in the pathogenesis of CRC. This review synthesizes the latest findings on miRNA deregulated in precancerous lesions and in CRC. By examining the deregulation patterns of miRNAs across different stages of CRC development, this review highlights their potential as diagnostic tools. We specifically analyse the roles and diagnostic relevance of four miRNAs-miR-15b, miR-21, miR-31, and miR-146a-that consistently exhibit altered expression in CRC. The current knowledge of their role in key oncogenic pathways, drug resistance, and clinical relevance is discussed. Despite challenges posed by the heterogeneity of the research findings on miRNA deregulation and their role in CRC, integrating miRNA diagnostics into current screening methods holds promise for enhancing personalized medicine approaches. This review emphasizes the transformative potential of miRNAs in CRC diagnosis, paving the way for improved patient outcomes and novel therapeutic paradigms.
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Affiliation(s)
- Maša Ždralević
- Institute for Advanced Studies, University of Montenegro, Cetinjska 2, 81000 Podgorica, Montenegro
| | - Andrijana Radović
- Faculty of Medicine, University of Montenegro, Kruševac bb, 81000 Podgorica, Montenegro (N.P.); (A.K.); (L.V.)
| | - Janja Raonić
- Center for Pathology, Clinical Center of Montenegro, Ljubljanska bb, 81000 Podgorica, Montenegro;
| | - Natasa Popovic
- Faculty of Medicine, University of Montenegro, Kruševac bb, 81000 Podgorica, Montenegro (N.P.); (A.K.); (L.V.)
| | - Aleksandra Klisic
- Faculty of Medicine, University of Montenegro, Kruševac bb, 81000 Podgorica, Montenegro (N.P.); (A.K.); (L.V.)
- Center for Laboratory Diagnostics, Primary Health Care Center, 81000 Podgorica, Montenegro
| | - Ljiljana Vučković
- Faculty of Medicine, University of Montenegro, Kruševac bb, 81000 Podgorica, Montenegro (N.P.); (A.K.); (L.V.)
- Center for Pathology, Clinical Center of Montenegro, Ljubljanska bb, 81000 Podgorica, Montenegro;
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Fan WX, Su F, Zhang Y, Zhang XL, Du YY, Gao YJ, Li WL, Hu WQ, Zhao J. Oncological characteristics, treatments and prognostic outcomes in MMR-deficient colorectal cancer. Biomark Res 2024; 12:89. [PMID: 39183366 PMCID: PMC11346251 DOI: 10.1186/s40364-024-00640-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 08/14/2024] [Indexed: 08/27/2024] Open
Abstract
Colorectal cancer (CRC) ranks as the third most prevalent cancer globally. It's recognized that the molecular subtype of CRC, characterized by mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H), plays a critical role in determining appropriate treatment strategies. This review examines the current molecular classifications, focusing on dMMR/MSI-H CRC and its subtypes: Lynch syndrome (LS), Lynch-like syndrome (LLS), and sporadic cases. Despite advances in understanding of these genetic backgrounds, clinical trials have not conclusively differentiated the efficacy of immune checkpoint inhibitors among these subgroups. Therefore, while this review details the molecular characteristics and their general implications for treatment and prognosis, it also highlights the limitations and the need for more refined clinical studies to ascertain tailored therapeutic strategies for each subtype. Furthermore, this review summarizes completed and ongoing clinical studies, emphasizing the importance of developing treatments aligned more closely with molecular profiles. By discussing these aspects, the review seeks to provide a comprehensive analysis of oncological characteristics, presenting a detailed understanding of their implications for treatment and prognosis in dMMR/MSI-H CRC.
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Affiliation(s)
- Wen-Xuan Fan
- Graduate School of Shanxi Medical University, Taiyuan, Shanxi, 030607, China
- Department of Oncology, Changzhi People's Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Fei Su
- Graduate School of Shanxi Medical University, Taiyuan, Shanxi, 030607, China
- Department of Oncology, Changzhi People's Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Yan Zhang
- Department of Oncology, Changzhi People's Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, 046000, China
- Graduate School of Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Xiao-Ling Zhang
- Department of Oncology, Changzhi People's Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Yun-Yi Du
- Department of Oncology, Changzhi People's Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Yang-Jun Gao
- Department of Oncology, Changzhi People's Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Wei-Ling Li
- Department of Oncology, Changzhi People's Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, 046000, China
- Graduate School of Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Wen-Qing Hu
- Department of Gastrointestinal Surgery, Changzhi People's Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Jun Zhao
- Department of Oncology, Changzhi People's Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, 046000, China.
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Brandaleone L, Dal Buono A, Gabbiadini R, Marcozzi G, Polverini D, Carvello M, Spinelli A, Hassan C, Repici A, Bezzio C, Armuzzi A. Hereditary Colorectal Cancer Syndromes and Inflammatory Bowel Diseases: Risk Management and Surveillance Strategies. Cancers (Basel) 2024; 16:2967. [PMID: 39272825 PMCID: PMC11394661 DOI: 10.3390/cancers16172967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 08/15/2024] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
Background and aims: Hereditary colorectal cancer syndromes (HCCS), including familial adenomatous polyposis (FAP) and Lynch syndrome (LS), are the two most important high-risk conditions for colorectal cancer (CRC). Inflammatory bowel disease (IBD) increases the risk by two to six times compared with that in the general population. The intersection of these two conditions has rarely been documented in literature. We aimed to summarize the prevalence, pathogenesis, and current evidence-based management of IBD and HCCS and the underlying molecular mechanisms of accelerated carcinogenesis due to combined inflammation and genetic predisposition. Methods: PubMed and Scopus were searched until June 2024 to identify relevant studies investigating the epidemiology, pathogenesis, and management of IBD and coexisting hereditary CRC syndromes. Results: Co-occurrence of IBD and hereditary CRC syndromes is exceptionally uncommon. Individuals with LS and IBD tend to develop CRC at a younger age than those without IBD, with patients with ulcerative colitis facing particularly elevated risks. The interaction between mismatch deficiency and chronic inflammation requires further investigation.
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Affiliation(s)
- Luca Brandaleone
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy
| | - Arianna Dal Buono
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Roberto Gabbiadini
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Giacomo Marcozzi
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy
| | - Davide Polverini
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy
| | - Michele Carvello
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy
- Colon and Rectal Surgery Division, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Antonino Spinelli
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy
- Colon and Rectal Surgery Division, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Cesare Hassan
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy
- Endoscopy Unit, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Alessandro Repici
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy
- Endoscopy Unit, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Cristina Bezzio
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy
| | - Alessandro Armuzzi
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy
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10
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Wang Z, Shi J, Tao D, Xie S, Yang Y, Liu Y. Nonsense suppression induces read-through of a novel BMPR1A variant in a Chinese family with hereditary colorectal cancer. Ann Hum Genet 2024; 88:300-306. [PMID: 38192234 DOI: 10.1111/ahg.12549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 12/17/2023] [Accepted: 12/20/2023] [Indexed: 01/10/2024]
Abstract
BACKGROUND BMPR1A-mediated signaling transduction plays an essential role in intestinal growth. Variations of BMPR1A lead to a rare autosomal dominant inherited juvenile polyposis syndrome (JPS) with high probability of developing into colorectal cancer (CRC). Nonsense and frameshift variations, generating premature termination codons (PTCs), are the most pathogenic variants in the BMPR1A gene. OBJECTIVE This study aimed to investigate the molecular genetic etiology in a Chinese family with three generations of CRC. METHODS Pathogenic variants of 18 known CRC susceptibility genes were examined in a Chinese CRC family through multigene panel testing using the next-generation sequencing platform. The candidate gene variant was validated in the family members by Sanger sequencing. Potential biological functions of the gene variant were further investigated in the RKO colon cancer cell line. RESULTS A novel nonsense variant (c.1114A > T, p.Lys372*) of BMPR1A was identified in the CRC family. This variant generated a PTC at the kinase domain and caused nonsense-mediated mRNA decay. Read-through inducing reagents G418 and PTC124 partially restored BMPR1A expression and its following signaling pathway. CONCLUSION The identification of the novel BMPR1A variant enriched the genotype-phenotype spectrum of BMPR1A. Meanwhile, our finding also provided support for future PTC-targeting therapy for BMPR1A-mediated JPS and CRC.
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Affiliation(s)
- Zhaokun Wang
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Jiaying Shi
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Dachang Tao
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Shengyu Xie
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Yuan Yang
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Yunqiang Liu
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
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11
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Putro E, Carnevale A, Marangio C, Fulci V, Paolini R, Molfetta R. New Insight into Intestinal Mast Cells Revealed by Single-Cell RNA Sequencing. Int J Mol Sci 2024; 25:5594. [PMID: 38891782 PMCID: PMC11171657 DOI: 10.3390/ijms25115594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 05/14/2024] [Accepted: 05/18/2024] [Indexed: 06/21/2024] Open
Abstract
Mast cells (MCs) are tissue-resident immune cells distributed in all tissues and strategically located close to blood and lymphatic vessels and nerves. Thanks to the expression of a wide array of receptors, MCs act as tissue sentinels, able to detect the presence of bacteria and parasites and to respond to different environmental stimuli. MCs originate from bone marrow (BM) progenitors that enter the circulation and mature in peripheral organs under the influence of microenvironment factors, thus differentiating into heterogeneous tissue-specific subsets. Even though MC activation has been traditionally linked to IgE-mediated allergic reactions, a role for these cells in other pathological conditions including tumor progression has recently emerged. However, several aspects of MC biology remain to be clarified. The advent of single-cell RNA sequencing platforms has provided the opportunity to understand MCs' origin and differentiation as well as their phenotype and functions within different tissues, including the gut. This review recapitulates how single-cell transcriptomic studies provided insight into MC development as well as into the functional role of intestinal MC subsets in health and disease.
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Affiliation(s)
| | | | | | | | - Rossella Paolini
- Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy; (E.P.); (A.C.); (C.M.); (V.F.); (R.M.)
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12
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Hibler EA, Szymaniak B, Abbass MA. Colorectal Cancer Risk between Mendelian and Non-Mendelian Inheritance. Clin Colon Rectal Surg 2024; 37:140-145. [PMID: 38606051 PMCID: PMC11006447 DOI: 10.1055/s-0043-1770382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/13/2024]
Abstract
Hereditary colorectal cancer has been an area of focus for research and public health practitioners due to our ability to quantify risk and then act based on such results by enrolling patients in surveillance programs. The wide access to genetic testing and whole-genome sequencing has resulted in identifying many low/moderate penetrance genes. Above all, our understanding of the family component of colorectal cancer has been improving. Polygenic scores are becoming part of the risk assessment for many cancers, and the data about polygenic risk scores for colorectal cancer is promising. The challenge is determining how we incorporate this data in clinical care.
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Affiliation(s)
- Elizabeth A. Hibler
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Brittany Szymaniak
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Mohammad Ali Abbass
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
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13
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Kim HM, Kim TI. Screening and surveillance for hereditary colorectal cancer. Intest Res 2024; 22:119-130. [PMID: 38311713 PMCID: PMC11079514 DOI: 10.5217/ir.2023.00112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/08/2023] [Accepted: 11/27/2023] [Indexed: 02/06/2024] Open
Abstract
Hereditary colorectal cancer is a type of cancer that is caused by a genetic mutation. Individuals with a family history of colorectal cancer, or who have a known hereditary syndrome, are at an increased risk of developing the disease. Screening and surveillance are important tools for managing the risk of hereditary colorectal cancer. Screening involves a combination of tests that can detect precancerous or cancerous changes in the colon and rectum. Surveillance involves regular follow-up examinations to monitor disease progression and to identify new developments. The frequency and type of screening and surveillance tests may vary depending on an individual's risk factors, genetic profile, and medical history. However, early detection and treatment of hereditary colorectal cancer can significantly improve patient outcomes and reduce mortality rates. By implementing comprehensive screening and surveillance strategies, healthcare providers can help individuals at risk of hereditary colorectal cancer to receive timely interventions and make informed decisions about their health. Specific examples of screening and surveillance tests for hereditary colorectal cancer include colonoscopy, genetic testing, and imaging tests. In this review article, we will discuss detailed screening and surveillance of hereditary colorectal cancer.
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Affiliation(s)
- Hee Man Kim
- Cancer Prevention Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
- Division of Gastroenterology, Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Tae Il Kim
- Cancer Prevention Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
- Division of Gastroenterology, Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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14
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Kanakaratne S, Hong J, Solomon MJ, Young CJ. Ileal pouch-anal anastomosis provides good functional and quality of life outcomes following proctocolectomy: A 33-year single centre experience. ANZ J Surg 2024; 94:404-411. [PMID: 38105626 DOI: 10.1111/ans.18827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 12/01/2023] [Accepted: 12/04/2023] [Indexed: 12/19/2023]
Abstract
BACKGROUND Restorative proctocolectomy (RP) with ileal pouch-anal anastomosis (IPAA) remains the gold standard for the surgical management of patients with medically refractive mucosal ulcerative colitis. We aimed to identify functional and quality of life (QOL) outcomes in RP and IPAA surgery patients at our institution. METHODS A retrospective observational study was performed including all patients who had undergone RP and IPAA between August 1984 and November 2017 at Royal Prince Alfred Hospital (RPAH). RESULTS 316 consecutive patients were identified, median age 39 (range 5 to 81) years. The median duration of disease was 60 (range 1 to 528) months. Ulcerative colitis was the main preoperative diagnosis with the main RP indication being failure of medical treatment. The median postoperative stay post-IPAA was 11 (range of 5 to 67) days. Pouchitis was the most common late complication (22.1%), bleeding pouch (3.5%) the earliest, with a 6.8% rate of symptomatic anastomotic leak. Visual analogue scale QOL measure (P-value <0.001), St Marks incontinence score (P-value = 0.001) and Cleveland clinic score (P-value = 0.002) all revealed significant improvement in functional outcomes and QOL. CONCLUSION QOL and functional outcomes following RP with IPAA in patients at our institution are excellent and comparable to institutions with larger patient numbers.
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Affiliation(s)
- Shaveen Kanakaratne
- Department of Colorectal Surgery, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- The University of Sydney, Faculty of Medicine and Health, Sydney Medical School, Sydney, New South Wales, Australia
| | - Jonathan Hong
- Department of Colorectal Surgery, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- The University of Sydney, Faculty of Medicine and Health, Sydney Medical School, Sydney, New South Wales, Australia
| | - Michael J Solomon
- Department of Colorectal Surgery, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- The University of Sydney, Faculty of Medicine and Health, Sydney Medical School, Sydney, New South Wales, Australia
| | - Christopher J Young
- The University of Sydney, Faculty of Medicine and Health, Sydney Medical School, Sydney, New South Wales, Australia
- Department of Surgery, University of Kansas School of Medicine, Abilene, Kansas, USA
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15
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Spier I, Yin X, Richardson M, Pineda M, Laner A, Ritter D, Boyle J, Mur P, Hansen TVO, Shi X, Mahmood K, Plazzer JP, Ognedal E, Nordling M, Farrington SM, Yamamoto G, Baert-Desurmont S, Martins A, Borras E, Tops C, Webb E, Beshay V, Genuardi M, Pesaran T, Capellá G, Tavtigian SV, Latchford A, Frayling IM, Plon SE, Greenblatt M, Macrae FA, Aretz S. Gene-specific ACMG/AMP classification criteria for germline APC variants: Recommendations from the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel. Genet Med 2024; 26:100992. [PMID: 37800450 PMCID: PMC10922469 DOI: 10.1016/j.gim.2023.100992] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 09/25/2023] [Accepted: 09/27/2023] [Indexed: 10/07/2023] Open
Abstract
PURPOSE The Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) was established by the International Society for Gastrointestinal Hereditary Tumours and the Clinical Genome Resource, who set out to develop recommendations for the interpretation of germline APC variants underlying Familial Adenomatous Polyposis, the most frequent hereditary polyposis syndrome. METHODS Through a rigorous process of database analysis, literature review, and expert elicitation, the APC VCEP derived gene-specific modifications to the ACMG/AMP (American College of Medical Genetics and Genomics and Association for Molecular Pathology) variant classification guidelines and validated such criteria through the pilot classification of 58 variants. RESULTS The APC-specific criteria represented gene- and disease-informed specifications, including a quantitative approach to allele frequency thresholds, a stepwise decision tool for truncating variants, and semiquantitative evaluations of experimental and clinical data. Using the APC-specific criteria, 47% (27/58) of pilot variants were reclassified including 14 previous variants of uncertain significance (VUS). CONCLUSION The APC-specific ACMG/AMP criteria preserved the classification of well-characterized variants on ClinVar while substantially reducing the number of VUS by 56% (14/25). Moving forward, the APC VCEP will continue to interpret prioritized lists of VUS, the results of which will represent the most authoritative variant classification for widespread clinical use.
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Affiliation(s)
- Isabel Spier
- Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany; National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany; European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) - Project ID No 739547
| | - Xiaoyu Yin
- Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany; Department of Colorectal Medicine and Genetics, Royal Melbourne Hospital, Parkville, Australia; Department of Medicine, University of Melbourne, Parkville, Australia.
| | | | - Marta Pineda
- European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) - Project ID No 739547; Hereditary Cancer Program, Catalan Institute of Oncology - ONCOBELL, IDIBELL, Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Salud Carlos III, Madrid, Spain
| | | | - Deborah Ritter
- Baylor College of Medicine, Houston, TX; Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX
| | - Julie Boyle
- Department of Oncological Sciences, School of Medicine, University of Utah, Salt Lake City, UT
| | - Pilar Mur
- Hereditary Cancer Program, Catalan Institute of Oncology - ONCOBELL, IDIBELL, Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Salud Carlos III, Madrid, Spain
| | - Thomas V O Hansen
- Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Khalid Mahmood
- Colorectal Oncogenomics Group, Department of Clinical Pathology, University of Melbourne, Parkville, Australia; Melbourne Bioinformatics, University of Melbourne, Parkville, Australia
| | - John-Paul Plazzer
- Department of Colorectal Medicine and Genetics, Royal Melbourne Hospital, Parkville, Australia
| | | | - Margareta Nordling
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Department of Clinical Genetics, Linköping University Hospital, Linköping, Sweden
| | - Susan M Farrington
- Cancer Research UK Edinburgh Centre, the University of Edinburgh, Edinburgh, United Kingdom
| | - Gou Yamamoto
- Department of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan
| | | | | | | | - Carli Tops
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | | | | | - Maurizio Genuardi
- Fondazione Policlinico Universitario A. Gemelli IRCCS, and Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
| | | | - Gabriel Capellá
- European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) - Project ID No 739547; Hereditary Cancer Program, Catalan Institute of Oncology - ONCOBELL, IDIBELL, Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Salud Carlos III, Madrid, Spain
| | - Sean V Tavtigian
- Department of Oncological Sciences, School of Medicine, University of Utah, Salt Lake City, UT; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
| | - Andrew Latchford
- Polyposis Registry, St. Mark's Hospital, London, United Kingdom; Department of Surgery and Cancer, Imperial College, London, United Kingdom
| | - Ian M Frayling
- Polyposis Registry, St. Mark's Hospital, London, United Kingdom; Inherited Tumour Syndromes Research Group, Institute of Cancer & Genetics, Cardiff University, United Kingdom
| | - Sharon E Plon
- Baylor College of Medicine, Houston, TX; Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX
| | - Marc Greenblatt
- Larner College of Medicine, University of Vermont, Burlington, VT
| | - Finlay A Macrae
- Department of Colorectal Medicine and Genetics, Royal Melbourne Hospital, Parkville, Australia; Department of Medicine, University of Melbourne, Parkville, Australia
| | - Stefan Aretz
- Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany; National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany; European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) - Project ID No 739547
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16
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Gallanis AF, Gamble LA, Samaranayake SG, Lopez R, Rhodes A, Rajasimhan S, Fasaye GA, Juma O, Connolly M, Joyce S, Berger A, Heller T, Blakely AM, Hernandez JM, Davis JL. Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy. J Clin Oncol 2024; 42:421-430. [PMID: 37903316 PMCID: PMC10824374 DOI: 10.1200/jco.23.01238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/01/2023] [Accepted: 09/13/2023] [Indexed: 11/01/2023] Open
Abstract
PURPOSE Risk-reducing surgery for cancer prevention in solid tumors is a pressing clinical topic because of the increasing availability of germline genetic testing. We examined the short- and long-term outcomes of risk-reducing total gastrectomy (RRTG) and its lesser-known impacts on health-related quality of life (QOL) in individuals with hereditary diffuse gastric cancer syndrome. METHODS Individuals who underwent RRTG as part of a single-institution natural history study of hereditary gastric cancers were examined. Clinicopathologic details, acute and chronic operative morbidity, and health-related QOL were assessed. Validated questionnaires were used to determine QOL scores and psycho-social-spiritual measures of healing. RESULTS One hundred twenty-six individuals underwent RRTG because of a pathogenic or likely pathogenic germline CDH1 variant between October 2017 and December 2021. Most patients (87.3%; 110/126) had pT1aN0 gastric carcinoma with signet ring cell features on final pathology. Acute (<30 days) postoperative major morbidity was low (5.6%; 7/126) and nearly all patients (98.4%) lost weight after total gastrectomy. At 2 years after gastrectomy, 94% (64/68) of patients exhibited at least one chronic complication (ie, bile reflux, dysphagia, and micronutrient deficiency). Occupation change (23.5%), divorce (3%), and alcohol dependence (1.5%) were life-altering consequences attributed to total gastrectomy by some patients. In patients with a median follow-up of 24 months, QOL scores decreased at 1 month after gastrectomy and returned to baseline by 6-12 months. CONCLUSION RRTG is associated with life-changing adverse events that should be discussed when counseling patients with CDH1 variants about gastric cancer prevention. The risks of cancer-prevention surgery should not only be judged in the context of likelihood of death due to disease if left untreated, but also based on the real consequences of organ removal.
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Affiliation(s)
- Amber F. Gallanis
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Lauren A. Gamble
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Sarah G. Samaranayake
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Rachael Lopez
- Clinical Center Nutrition Department, National Institutes of Health, Bethesda, MD
| | - Amanda Rhodes
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Suraj Rajasimhan
- Pharmacy Department, National Institutes of Health Clinical Center, Bethesda, MD
| | - Grace-Ann Fasaye
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | | | - Maureen Connolly
- Clincal Center Nursing Department, National Institutes of Health, Bethesda, MD
| | - Stacy Joyce
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Ann Berger
- Pain and Palliative Care Service, Clinical Center, National Institutes of Health, Bethesda, MD
| | - Theo Heller
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Andrew M. Blakely
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Jonathan M. Hernandez
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Jeremy L. Davis
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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17
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Hussan H, Patel A, Ma J, Hinton A, Clinton SK. Historical Obesity and Early-Onset Cancers: A Propensity-Weighted Analysis of the National Health and Nutrition Examination Survey. Dig Dis Sci 2024; 69:419-425. [PMID: 38030832 DOI: 10.1007/s10620-023-08194-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 11/09/2023] [Indexed: 12/01/2023]
Abstract
BACKGROUND The incidence of early-onset obesity-related cancers (diagnosed < 50 years) is increasing in the U.S. We examined the reported historical body mass index (BMI) of adults with early and later-onset cancers to explore relation to obesity. METHODS We queried the 1999-2018 NHANES database for adults diagnosed with obesity-related cancers (colorectal, non-colorectal gastrointestinal, uterine, breast). We classified early and late-onset cancer based on a diagnosis age of < 50 and ≥ 50 years, respectively. Propensity-weighted analysis was used to compare prior historical BMIs between the matched groups. RESULTS After weighing, we included 2,966,528 patients with obesity-related cancers, 846,211 (28%) of which were < 50 years. In the matched analysis, 69.1% of early-onset CRC cases were diagnosed as obese (BMI ≥ 30 kg/m2) before cancer diagnosis, compared to 47.2% of late-onset cases (p < 0.03). Similarly, a higher percentage of adults with other early-onset gastrointestinal cancers had prior obesity as compared to the late-onset cohort (70.3% vs. 40.5%, p = 0.0002). BMI showed a trend toward higher values at ages 20-24 for early-onset CRC and 30-34 for other gastrointestinal cancers. In contrast, later-onset CRC and other gastrointestinal cancers exhibited higher BMI values at later ages (30-34 and 35-39, respectively). Early-onset uterine cancer was linked to a higher BMI compared to later-onset cancer (34.0 vs. 31.1 kg/m2, p < 0.0001), with a trend towards a higher BMI before 19 years old. CONCLUSIONS Our nationally representative data reveal that higher and earlier body fatness in adulthood associates with early-onset gastrointestinal and uterine cancers. These findings underscore the importance of intensifying efforts to combat early-life obesity.
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Affiliation(s)
- Hisham Hussan
- Division of Gastroenterology, Department of Internal Medicine, University of California, Davis, Sacramento, CA, USA.
- Comprehensive Cancer Center, University of California, Davis, Sacramento, CA, USA.
- Division of Gastroenterology, Department of Internal Medicine, UC Davis Medical Center, 4150 V Street, Suite 3500, Sacramento, CA, 95817, USA.
| | - Arsheya Patel
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
| | - Jianing Ma
- Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA
| | - Alice Hinton
- Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, OH, USA
| | - Steven K Clinton
- Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
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18
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Chew DCH, Yim CHH, Ali RA, El‐Omar EM. Epidemiology, Microbiome, and Risk Factors Involved in Carcinogenesis of Esophagus, Gastric, and Intestine. GASTROINTESTINAL ONCOLOGY ‐ A CRITICAL MULTIDISCIPLINARY TEAM APPROACH 2E 2024:2-22. [DOI: 10.1002/9781119756422.ch1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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19
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Shatynska T, Lembryk I, Tsytsiura O, Zhyliak O, Stefanyshyn A, Kostyrko N, Bodnarchuk Y. Diffuse familial adenomatous intestinal polyposis in childhood: current state of the problem and case report. WIADOMOSCI LEKARSKIE (WARSAW, POLAND : 1960) 2024; 77:338-344. [PMID: 38592998 DOI: 10.36740/wlek202402122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/11/2024]
Abstract
OBJECTIVE Aim: To explore the prevalence, clinical characteristics, and diagnostic aspects of diffuse familial adenomatous polyposis in childhood. This objective is accomplished through an extensive review of recent literature, and the presentation of case report from our clinical practice. PATIENTS AND METHODS Materials and Methods: We analyzed 75 scientific papers, the findings of which have been documented in the PubMed database. Our search criteria included keywords such as ≪diffuse familial adenomatous intestinal polyposis,≫ ≪children,≫ and ≪diagnosis.≫ Then we conducted a second-stage analysis that involved a detailed review of a practical case - the medical records of inpatient Kh.V. who had been diagnosed with familial adenomatous polyposis. CONCLUSION Conclusions: The analysis of the literature data is consistent with the findings from our clinical observations of familial adenomatous polyposis in a patient with complicated family anamnesis. It is worth noting that clinical features do not significantly differ across various types of polyposis. In cases of suspected familial adenomatous polyposis in adolescents, genetic testing is crucial.
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Affiliation(s)
- Tetiana Shatynska
- IVANO-FRANKIVSK NATIONAL MEDICAL UNIVERSITY, IVANO-FRANKIVSK, UKRAINE
| | - Iryna Lembryk
- IVANO-FRANKIVSK NATIONAL MEDICAL UNIVERSITY, IVANO-FRANKIVSK, UKRAINE
| | - Orysia Tsytsiura
- IVANO-FRANKIVSK NATIONAL MEDICAL UNIVERSITY, IVANO-FRANKIVSK, UKRAINE
| | | | | | - Nataliia Kostyrko
- IVANO-FRANKIVSK NATIONAL MEDICAL UNIVERSITY, IVANO-FRANKIVSK, UKRAINE
| | - Yuliia Bodnarchuk
- IVANO-FRANKIVSK NATIONAL MEDICAL UNIVERSITY, IVANO-FRANKIVSK, UKRAINE
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20
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Sado AI, Batool W, Ahmed A, Zafar S, Patel SK, Mohan A, Zia U, Aminpoor H, Kumar V, Tejwaney U. Role of microRNA in colorectal carcinoma (CRC): a narrative review. Ann Med Surg (Lond) 2024; 86:308-318. [PMID: 38222721 PMCID: PMC10783342 DOI: 10.1097/ms9.0000000000001494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 11/01/2023] [Indexed: 01/16/2024] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs that play a critical role in regulating gene expression by binding to target messenger RNAs (mRNAs). They were first discovered around 8 years after the identification of the first miRNA in 1993, and since then, there has been a significant increase in miRNA-related research and discoveries. MiRNAs have been implicated in various biological processes, including cancer, particularly in colorectal cancer (CRC). In CRC, miRNAs act as either oncogenes or tumor suppressors, influencing essential cellular functions such as cell proliferation, apoptosis, angiogenesis, and metastasis. The dysregulation of miRNAs in CRC can arise from different factors, leading to abnormal expression levels of their target mRNAs and subsequently affecting protein production. Consequently, miRNAs may directly target oncogenes or tumor suppressor genes, thereby contributing to cancer initiation and progression. Notably, tumors often exhibit reduced expression of mature miRNAs. In CRC research, miRNAs offer potential as diagnostic biomarkers and therapeutic targets. Specific miRNA profiles could serve as non-invasive tools for early CRC detection and risk assessment. Additionally, miRNA-based therapies present a promising approach for targeted cancer treatment by modulating miRNA expression. However, challenges related to delivery systems and long-term safety must be addressed to fully harness their therapeutic potential.
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Affiliation(s)
| | | | | | | | | | | | - Umar Zia
- Khyber Medical University, Peshawar, Pakistan
| | | | - Vikash Kumar
- The Brooklyn Hospital Center, Brooklyn, New York
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21
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Haas S, Strassburg CP, Nattermann J, Hueneburg R. [Results of Endoscopic Screening and Therapy of the Duodenum in MUTYH-associated Polyposis]. Zentralbl Chir 2023; 148:502-507. [PMID: 37995714 DOI: 10.1055/a-2194-0901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2023]
Abstract
MUTYH-associated polyposis (MAP) is a very rare autosomal recessive polyposis syndrome. It is caused by a homozygous or compound heterozygous germline mutation in the MUTYH gene. MAP is characterised by numerous colorectal adenomas; furthermore there is an increased risk for colorectal cancer (CRC). However, the phenotype can be highly variable; for example, affected individuals also have an increased risk of polyps of the upper gastrointestinal tract and development of duodenal carcinomas.This study included 15 patients with evidence of a pathogenic MUTYH variant, who were screened at the National Center for Hereditary Tumor Syndromes. Oesophagogastroduodenoscopy (EGD) results were prospectively recorded in a database from 2012 to 2023.At least one EGD (median 4, range 1-15) was performed in 15 patients, seven of whom carried a homozygous and 8 a compound heterozygous pathogenic MUTYH variant. The median surveillance period was 115 months (range, 3-215 months). The median age at baseline was 44 (range 17-65) years. A total of 72 EGDs were performed (median 4; range 1-15). Five patients had duodenal adenomas; histology showed tubular adenomas with low grade intraepithelial dysplasia (LGIEN) in all of these cases. The total number of duodenal adenomas detected was 48, and the median number was 3 (range, 1-37). Neither high grade intraepithelial neoplasia (HGIEN) nor duodenal cancer was detected during the surveillance period.Patients with MUTYH-associated polyposis should be managed in a multidisciplinary centre for hereditary tumour disease. Our cohort showed more patients with duodenal adenomas than in previously published data. However, no progression to HGIEN or duodenal carcinomas was observed as a result of the endoscopic therapy performed.
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Affiliation(s)
- Sonja Haas
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Bonn, Bonn, Deutschland
- Nationales Zentrum für erbliche Tumorerkrankungen, Universitätsklinikum Bonn, Bonn, Deutschland
| | - Christian P Strassburg
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Bonn, Bonn, Deutschland
- Nationales Zentrum für erbliche Tumorerkrankungen, Universitätsklinikum Bonn, Bonn, Deutschland
| | - Jacob Nattermann
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Bonn, Bonn, Deutschland
- Nationales Zentrum für erbliche Tumorerkrankungen, Universitätsklinikum Bonn, Bonn, Deutschland
| | - Robert Hueneburg
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Bonn, Bonn, Deutschland
- Nationales Zentrum für erbliche Tumorerkrankungen, Universitätsklinikum Bonn, Bonn, Deutschland
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22
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Sanchez-Mete L, Mosciatti L, Casadio M, Vittori L, Martayan A, Stigliano V. MUTYH-associated polyposis: Is it time to change upper gastrointestinal surveillance? A single-center case series and a literature overview. World J Gastrointest Oncol 2023; 15:1891-1899. [DOI: 10.4251/wjgo.v15.i11.1891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 05/28/2023] [Accepted: 06/13/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND The presence of Spigelman stage (SS) IV duodenal polyposis is considered the most significant risk factor for duodenal cancer in patients with MUTYH-associated polyposis (MAP). However, advanced SS disease is rarely reported in MAP patients, and no clear recommendations on small bowel (SB) surveillance have been proposed in this patient setting.
AIM To research more because that case reports of duodenal cancers in MAP suggest that they may develop in the absence of advanced benign SS disease and often involve the distal portion of the duodenum.
METHODS We describe a series of MAP patients followed up at the Regina Elena National Cancer Institute of Rome (Italy). A literature overview on previously reported SB cancers in MAP is also provided.
RESULTS We identified two (6%) SB adenocarcinomas with no previous history of duodenal polyposis. Our observations, supported by literature evidence, suggest that the formula for staging duodenal polyposis and predicting risk factors for distal duodenum and jejunal cancer may need to be adjusted to take this into account rather than focusing solely on the presence or absence of SS IV disease.
CONCLUSION Our study emphasizes the need for further studies to define appropriate upper gastrointestinal surveillance programs in MAP patients.
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Affiliation(s)
- Lupe Sanchez-Mete
- Gastroenterology and Digestive Endoscopy, Regina Elena National Cancer Institute, IRCCS, Rome 00144, Italy
| | - Lorenzo Mosciatti
- Gastroenterology and Digestive Endoscopy, Regina Elena National Cancer Institute, IRCCS, Rome 00144, Italy
| | - Marco Casadio
- Gastroenterology and Digestive Endoscopy, Regina Elena National Cancer Institute, IRCCS, Rome 00144, Italy
| | - Luigi Vittori
- Department of Radiological, Oncological and Pathological Sciences, Regina Elena National Cancer Institute, IRCCS, Rome 00144, Italy
| | - Aline Martayan
- Gastroenterology and Digestive Endoscopy, Regina Elena National Cancer Institute, IRCCS, Rome 00144, Italy
| | - Vittoria Stigliano
- Gastroenterology and Digestive Endoscopy, Regina Elena National Cancer Institute, IRCCS, Rome 00144, Italy
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23
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Yuan Z, Yang M, Yuan Y. The Progress of Colorectal Polyposis Syndrome in Chinese Population. Clin Colon Rectal Surg 2023; 36:391-399. [PMID: 37795462 PMCID: PMC10547542 DOI: 10.1055/s-0043-1767708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/06/2023]
Abstract
The pathogenesis, clinical phenotype, treatment strategy, and family management of hereditary tumor syndromes are different from those of sporadic tumors. Nearly a quarter of patients with colorectal cancer show significant familial aggregation and genetic predisposition, and 5 to 10% are associated with definite genetic factors. According to the clinical phenotype, it can be divided into nonpolyposis syndrome and polyposis syndrome. Among the polyposis syndrome patients with definite clinical symptoms, there are still some patients with unknown etiology (especially attenuated familial adenomatous polyposis), which is a difficult problem in clinical diagnosis and treatment. Therefore, for this rare disease, it is urgent to carry out multicenter studies, complete the gene variation spectrum, explore new pathogenic factors, and accumulate clinical experience. This article mainly introduces the research progress and related work of colorectal polyposis syndrome in China.
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Affiliation(s)
- Zhijun Yuan
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Mengyuan Yang
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Zhejiang Provincial Clinical Research Center for CANCER, Cancer Center of Zhejiang University, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Ying Yuan
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Zhejiang Provincial Clinical Research Center for CANCER, Cancer Center of Zhejiang University, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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24
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Ascrizzi S, Arillotta GM, Grillone K, Caridà G, Signorelli S, Ali A, Romeo C, Tassone P, Tagliaferri P. Lynch Syndrome Biopathology and Treatment: The Potential Role of microRNAs in Clinical Practice. Cancers (Basel) 2023; 15:3930. [PMID: 37568746 PMCID: PMC10417124 DOI: 10.3390/cancers15153930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/27/2023] [Accepted: 07/31/2023] [Indexed: 08/13/2023] Open
Abstract
Lynch syndrome (LS), also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is an autosomal dominant cancer syndrome which causes about 2-3% of cases of colorectal carcinoma. The development of LS is due to the genetic and epigenetic inactivation of genes involved in the DNA mismatch repair (MMR) system, causing an epiphenomenon known as microsatellite instability (MSI). Despite the fact that the genetics of the vast majority of MSI-positive (MSI+) cancers can be explained, the etiology of this specific subset is still poorly understood. As a possible new mechanism, it has been recently demonstrated that the overexpression of certain microRNAs (miRNAs, miRs), such as miR-155, miR-21, miR-137, can induce MSI or modulate the expression of the genes involved in LS pathogenesis. MiRNAs are small RNA molecules that regulate gene expression at the post-transcriptional level by playing a critical role in the modulation of key oncogenic pathways. Increasing evidence of the link between MSI and miRNAs in LS prompted a deeper investigation into the miRNome involved in these diseases. In this regard, in this study, we discuss the emerging role of miRNAs as crucial players in the onset and progression of LS as well as their potential use as disease biomarkers and therapeutic targets in the current view of precision medicine.
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Affiliation(s)
- Serena Ascrizzi
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (G.M.A.); (K.G.); (G.C.); (S.S.); (A.A.); (C.R.); (P.T.)
| | - Grazia Maria Arillotta
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (G.M.A.); (K.G.); (G.C.); (S.S.); (A.A.); (C.R.); (P.T.)
| | - Katia Grillone
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (G.M.A.); (K.G.); (G.C.); (S.S.); (A.A.); (C.R.); (P.T.)
| | - Giulio Caridà
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (G.M.A.); (K.G.); (G.C.); (S.S.); (A.A.); (C.R.); (P.T.)
| | - Stefania Signorelli
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (G.M.A.); (K.G.); (G.C.); (S.S.); (A.A.); (C.R.); (P.T.)
| | - Asad Ali
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (G.M.A.); (K.G.); (G.C.); (S.S.); (A.A.); (C.R.); (P.T.)
| | - Caterina Romeo
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (G.M.A.); (K.G.); (G.C.); (S.S.); (A.A.); (C.R.); (P.T.)
| | - Pierfrancesco Tassone
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (G.M.A.); (K.G.); (G.C.); (S.S.); (A.A.); (C.R.); (P.T.)
- Medical Oncology and Translational Medical Oncology Units, University Hospital Renato Dulbecco, 88100 Catanzaro, Italy
| | - Pierosandro Tagliaferri
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (G.M.A.); (K.G.); (G.C.); (S.S.); (A.A.); (C.R.); (P.T.)
- Medical Oncology and Translational Medical Oncology Units, University Hospital Renato Dulbecco, 88100 Catanzaro, Italy
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25
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Foote MB, Walch H, Kemel Y, Vakiani E, Johannet P, Sheehan M, Chatila W, Chung S, Nash GM, Maio A, Shia J, Mandelker D, Berger M, Schultz N, Diaz LA, Cercek A, Stadler ZK. The Impact of Germline Alterations in Appendiceal Adenocarcinoma. Clin Cancer Res 2023; 29:2631-2637. [PMID: 37289003 PMCID: PMC10642170 DOI: 10.1158/1078-0432.ccr-22-3956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 03/08/2023] [Accepted: 05/15/2023] [Indexed: 05/19/2023]
Abstract
PURPOSE More than 10% of assessed patients with appendiceal adenocarcinoma have a pathogenic (P) or likely pathogenic (LP) germline variant, including genes implicated in heritable gastrointestinal cancer syndromes, such as Lynch syndrome. We defined the clinical and molecular impact of heritable alterations in appendiceal adenocarcinoma to evaluate the need for dedicated appendiceal screening and prevention strategies in patients with LP/P germline variants. EXPERIMENTAL DESIGN We performed an integrated germline and somatic molecular analysis for patients with confirmed appendiceal adenocarcinoma. Patients underwent paired tumor-normal sequencing for up to 90 hereditary cancer risk genes and 505 genes for somatic mutation profiling. We defined the cooccurrence of LP/P germline variants and second-hit pathogenic somatic alterations. The associations between germline variants and patient clinicopathologic features were also evaluated. RESULTS Twenty-five of 237 patients (10.5%) carried pathogenic or likely pathogenic germline variants in cancer susceptibility genes. Clinicopathologic characteristics and appendiceal adenocarcinoma-specific survival were similar in patients with or without germline variants. Most (92%, N = 23/25) patients with germline variants demonstrated no second-hit somatic alterations, including loss of heterozygosity. Two patients with a germline APC I1307K low-penetrance founder variant exhibited secondary somatic pathogenic alterations in APC. However, only one patient tumor exhibited APC-mediated WNT signaling dysregulation: a plausible consequence of multiple somatic APC mutations with no germline variant contribution. Four patients had germline variants in PMS2 or MSH2 associated with Lynch syndrome, yet their cancers were microsatellite-stable. CONCLUSIONS Germline variants are likely incidental without a contributory driver role in appendiceal adenocarcinoma. Appendiceal adenocarcinoma screening in patients with germline variants is not clearly merited.
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Affiliation(s)
- Michael B. Foote
- Division of Solid Tumor Oncology; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Henry Walch
- Human Oncology and Pathogenesis Program; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Yelena Kemel
- Niehaus Center for Inherited Cancer Genomics; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Efsevia Vakiani
- Department of Pathology and Laboratory Medicine; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Paul Johannet
- Division of Solid Tumor Oncology; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Margaret Sheehan
- Niehaus Center for Inherited Cancer Genomics; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Walid Chatila
- Human Oncology and Pathogenesis Program; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Sebastian Chung
- Department of Surgery; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Garrett M. Nash
- Department of Surgery; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Anna Maio
- Niehaus Center for Inherited Cancer Genomics; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Jinru Shia
- Department of Pathology and Laboratory Medicine; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Diana Mandelker
- Department of Pathology and Laboratory Medicine; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Michael Berger
- Human Oncology and Pathogenesis Program; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
- Department of Pathology and Laboratory Medicine; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Nikolaus Schultz
- Human Oncology and Pathogenesis Program; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Luis A. Diaz
- Division of Solid Tumor Oncology; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Andrea Cercek
- Division of Solid Tumor Oncology; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Zsofia K. Stadler
- Division of Solid Tumor Oncology; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
- Niehaus Center for Inherited Cancer Genomics; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
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26
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Mirchev MB, Boeva I, Peshevska-Sekulovska M, Stoitsov V, Peruhova M. Synchronous manifestation of colorectal cancer and intraductal papillary mucinous neoplasms. World J Clin Cases 2023; 11:3408-3417. [PMID: 37383909 PMCID: PMC10294181 DOI: 10.12998/wjcc.v11.i15.3408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/26/2023] [Accepted: 04/17/2023] [Indexed: 05/25/2023] Open
Abstract
High rates of extrapancreatic malignancies, in particular colorectal cancer (CRC), have been detected in patients with intraductal papillary mucinous neoplasm (IPMN). So far, there is no distinct explanation in the literature for the development of secondary or synchronous malignancies in patients with IPMN. In the past few years, some data related to common genetic alterations in IPMN and other affiliated cancers have been published. This review elucidated the association between IPMN and CRC, shedding light on the most relevant genetic alterations that may explain the possible relationship between these entities. In keeping with our findings, we suggested that once the diagnosis of IPMN is made, special consideration of CRC should be undertaken. Presently, there are no specific guidelines regarding colorectal screening programs for patients with IPMN. We recommend that patients with IPMNs are at high-risk for CRC, and a more rigorous colorectal surveillance program should be implemented.
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Affiliation(s)
| | - Irina Boeva
- Department of Gastroenterology, Heart and Brain Hospital, Burgas 8000, Bulgaria
| | | | - Veselin Stoitsov
- Department of Gastroenterology, Heart and Brain Hospital, Burgas 8000, Bulgaria
| | - Milena Peruhova
- Department of Gastroenterology, Heart and Brain Hospital, Burgas 8000, Bulgaria
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27
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Matsumoto R, Mori S, Nepal P, Kita Y, Tanabe K, Hokonohara K, Satake S, Hamada Y, Wada M, Arigami T, Sasaki K, Kurahara H, Ohtsuka T. Mucosectomy of the anal canal via transanal minimally invasive surgery combined with transanal total mesorectal excision for familial adenomatous polyposis: A technical note. Colorectal Dis 2023. [PMID: 37183353 DOI: 10.1111/codi.16595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 04/11/2023] [Accepted: 04/12/2023] [Indexed: 05/16/2023]
Abstract
AIM Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the standard surgical treatment modality for familial adenomatous polyposis (FAP). It is challenging to perform proctectomy and preserve anal sphincter function. In this video, precise mucosectomy of the anal canal via transanal minimally invasive surgery (MAC-TAMIS) is reported. METHODS An asymptomatic 35-year-old man was found to have a positive faecal occult blood test in routine screening examination and was diagnosed with FAP on colonoscopic examination. The patient was scheduled for total proctocolectomy with IPAA using the TAMIS approach combined with transanal total mesorectal excision. MAC-TAMIS was performed to preserve the internal anal sphincter during laparoscopy. RESULTS The total duration of surgery was 543 min, blood loss was minimal, and the postoperative course was uneventful. The postoperative hospital stay was 12 days. The pathological findings demonstrated no evidence of malignancy. Gastrographic imaging from the ileostomy showed sufficient size of the J pouch and good tonus of the anus at 6 months after surgery. The Wexner scores at 1, 3 and 6 months after ileostomy closure were 5, 3 and 0, respectively. CONCLUSION The MAC-TAMIS technique is safe and feasible during total proctocolectomy with IPAA in patients with FAP. This technique allows us to precisely preserve the internal anal sphincter using a laparoscopic approach.
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Affiliation(s)
- Ryu Matsumoto
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan
| | - Shinichiro Mori
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan
| | - Pramod Nepal
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan
| | - Yoshiaki Kita
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan
| | - Kan Tanabe
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan
| | - Kentaro Hokonohara
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan
| | - Soichi Satake
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan
| | - Yuki Hamada
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan
| | - Masumi Wada
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan
| | - Takaaki Arigami
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan
| | - Ken Sasaki
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan
| | - Hiroshi Kurahara
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan
| | - Takao Ohtsuka
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan
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28
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Soons E, Siersema PD, van Lierop LMA, Bisseling TM, van Kouwen MCA, Nagtegaal ID, van der Post RS, Atsma F. Laboratory variation in the grading of dysplasia of duodenal adenomas in familial adenomatous polyposis patients. Fam Cancer 2023; 22:177-186. [PMID: 36401146 PMCID: PMC10020317 DOI: 10.1007/s10689-022-00320-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 11/06/2022] [Indexed: 11/20/2022]
Abstract
To prevent duodenal and ampullary cancer in familial adenomatous polyposis (FAP) patients, a diagnosis of high grade dysplasia (HGD) plays an important role in the clinical management. Previous research showed that FAP patients are both over- and undertreated after a misdiagnosis of HGD, indicating unwarranted variation. We aimed to investigate the laboratory variation in dysplasia grading of duodenal adenomas and explore possible explanations for this variation. We included data from all Dutch pathology laboratories between 1991 and 2020 by retrieving histology reports from upper endoscopy specimens of FAP patients from the Dutch nationwide pathology databank (PALGA). Laboratory variation was investigated by comparing standardized proportions of HGD. To describe the degree of variation between the laboratories a factor score was calculated. A funnel plot was used to identify outliers. A total of 3050 specimens from 25 laboratories were included in the final analyses. The mean observed HGD proportion was 9.4%. The top three HGD-diagnosing laboratories diagnosed HGD 3.9 times more often than the lowest three laboratories, even after correcting for case-mix. No outliers were identified. Moderate laboratory variation was found in HGD diagnoses of duodenal tissue of FAP patients after adjusting for case-mix. Despite the fact that no outliers were observed, there may well be room for quality improvement. Concentration of these patients in expertise centers may decrease variation. To further reduce unwarranted variation, we recommend (inter)national guidelines to become more uniform in their recommendations regarding duodenal tissue sampling and consequences of HGD diagnoses.
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Affiliation(s)
- E Soons
- Department of Gastroenterology and Hepatology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
| | - P D Siersema
- Department of Gastroenterology and Hepatology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - L M A van Lierop
- Department of Gastroenterology and Hepatology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - T M Bisseling
- Department of Gastroenterology and Hepatology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - M C A van Kouwen
- Department of Gastroenterology and Hepatology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - I D Nagtegaal
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - R S van der Post
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - F Atsma
- Department of IQ Healthcare, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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29
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Rashid G, Khan NA, Elsori D, Rehman A, Tanzeelah, Ahmad H, Maryam H, Rais A, Usmani MS, Babker AM, Kamal MA, Hafez W. Non-steroidal anti-inflammatory drugs and biomarkers: A new paradigm in colorectal cancer. Front Med (Lausanne) 2023; 10:1130710. [PMID: 36950511 PMCID: PMC10025514 DOI: 10.3389/fmed.2023.1130710] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 02/08/2023] [Indexed: 03/08/2023] Open
Abstract
Colorectal cancer is a sporadic, hereditary, or familial based disease in its origin, caused due to diverse set of mutations in large intestinal epithelial cells. Colorectal cancer (CRC) is a common and deadly disease that accounts for the 4th worldwide highly variable malignancy. For the early detection of CRC, the most common predictive biomarker found endogenously are KRAS and ctDNA/cfDNA along with SEPT9 methylated DNA. Early detection and screening for CRC are necessary and multiple methods can be employed to screen and perform early diagnosis of CRC. Colonoscopy, an invasive method is most prevalent for diagnosing CRC or confirming the positive result as compared to other screening methods whereas several non-invasive techniques such as molecular analysis of breath, urine, blood, and stool can also be performed for early detection. Interestingly, widely used medicines known as non-steroidal anti-inflammatory drugs (NSAIDs) to reduce pain and inflammation have reported chemopreventive impact on gastrointestinal malignancies, especially CRC in several epidemiological and preclinical types of research. NSAID acts by inhibiting two cyclooxygenase enzymes, thereby preventing the synthesis of prostaglandins (PGs) and causing NSAID-induced apoptosis and growth inhibition in CRC cells. This review paper majorly focuses on the diversity of natural and synthetic biomarkers and various techniques for the early detection of CRC. An approach toward current advancement in CRC detection techniques and the role of NSAIDs in CRC chemoprevention has been explored systematically. Several prominent governing mechanisms of the anti-cancer effects of NSAIDs and their synergistic effect with statins for an effective chemopreventive measure have also been discussed in this review paper.
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Affiliation(s)
- Gowhar Rashid
- Department of Amity Medical School, Amity University, Gurugram, India
| | - Nihad Ashraf Khan
- Department of Biosciences, Jamia Millia Islamia, Central University, New Delhi, India
| | - Deena Elsori
- Faculty of Resillience, Deans Office Rabdan Academy, Abu Dhabi, United Arab Emirates
| | - Andleeb Rehman
- Department of Biotechnology, Shri Mata Vaishno Devi University, Katra, India
| | - Tanzeelah
- Department of Biochemistry, University of Kashmir, Srinagar, India
| | - Haleema Ahmad
- Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, India
| | - Humaira Maryam
- Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, India
| | - Amaan Rais
- Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, India
| | - Mohd Salik Usmani
- The Department of Surgery, Faculty of Medicine, JNMCH, AMU, Uttar Pradesh, India
| | - Asaad Ma Babker
- Department of Medical Laboratory Sciences, Gulf Medical University, Ajman, United Arab Emirates
| | - Mohammad Azhar Kamal
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia
| | - Wael Hafez
- Department of Internal Medicine, NMC Royal Hospital, Abu Dhabi, United Arab Emirates
- The Medical Research Division, Department of Internal Medicine, The National Research Center, Ad Doqi, Egypt
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30
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Hassanin E, Spier I, Bobbili DR, Aldisi R, Klinkhammer H, David F, Dueñas N, Hüneburg R, Perne C, Brunet J, Capella G, Nöthen MM, Forstner AJ, Mayr A, Krawitz P, May P, Aretz S, Maj C. Clinically relevant combined effect of polygenic background, rare pathogenic germline variants, and family history on colorectal cancer incidence. BMC Med Genomics 2023; 16:42. [PMID: 36872334 PMCID: PMC9987090 DOI: 10.1186/s12920-023-01469-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 02/21/2023] [Indexed: 03/07/2023] Open
Abstract
BACKGROUND AND AIMS Summarised in polygenic risk scores (PRS), the effect of common, low penetrant genetic variants associated with colorectal cancer (CRC), can be used for risk stratification. METHODS To assess the combined impact of the PRS and other main factors on CRC risk, 163,516 individuals from the UK Biobank were stratified as follows: 1. carriers status for germline pathogenic variants (PV) in CRC susceptibility genes (APC, MLH1, MSH2, MSH6, PMS2), 2. low (< 20%), intermediate (20-80%), or high PRS (> 80%), and 3. family history (FH) of CRC. Multivariable logistic regression and Cox proportional hazards models were applied to compare odds ratios and to compute the lifetime incidence, respectively. RESULTS Depending on the PRS, the CRC lifetime incidence for non-carriers ranges between 6 and 22%, compared to 40% and 74% for carriers. A suspicious FH is associated with a further increase of the cumulative incidence reaching 26% for non-carriers and 98% for carriers. In non-carriers without FH, but high PRS, the CRC risk is doubled, whereas a low PRS even in the context of a FH results in a decreased risk. The full model including PRS, carrier status, and FH improved the area under the curve in risk prediction (0.704). CONCLUSION The findings demonstrate that CRC risks are strongly influenced by the PRS for both a sporadic and monogenic background. FH, PV, and common variants complementary contribute to CRC risk. The implementation of PRS in routine care will likely improve personalized risk stratification, which will in turn guide tailored preventive surveillance strategies in high, intermediate, and low risk groups.
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Affiliation(s)
- Emadeldin Hassanin
- Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Bonn, Germany.,Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-Sur-Alzette, Luxembourg
| | - Isabel Spier
- Institute of Human Genetics, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.,National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,European Reference Network on Genetic Tumour Rsik Syndromes (ERNGENTURIS) - Project ID No 739547, Nijmegen, The Netherlands
| | - Dheeraj R Bobbili
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-Sur-Alzette, Luxembourg
| | - Rana Aldisi
- Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Bonn, Germany
| | - Hannah Klinkhammer
- Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Bonn, Germany.,Medical Faculty, Institute for Medical Biometry, Informatics and Epidemiology, University Bonn, Bonn, Germany
| | - Friederike David
- Institute of Human Genetics, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Nuria Dueñas
- Hereditary Cancer Program, Catalan Institute of Oncology-IDIBELL, ONCOBELL, Hospitalet de Llobregat, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Salud Carlos III, Madrid, Spain
| | - Robert Hüneburg
- National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
| | - Claudia Perne
- Institute of Human Genetics, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.,National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Joan Brunet
- European Reference Network on Genetic Tumour Rsik Syndromes (ERNGENTURIS) - Project ID No 739547, Nijmegen, The Netherlands.,Hereditary Cancer Program, Catalan Institute of Oncology-IDIBELL, ONCOBELL, Hospitalet de Llobregat, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Salud Carlos III, Madrid, Spain.,Hereditary Cancer Program, Catalan Institute of Oncology-IDBIGI, 17007, Girona, Spain
| | - Gabriel Capella
- European Reference Network on Genetic Tumour Rsik Syndromes (ERNGENTURIS) - Project ID No 739547, Nijmegen, The Netherlands.,Hereditary Cancer Program, Catalan Institute of Oncology-IDIBELL, ONCOBELL, Hospitalet de Llobregat, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Salud Carlos III, Madrid, Spain
| | - Markus M Nöthen
- Institute of Human Genetics, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Andreas J Forstner
- Institute of Human Genetics, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.,Centre for Human Genetics, University of Marburg, Marburg, Germany.,Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany
| | - Andreas Mayr
- Medical Faculty, Institute for Medical Biometry, Informatics and Epidemiology, University Bonn, Bonn, Germany
| | - Peter Krawitz
- Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Bonn, Germany
| | - Patrick May
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-Sur-Alzette, Luxembourg
| | - Stefan Aretz
- Institute of Human Genetics, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany. .,National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany. .,European Reference Network on Genetic Tumour Rsik Syndromes (ERNGENTURIS) - Project ID No 739547, Nijmegen, The Netherlands.
| | - Carlo Maj
- Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Bonn, Germany
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D’Elia G, Caliendo G, Passariello L, Albanese L, Makker J, Molinari AM, Vietri MT. Hereditary Cancer Syndrome in a Family with Double Mutation in BRIP1 and MUTYH Genes. Genes (Basel) 2023; 14:428. [PMID: 36833355 PMCID: PMC9957058 DOI: 10.3390/genes14020428] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/31/2023] [Accepted: 02/06/2023] [Indexed: 02/10/2023] Open
Abstract
Hereditary cancer syndromes predispose to several types of cancer due to inherited pathogenic variants in susceptibility genes. We describe the case of a 57-year-old woman, diagnosed with breast cancer, and her family. The proband belongs to a family with a suspected tumor syndrome, due to other cancer cases in her family from the paternal and maternal sides. After oncogenetic counseling, she was subjected to mutational analysis with an NGS panel analyzing 27 genes. The genetic analysis showed two monoallelic mutations in low penetrance genes, c.1187G>A (p.G396D) in MUTYH and c.55dup (p.Tyr19Leufs*2) in BRIP1. One of the mutations was inherited from the maternal side and the other from the paternal side, suggesting two different cancer syndrome types in the family. MUTYH mutation was related to the onset of cancers on the paternal side, as confirmed by the occurrence of the same mutation in the proband's cousin. BRIP1 mutation was found in the proband's mother, indicating that it was related to the cancer cases observed on the maternal side, including breast cancer and sarcoma. Advances in NGS technologies have allowed the identification of mutations in families with hereditary cancers in genes other than those related to a specific suspected syndrome. A complete oncogenetic counseling, together with molecular tests that enable a simultaneous analysis of multiple genes, is essential for the identification of a correct tumor syndrome and for clinical decision-making in a patient and his/her family. The detection of mutations in multiple susceptibility genes allows the initiation of early risk-reducing measures for identified mutation carriers among family members and to include them in a proper surveillance program for specific syndromes. Moreover, it may enable an adapted treatment for the affected patient, permitting personalized therapeutic options.
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Affiliation(s)
- Giovanna D’Elia
- Unity of Clinical and Molecular Pathology, AOU University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
| | - Gemma Caliendo
- Unity of Clinical and Molecular Pathology, AOU University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
| | - Luana Passariello
- Unity of Clinical and Molecular Pathology, AOU University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
| | - Luisa Albanese
- Unity of Clinical and Molecular Pathology, AOU University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
| | - Jasmine Makker
- Department of GKT, School of Medical Education, King’s College London, London WC2R 2LS, UK
| | - Anna Maria Molinari
- Unity of Clinical and Molecular Pathology, AOU University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
| | - Maria Teresa Vietri
- Unity of Clinical and Molecular Pathology, AOU University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
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32
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De S, Paul S, Manna A, Majumder C, Pal K, Casarcia N, Mondal A, Banerjee S, Nelson VK, Ghosh S, Hazra J, Bhattacharjee A, Mandal SC, Pal M, Bishayee A. Phenolic Phytochemicals for Prevention and Treatment of Colorectal Cancer: A Critical Evaluation of In Vivo Studies. Cancers (Basel) 2023; 15:993. [PMID: 36765950 PMCID: PMC9913554 DOI: 10.3390/cancers15030993] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/30/2023] [Accepted: 01/30/2023] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) is the third most diagnosed and second leading cause of cancer-related death worldwide. Limitations with existing treatment regimens have demanded the search for better treatment options. Different phytochemicals with promising anti-CRC activities have been reported, with the molecular mechanism of actions still emerging. This review aims to summarize recent progress on the study of natural phenolic compounds in ameliorating CRC using in vivo models. This review followed the guidelines of the Preferred Reporting Items for Systematic Reporting and Meta-Analysis. Information on the relevant topic was gathered by searching the PubMed, Scopus, ScienceDirect, and Web of Science databases using keywords, such as "colorectal cancer" AND "phenolic compounds", "colorectal cancer" AND "polyphenol", "colorectal cancer" AND "phenolic acids", "colorectal cancer" AND "flavonoids", "colorectal cancer" AND "stilbene", and "colorectal cancer" AND "lignan" from the reputed peer-reviewed journals published over the last 20 years. Publications that incorporated in vivo experimental designs and produced statistically significant results were considered for this review. Many of these polyphenols demonstrate anti-CRC activities by inhibiting key cellular factors. This inhibition has been demonstrated by antiapoptotic effects, antiproliferative effects, or by upregulating factors responsible for cell cycle arrest or cell death in various in vivo CRC models. Numerous studies from independent laboratories have highlighted different plant phenolic compounds for their anti-CRC activities. While promising anti-CRC activity in many of these agents has created interest in this area, in-depth mechanistic and well-designed clinical studies are needed to support the therapeutic use of these compounds for the prevention and treatment of CRC.
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Affiliation(s)
- Samhita De
- Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India
| | - Sourav Paul
- Department of Biotechnology, National Institute of Technology, Durgapur 713 209, India
| | - Anirban Manna
- Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India
| | | | - Koustav Pal
- Jawaharlal Institute Post Graduate Medical Education and Research, Puducherry 605 006, India
| | - Nicolette Casarcia
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
| | - Arijit Mondal
- Department of Pharmaceutical Chemistry, M.R. College of Pharmaceutical Sciences and Research, Balisha 743 234, India
| | - Sabyasachi Banerjee
- Department of Pharmaceutical Chemistry, Gupta College of Technological Sciences, Asansol 713 301, India
| | - Vinod Kumar Nelson
- Department of Pharmacology, Raghavendra Institute of Pharmaceutical Education and Research, Anantapur 515 721, India
| | - Suvranil Ghosh
- Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India
| | - Joyita Hazra
- Department of Biotechnology, Indian Institute of Technology, Chennai 600 036, India
| | - Ashish Bhattacharjee
- Department of Biotechnology, National Institute of Technology, Durgapur 713 209, India
| | | | - Mahadeb Pal
- Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
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33
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Samadder NJ, Foster N, McMurray RP, Burke CA, Stoffel E, Kanth P, Das R, Cruz-Correa M, Vilar E, Mankaney G, Buttar N, Thirumurthi S, Turgeon DK, Sossenheimer M, Westover M, Richmond E, Umar A, Della'Zanna G, Rodriguez LM, Szabo E, Zahrieh D, Limburg PJ. Phase II trial of weekly erlotinib dosing to reduce duodenal polyp burden associated with familial adenomatous polyposis. Gut 2023; 72:256-263. [PMID: 35636921 PMCID: PMC9708943 DOI: 10.1136/gutjnl-2021-326532] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 05/14/2022] [Indexed: 01/27/2023]
Abstract
IMPORTANCE Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal adenomas and cancer. Combination sulindac and erlotinib was previously shown to reduce duodenal polyp burden but was associated with a relatively high adverse event (AE) rate. OBJECTIVE To evaluate if a once weekly dosing schedule for erlotinib intervention improves the AE profile, while still providing efficacy with respect to reduced polyp burden, in participants with FAP. DESIGN, SETTING AND PARTICIPANTS Single-arm trial, enrolling 46 participants with FAP, conducted from October 2017 to September 2019 in eight academic cancer centres. EXPOSURES Participants self-administered 350 mg of erlotinib by mouth, one time per week for 6 months. MAIN OUTCOMES AND MEASURES Duodenal polyp burden (sum of polyp diameters) was assessed in the proximal duodenum by esophagogastroduodenoscopy performed at baseline and 6 months, with mean per cent change defined as the primary efficacy outcome of interest. Rate of grade 2-3 AEs was evaluated as a co-primary outcome. Secondary outcomes included changes in total duodenal polyp count, along with changes in lower gastrointestinal (GI) polyp burden and count (for participants examined by optional lower endoscopy). RESULTS Forty-six participants (mean age, 44.1 years (range, 18-68); women, 22 (48%)) were enrolled; 42 participants completed 6 months of intervention and were included in the per-protocol analysis. Duodenal polyp burden was significantly reduced after 6 months of weekly erlotinib intervention, with a mean per cent change of -29.6% (95% CI, -39.6% to -19.7%; p<0.0001). Similar results were observed in subgroup analyses defined by participants with advanced duodenal polyposis (Spigelman 3) at baseline (mean, -27%; 95% CI, -38.7% to -15.2%; p<0.0001). Post-intervention Spigelman stage was downstaged in 12% of the participants. Lower GI polyp number was also decreased after 6 months of intervention (median, -30.8%; IQR, -47.4% to 0.0%; p=0.0256). Grade 2 or 3 AEs were reported in 71.7% of subjects, with only two experiencing grade 3 toxicity at least possibly related to intervention. CONCLUSION In this single-arm, multi-centre trial of participants with FAP, erlotinib one time per week resulted in markedly lower duodenal polyp burden, and modestly reduced lower GI polyp burden, after 6 months of intervention. While AEs were still reported by nearly three-quarters of all participants, these events were generally lower grade and well-tolerated. These findings support further investigation of erlotinib as an effective, acceptable cancer preventive agent for FAP-associated GI polyposis. TRIAL REGISTRATION NUMBER NCT02961374.
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Affiliation(s)
- N Jewel Samadder
- Gastroenterology and Hepatology, Mayo Clinic Minnesota, Rochester, Minnesota, USA
| | - Nathan Foster
- Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Ryan P McMurray
- Gastroenterology and Hepatology, Mayo Clinic Minnesota, Rochester, Minnesota, USA
| | - Carol A Burke
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
| | - Elena Stoffel
- Department of Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA
| | - Priyanka Kanth
- Gastroenterology & Hepatology, University of Utah, Salt Lake City, Utah, USA
| | - Rohit Das
- Department of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Marcia Cruz-Correa
- Medicine, University of Puerto Rico, San Juan, Puerto Rico,Cancer Biology, UPR Comprehensive Cancer Center, San Juan, Puerto Rico
| | - E Vilar
- Clinical Cancer Prevention, UT MD Anderson Cancer Center, Houston, Texas, USA
| | - Gautam Mankaney
- Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic, Cleveland, Ohio, USA
| | - Navtej Buttar
- Gastroenterology, Mayo Clinic, Rochester, Minnesota, Rochester, Minnesota, USA
| | - Selvi Thirumurthi
- Gastroenterology, Hepatology and Nutrition, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
| | - Danielle K Turgeon
- Medicine/Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA
| | | | - Michelle Westover
- Gastroenterology & Hepatology, University of Utah, Salt Lake City, Utah, USA
| | - Ellen Richmond
- Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland, USA
| | - Asad Umar
- Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland, USA
| | - Gary Della'Zanna
- Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland, USA
| | - Luz M Rodriguez
- Walter Reed National Military Medical Center, Bethesda, Maryland, USA
| | - Eva Szabo
- Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland, USA
| | - David Zahrieh
- Gastroenterology and Hepatology, Mayo Clinic Minnesota, Rochester, Minnesota, USA
| | - Paul J Limburg
- Gastroenterology and Hepatology, Mayo Clinic Minnesota, Rochester, Minnesota, USA
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The Controversial Role of Intestinal Mast Cells in Colon Cancer. Cells 2023; 12:cells12030459. [PMID: 36766801 PMCID: PMC9914221 DOI: 10.3390/cells12030459] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/24/2023] [Accepted: 01/26/2023] [Indexed: 02/04/2023] Open
Abstract
Mast cells are tissue-resident sentinels involved in large number of physiological and pathological processes, such as infection and allergic response, thanks to the expression of a wide array of receptors. Mast cells are also frequently observed in a tumor microenvironment, suggesting their contribution in the transition from chronic inflammation to cancer. In particular, the link between inflammation and colorectal cancer development is becoming increasingly clear. It has long been recognized that patients with inflammatory bowel disease have an increased risk of developing colon cancer. Evidence from experimental animals also implicates the innate immune system in the development of sporadically occurring intestinal adenomas, the precursors to colorectal cancer. However, the exact role of mast cells in tumor initiation and growth remains controversial: mast cell-derived mediators can either exert pro-tumorigenic functions, causing the progression and spread of the tumor, or anti-tumorigenic functions, limiting the tumor's growth. Here, we review the multifaceted and often contrasting findings regarding the role of the intestinal mast cells in colon cancer progression focusing on the molecular pathways mainly involved in the regulation of mast cell plasticity/functions during tumor progression.
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35
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Liu J, Mroczek M, Mach A, Stępień M, Aplas A, Pronobis-Szczylik B, Bukowski S, Mielczarek M, Gajewska E, Topolski P, Król ZJ, Szyda J, Dobosz P. Genetics, Genomics and Emerging Molecular Therapies of Pancreatic Cancer. Cancers (Basel) 2023; 15:779. [PMID: 36765737 PMCID: PMC9913594 DOI: 10.3390/cancers15030779] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/14/2023] [Accepted: 01/18/2023] [Indexed: 02/01/2023] Open
Abstract
The number of cases of pancreatic cancers in 2019 in Poland was 3852 (approx. 2% of all cancers). The course of the disease is very fast, and the average survival time from the diagnosis is 6 months. Only <2% of patients live for 5 years from the diagnosis, 8% live for 2 years, and almost half live for only about 3 months. A family predisposition to pancreatic cancer occurs in about 10% of cases. Several oncogenes in which somatic changes lead to the development of tumours, including genes BRCA1/2 and PALB2, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1, are involved in pancreatic cancer. Between 4% and 10% of individuals with pancreatic cancer will have a mutation in one of these genes. Six percent of patients with pancreatic cancer have NTRK pathogenic fusion. The pathogenesis of pancreatic cancer can in many cases be characterised by homologous recombination deficiency (HRD)-cell inability to effectively repair DNA. It is estimated that from 24% to as many as 44% of pancreatic cancers show HRD. The most common cause of HRD are inactivating mutations in the genes regulating this DNA repair system, mainly BRCA1 and BRCA2, but also PALB2, RAD51C and several dozen others.
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Affiliation(s)
- Jakub Liu
- Biostatistics Group, Wroclaw University of Environmental and Life Sciences, 51-631 Wroclaw, Poland
| | - Magdalena Mroczek
- Centre for Cardiovascular Genetics and Gene Diagnostics, Foundation for People with Rare Diseases, Wagistrasse 25, 8952 Schlieren, Switzerland
| | - Anna Mach
- Department of Psychiatry, Medical University of Warsaw, 00-665 Warsaw, Poland
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Maria Stępień
- Department of Infectious Diseases, Doctoral School, Medical University of Lublin, 20-059 Lublin, Poland
| | - Angelika Aplas
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Bartosz Pronobis-Szczylik
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Szymon Bukowski
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Magda Mielczarek
- Biostatistics Group, Wroclaw University of Environmental and Life Sciences, 51-631 Wroclaw, Poland
- National Research Institute of Animal Production, Krakowska 1, 32-083 Balice, Poland
| | - Ewelina Gajewska
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Piotr Topolski
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Zbigniew J. Król
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Joanna Szyda
- Biostatistics Group, Wroclaw University of Environmental and Life Sciences, 51-631 Wroclaw, Poland
- National Research Institute of Animal Production, Krakowska 1, 32-083 Balice, Poland
| | - Paula Dobosz
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
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Pachler FR, Byrjalsen A, Karstensen JG, Jelsig AM. Hereditary polyposis syndromes remain a challenging disease entity: Old dilemmas and new insights. World J Gastrointest Surg 2023; 15:1-8. [PMID: 36741069 PMCID: PMC9896492 DOI: 10.4240/wjgs.v15.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 11/18/2022] [Accepted: 01/04/2023] [Indexed: 01/17/2023] Open
Abstract
In this editorial we present an overview and insights of the management of hereditary polyposis syndromes. The primary focus was on familial adenomatous polyposis, juvenile polyposis syndrome and Peutz-Jegher syndrome. Genetic testing has become increasingly available and is easier than ever to integrate into clinical practice. Furthermore, several genes have been added to the expanding list of genes associated with hereditary polyposis syndromes, allowing for precise diagnostics and tailored follow-up. Endoscopic evaluation of patients with hereditary polyposis syndromes is paramount in the surveillance strategies. Current endoscopic procedures include both diagnostic procedures and surveillance as well as therapeutic interventions. Recommendations for endoscopic procedures in the upper and lower gastrointestinal canal were described. Surgery is still a key component in the management of patients with hereditary polyposis syndromes. The increased cancer risk in these patients often render prophylactic procedures or intended curative procedures in the case of cancer development. Surgical interventions in the upper and lower gastrointestinal canal were described with relevant considerations. Development of chemopreventive medications is ongoing. Few drugs have been investigated, including nonsteroidal anti-inflammatory drugs. It has been demonstrated that cyclooxygenase-2 inhibitors may lower the number of polyps. Other medications are currently under investigation, but none have, to date, consistently been able to prevent development of disease.
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Affiliation(s)
- Frederik Rønne Pachler
- Danish Polyposis Registry, Gastrounit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre 2650, Denmark
| | - Anna Byrjalsen
- Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, Copenhagen 2100, Denmark
| | - John Gásdal Karstensen
- Danish Polyposis Registry, Gastrounit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre 2650, Denmark
- Department of Clinical Medicine, University of Copenhagen, Hvidovre 2650, Denmark
| | - Anne Marie Jelsig
- Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, Copenhagen 2100, Denmark
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MEIRA-JÚNIOR JD, YOGOLARE GG, MAGALHÃES DDP, NAMUR GN, CAMPOS FG, SEGATELLI V, NAHAS SC, JUKEMURA J. PANCREATIC SOLID-PSEUDOPAPILLARY NEOPLASM IN PATIENTS WITH FAMILIAL ADENOMATOUS POLYPOSIS. ARQUIVOS BRASILEIROS DE CIRURGIA DIGESTIVA : ABCD = BRAZILIAN ARCHIVES OF DIGESTIVE SURGERY 2023; 35:e1718. [PMID: 36629695 PMCID: PMC9831633 DOI: 10.1590/0102-672020220002e1718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 10/15/2022] [Indexed: 01/11/2023]
Abstract
BACKGROUND Solid pseudopapillary neoplasm of the pancreas is an uncommon pancreatic tumor, which is more frequent in young adult women. Familial adenomatous polyposis is a genetic condition associated with colorectal cancer that also increases the risk of developing other tumors as well. AIM The aim of this study was to discuss the association of familial adenomatous polyposis with solid pseudopapillary neoplasm of the pancreas, which is very rare. METHODS We report two cases of patients with familial adenomatous polyposis who developed solid pseudopapillary neoplasm of the pancreas of the pancreas and were submitted to laparoscopic pancreatic resections with splenic preservation (one male and one female). RESULTS ß-catenin and Wnt signaling pathways have been found to play an important role in the tumorigenesis of solid pseudopapillary neoplasm of the pancreas, and their constitutive activation due to adenomatous polyposis coli gene inactivation in familial adenomatous polyposis may explain the relationship between familial adenomatous polyposis and solid pseudopapillary neoplasm of the pancreas. CONCLUSION Colonic resection must be prioritized, and a minimally invasive approach is preferred to minimize the risk of developing desmoid tumor. Pancreatic resection usually does not require extensive lymphadenectomy for solid pseudopapillary neoplasm of the pancreas, and splenic preservation is feasible.
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Affiliation(s)
- José Donizeti MEIRA-JÚNIOR
- Universidade de São Paulo, Faculty of Medicine, University Hospital, Gastroenterology Department, Digestive Surgery Division – São Paulo (SP), Brazil
| | - Gustavo Gonçalves YOGOLARE
- Universidade de São Paulo, Faculty of Medicine, University Hospital, Gastroenterology Department, Digestive Surgery Division – São Paulo (SP), Brazil
| | - Daniel de Paiva MAGALHÃES
- Universidade de São Paulo, Faculty of Medicine, University Hospital, Gastroenterology Department, Digestive Surgery Division – São Paulo (SP), Brazil
| | - Guilherme Naccache NAMUR
- Universidade de São Paulo, Faculty of Medicine, University Hospital, Gastroenterology Department, Digestive Surgery Division – São Paulo (SP), Brazil
| | - Fabio Guilherme CAMPOS
- Universidade de São Paulo, Faculty of Medicine, University Hospital, Gastroenterology Department, Digestive Surgery Division – São Paulo (SP), Brazil
| | - Vanderlei SEGATELLI
- Universidade de São Paulo, Faculty of Medicine, University Hospital, Pathology Department – São Paulo (SP), Brasil
| | - Sergio Carlos NAHAS
- Universidade de São Paulo, Faculty of Medicine, University Hospital, Gastroenterology Department, Digestive Surgery Division – São Paulo (SP), Brazil
| | - Jose JUKEMURA
- Universidade de São Paulo, Faculty of Medicine, University Hospital, Gastroenterology Department, Digestive Surgery Division – São Paulo (SP), Brazil
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Fukushi G, Yamada M, Kakugawa Y, Gotoh M, Tanabe N, Ushiama M, Watanabe T, Yamazaki T, Matsumoto M, Hirata M, Nakajima T, Sugano K, Yoshida T, Matsuda T, Igarashi Y, Saito Y. Genotype-phenotype correlation of small-intestinal polyps on small-bowel capsule endoscopy in familial adenomatous polyposis. Gastrointest Endosc 2023; 97:59-68.e7. [PMID: 36084716 DOI: 10.1016/j.gie.2022.08.042] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 08/18/2022] [Accepted: 08/30/2022] [Indexed: 01/20/2023]
Abstract
BACKGROUND AND AIMS In familial adenomatous polyposis (FAP), neoplastic lesions outside the colon have become increasingly important. The genotype-phenotype correlation has been established for duodenal polyps, and regular screening is recommended. However, this correlation remains unclear for small-intestinal lesions, except for reports on the relationship between their occurrence and Spigelman stage. Here, we used small-bowel capsule endoscopy (SBCE) to investigate the genotype-phenotype correlation of small-intestinal polyps in FAP. METHODS The genotype-phenotype correlation of small-intestinal polyps was investigated in patients with FAP who underwent SBCE, Esophagogastroduodenoscopy (EGD), and adenomatous polyposis coli (APC) gene analysis. Of 64 patients with FAP who underwent SBCE, 41 were included in the final analysis, 4 did not undergo a complete small intestine examination, and 19 did not undergo genetic analysis. RESULTS The prevalence (median number) of small-intestinal polyps by Spigelman stage was 26% (1.5), 0% (0), 44% (5), 60% (4), and 73% (25.5) for stages 0 to IV, respectively. Significantly more small-intestinal polyps were found in Spigelman stage III and IV groups than in the stage 0 group (P < .05). The APC variant was negative for 6 patients (15%), and the sites associated with more than 5 small-intestinal polyps were codons 278, 1062, 1114, 1281, 1307, 1314, and 1504. CONCLUSIONS In FAP patients, SBCE surveillance is potentially recommended for patients with pathogenic variants in the APC gene at codons 278 and 1062 to 1504 or with Spigelman stage III or higher.
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Affiliation(s)
- Gozo Fukushi
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan; Cancer Screening Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan; Division of Gastroenterology and Hepatology, Toho University Omori Medical Center, Tokyo, Japan
| | - Masayoshi Yamada
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan; Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan
| | - Yasuo Kakugawa
- Cancer Screening Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
| | - Masahiro Gotoh
- Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Noriko Tanabe
- Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan
| | - Mineko Ushiama
- Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan; Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Tomoko Watanabe
- Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan
| | | | - Minori Matsumoto
- Cancer Screening Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
| | - Makoto Hirata
- Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan; Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Takeshi Nakajima
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Kokichi Sugano
- Department of Genetic Medicine, Koundo Hospital, Sasaki Foundation, Tokyo, Japan
| | - Teruhiko Yoshida
- Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan; Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Takahisa Matsuda
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan; Cancer Screening Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan; Division of Gastroenterology and Hepatology, Toho University Omori Medical Center, Tokyo, Japan
| | - Yoshinori Igarashi
- Division of Gastroenterology and Hepatology, Toho University Omori Medical Center, Tokyo, Japan
| | - Yutaka Saito
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
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Mei WJ, Mi M, Qian J, Xiao N, Yuan Y, Ding PR. Clinicopathological characteristics of high microsatellite instability/mismatch repair-deficient colorectal cancer: A narrative review. Front Immunol 2022; 13:1019582. [PMID: 36618386 PMCID: PMC9822542 DOI: 10.3389/fimmu.2022.1019582] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 11/28/2022] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancers (CRCs) with high microsatellite instability (MSI-H) and deficient mismatch repair (dMMR) show molecular and clinicopathological characteristics that differ from those of proficient mismatch repair/microsatellite stable CRCs. Despite the importance of MSI-H/dMMR status in clinical decision making, the testing rates for MSI and MMR in clinical practice remain low, even in high-risk populations. Additionally, the real-world prevalence of MSI-H/dMMR CRC may be lower than that reported in the literature. Insufficient MSI and MMR testing fails to identify patients with MSI-H/dMMR CRC, who could benefit from immunotherapy. In this article, we describe the current knowledge of the clinicopathological features, molecular landscape, and radiomic characteristics of MSI-H/dMMR CRCs. A better understanding of the importance of MMR/MSI status in the clinical characteristics and prognosis of CRC may help increase the rates of MMR/MSI testing and guide the development of more effective therapies based on the unique features of these tumors.
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Affiliation(s)
- Wei-Jian Mei
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Mi Mi
- Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jing Qian
- Global Medical Affairs, MSD China, Shanghai, China
| | - Nan Xiao
- Global Medical Affairs, MSD China, Shanghai, China
| | - Ying Yuan
- Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Clinical Research Center for CANCER, Hangzhou, China
- Cancer Center of Zhejiang University, Hangzhou, China
| | - Pei-Rong Ding
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
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Chen L, Ye L, Hu B. Hereditary Colorectal Cancer Syndromes: Molecular Genetics and Precision Medicine. Biomedicines 2022; 10:biomedicines10123207. [PMID: 36551963 PMCID: PMC9776295 DOI: 10.3390/biomedicines10123207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 11/28/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Hereditary CRC syndromes account for approximately 5-10% of all CRC, with a lifetime risk of CRC that approaches 50-80% in the absence of endoscopic or surgical treatment. Hereditary CRC syndromes can be phenotypically divided into polyposis and non-polyposis syndrome, mainly according to the conditions of polyps. The typical representatives are familial adenomatous polyposis (FAP) and Lynch syndromes (LS), respectively. Over the past few decades, molecular genetics enhanced the discovery of cancer-predisposing genes and revolutionized the field of clinical oncology. Hereditary CRC syndromes have been a key part of this effort, with data showing that pathogenic variants are present in up to 10% of cases. Molecular phenotypes of tumors can not only help identify individuals with genetic susceptibility to CRC but also guide the precision prevention and treatment for the development of CRC. This review emphasizes the molecular basis and prevention strategies for hereditary CRC syndromes.
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Affiliation(s)
| | | | - Bing Hu
- Correspondence: ; Tel.: +86-18980601278
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Attard TM, Septer S, Lawson CE, Attard MI, Lee STM, Umar S. Microbiome insights into pediatric familial adenomatous polyposis. Orphanet J Rare Dis 2022; 17:416. [PMID: 36376984 PMCID: PMC9664625 DOI: 10.1186/s13023-022-02569-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 10/30/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Individuals with familial adenomatous polyposis (FAP) harbor numerous polyps with inevitable early progression to colon cancer. Complex microbiotic-tumor microenvironment perturbations suggest a dysbiotic relationship between polyp and microbiome. In this study, we performed comprehensive analyses of stool and tissue microbiome of pediatric FAP subjects and compared with unaffected cohabiting relatives through 16S V4 region amplicon sequencing and machine learning platforms. RESULTS Within our FAP and control patient population, Firmicutes and Bacteroidetes were the predominant phyla in the tissue and stool samples, while Proteobacteria dominated the polyp/non-polyp mucosa. A decline in Faecalibacterium in polyps contrasted with a decline in Bacteroides in the FAP stool. The alpha- and beta-diversity indices differed significantly within the polyp/non-polyp groups, with a concurrent shift towards lower diversity in polyps. In a limited 3-year longitudinal study, the relative abundance of Proteobacteria and Fusobacteria was higher in polyps compared to non-polyp and stool specimens over time. Through machine learning, we discovered that Archaeon_enrichment_culture_clone_A13, Micrococcus_luteus, and Eubacterium_hallii in stool and PL-11B10, S1-80, and Blastocatellaceae in tissues were significantly different between patients with and without polyps. CONCLUSIONS Detection of certain bacterial concentrations within stool or biopsied polyps could serve as adjuncts to current screening modalities to help identify higher-risk patients.
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Affiliation(s)
- Thomas M. Attard
- Department of Gastroenterology, Children’s Mercy Hospital, 1MO2.37, 2401 Gilham Road, Kansas City, MO 64108 USA
| | - Seth Septer
- Department of Pediatric Gastroenterology, Children’s Hospital Colorado, Aurora, CO USA
| | - Caitlin E. Lawson
- Division of Genetics, Children’s Mercy Hospital, Kansas City, MO USA
| | - Mark I. Attard
- Neonatal Unit, Aberdeen Maternity Hospital, Aberdeen, AB25 2ZL UK
| | - Sonny T. M. Lee
- Division of Biology, Kansas State University, Manhattan, KS USA
| | - Shahid Umar
- Department of Surgery, University of Kansas Medical Center, 3901 Rainbow Blvd, 4028 Wahl Hall East, Kansas City, KS 66160 USA
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Biallelic PMS2 Mutations in a Family with Uncommon Clinical and Molecular Features. Genes (Basel) 2022; 13:genes13111953. [PMID: 36360190 PMCID: PMC9690098 DOI: 10.3390/genes13111953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/20/2022] [Accepted: 10/23/2022] [Indexed: 11/29/2022] Open
Abstract
We describe a patient with constitutional mismatch repair-deficiency (CMMR-D) in whom the syndrome started at age 10 with the development of multiple adenomas in the large bowel. In the successive 25 years, four malignancies developed in different organs (rectum, ileum, duodenum, and lymphoid tissue). The patient had biallelic constitutional pathogenic variants in the PMS2 gene. We speculate that besides the PMS2 genotype, alterations of other genes might have contributed to the development of the complex phenotype. In the nuclear family, both parents carried different PMS2 germline mutations. They appeared in good clinical condition and did not develop polyps or cancer. The index case had a brother who died at age three of lymphoblastic leukemia, and a sister who was affected by sarcoidosis. Tumor tissue showed diffuse DNA microsatellite instability. A complete absence of immunoreactivity was observed for the PMS2 protein both in the tumors and normal tissues. Next-generation sequencing and multiple ligation-dependent probe amplification analyses revealed biallelic PMS2 germline pathogenic variants in the proband (genotype c.[137G>T];[(2174+1_2175-1)_(*160_?)del]), and one of the two variants was present in both parents—c.137G>T in the father and c.(2174+1-2175-1)_(*160_?)del in the mother—as well as c.137G>T in the sister. Moreover, Class 3 variants of MSH2 (c.1787A>G), APC (c.1589T>C), and CHEK2 (c.331G>T) genes were also detected in the proband. In conclusion, the recognition of CMMR-D may sometimes be difficult; however, the possible role of constitutional alterations of other genes in the development of the full-blown phenotype should be investigated in more detail.
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Whole Genome Sequencing Applied in Familial Hamartomatous Polyposis Identifies Novel Structural Variations. Genes (Basel) 2022; 13:genes13081408. [PMID: 36011318 PMCID: PMC9407864 DOI: 10.3390/genes13081408] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 08/03/2022] [Accepted: 08/04/2022] [Indexed: 11/25/2022] Open
Abstract
Hamartomatous polyposis syndromes (HPS) are rare cancer-predisposing disorders including Juvenile polyposis (JPS), Peutz–Jeghers (PJS) and PTEN hamartomatous syndromes (PHS). Penetrant mutations in corresponding genes (SMAD4, BMPR1A, STK11, PTEN and AKT1), are usually diagnosed via a next-generation-sequencing gene panel (NGS-GP) for tailored surveillance and preimplantation testing for monogenic disorders (PGT-M). Five probands with HPS phenotype, with no genetic diagnosis per genetic workup, underwent whole-genome sequencing (WGS) that identified structural genetic alterations: two novel inversions in BMPRA1 and STK11, two BMPR1A-deletions, known as founders among Bukharan Jews, and BMPR1A microdeletion. BMPR1A inversion was validated by “junction fragment” amplification and direct testing. PGT-M was performed via multiplex-PCR and enabled successful birth of a non-carrier baby. WGS may be considered for HPS patients with no NGS-GP findings to exclude structural alterations.
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Kabbage M, Ben Aissa-Haj J, Othman H, Jaballah-Gabteni A, Laarayedh S, Elouej S, Medhioub M, Kettiti HT, Khsiba A, Mahmoudi M, BelFekih H, Maaloul A, Touinsi H, Hamzaoui L, Chelbi E, Abdelhak S, Boubaker MS, Azzouz MM. A Rare MSH2 Variant as a Candidate Marker for Lynch Syndrome II Screening in Tunisia: A Case of Diffuse Gastric Carcinoma. Genes (Basel) 2022; 13:genes13081355. [PMID: 36011265 PMCID: PMC9407052 DOI: 10.3390/genes13081355] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/17/2022] [Accepted: 07/21/2022] [Indexed: 12/24/2022] Open
Abstract
Several syndromic forms of digestive cancers are known to predispose to early-onset gastric tumors such as Hereditary Diffuse Gastric Cancer (HDGC) and Lynch Syndrome (LS). LSII is an extracolonic cancer syndrome characterized by a tumor spectrum including gastric cancer (GC). In the current work, our main aim was to identify the mutational spectrum underlying the genetic predisposition to diffuse gastric tumors occurring in a Tunisian family suspected of both HDGC and LS II syndromes. We selected the index case “JI-021”, which was a woman diagnosed with a Diffuse Gastric Carcinoma and fulfilling the international guidelines for both HDGC and LSII syndromes. For DNA repair, a custom panel targeting 87 candidate genes recovering the four DNA repair pathways was used. Structural bioinformatics analysis was conducted to predict the effect of the revealed variants on the functional properties of the proteins. DNA repair genes panel screening identified two variants: a rare MSH2 c.728G>A classified as a variant with uncertain significance (VUS) and a novel FANCD2 variant c.1879G>T. The structural prediction model of the MSH2 variant and electrostatic potential calculation showed for the first time that MSH2 c.728G>A is likely pathogenic and is involved in the MSH2-MLH1 complex stability. It appears to affect the MSH2-MLH1 complex as well as DNA-complex stability. The c.1879G>T FANCD2 variant was predicted to destabilize the protein structure. Our results showed that the MSH2 p.R243Q variant is likely pathogenic and is involved in the MSH2-MLH1 complex stability, and molecular modeling analysis highlights a putative impact on the binding with MLH1 by disrupting the electrostatic potential, suggesting the revision of its status from VUS to likely pathogenic. This variant seems to be a shared variant in the Mediterranean region. These findings emphasize the importance of testing DNA repair genes for patients diagnosed with diffuse GC with suspicion of LSII and colorectal cancer allowing better clinical surveillance for more personalized medicine.
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Affiliation(s)
- Maria Kabbage
- Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia; (J.B.A.-H.); (A.J.-G.); (S.L.); (H.T.K.); (A.M.); (M.S.B.)
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia; (M.M.); (A.K.); (M.M.); (H.B.); (L.H.); (E.C.); (S.A.); (M.M.A.)
- Correspondence:
| | - Jihenne Ben Aissa-Haj
- Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia; (J.B.A.-H.); (A.J.-G.); (S.L.); (H.T.K.); (A.M.); (M.S.B.)
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia; (M.M.); (A.K.); (M.M.); (H.B.); (L.H.); (E.C.); (S.A.); (M.M.A.)
| | - Houcemeddine Othman
- Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg 2000, South Africa;
| | - Amira Jaballah-Gabteni
- Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia; (J.B.A.-H.); (A.J.-G.); (S.L.); (H.T.K.); (A.M.); (M.S.B.)
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia; (M.M.); (A.K.); (M.M.); (H.B.); (L.H.); (E.C.); (S.A.); (M.M.A.)
| | - Sarra Laarayedh
- Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia; (J.B.A.-H.); (A.J.-G.); (S.L.); (H.T.K.); (A.M.); (M.S.B.)
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia; (M.M.); (A.K.); (M.M.); (H.B.); (L.H.); (E.C.); (S.A.); (M.M.A.)
| | - Sahar Elouej
- Marseille Medical Genetics, Aix Marseille University, INSERM, 13007 Marseille, France;
| | - Mouna Medhioub
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia; (M.M.); (A.K.); (M.M.); (H.B.); (L.H.); (E.C.); (S.A.); (M.M.A.)
- Gastroenterology Department, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia
| | - Haifa Tounsi Kettiti
- Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia; (J.B.A.-H.); (A.J.-G.); (S.L.); (H.T.K.); (A.M.); (M.S.B.)
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia; (M.M.); (A.K.); (M.M.); (H.B.); (L.H.); (E.C.); (S.A.); (M.M.A.)
| | - Amal Khsiba
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia; (M.M.); (A.K.); (M.M.); (H.B.); (L.H.); (E.C.); (S.A.); (M.M.A.)
- Gastroenterology Department, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia
| | - Moufida Mahmoudi
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia; (M.M.); (A.K.); (M.M.); (H.B.); (L.H.); (E.C.); (S.A.); (M.M.A.)
- Gastroenterology Department, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia
| | - Houda BelFekih
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia; (M.M.); (A.K.); (M.M.); (H.B.); (L.H.); (E.C.); (S.A.); (M.M.A.)
- Department of Oncology, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia
| | - Afifa Maaloul
- Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia; (J.B.A.-H.); (A.J.-G.); (S.L.); (H.T.K.); (A.M.); (M.S.B.)
| | - Hassen Touinsi
- Department of Surgery, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia;
| | - Lamine Hamzaoui
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia; (M.M.); (A.K.); (M.M.); (H.B.); (L.H.); (E.C.); (S.A.); (M.M.A.)
- Gastroenterology Department, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia
| | - Emna Chelbi
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia; (M.M.); (A.K.); (M.M.); (H.B.); (L.H.); (E.C.); (S.A.); (M.M.A.)
- Department of Pathology, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia
| | - Sonia Abdelhak
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia; (M.M.); (A.K.); (M.M.); (H.B.); (L.H.); (E.C.); (S.A.); (M.M.A.)
| | - Mohamed Samir Boubaker
- Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia; (J.B.A.-H.); (A.J.-G.); (S.L.); (H.T.K.); (A.M.); (M.S.B.)
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia; (M.M.); (A.K.); (M.M.); (H.B.); (L.H.); (E.C.); (S.A.); (M.M.A.)
| | - Mohamed Mousaddak Azzouz
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia; (M.M.); (A.K.); (M.M.); (H.B.); (L.H.); (E.C.); (S.A.); (M.M.A.)
- Gastroenterology Department, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia
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NK Cells and Other Cytotoxic Innate Lymphocytes in Colorectal Cancer Progression and Metastasis. Int J Mol Sci 2022; 23:ijms23147859. [PMID: 35887206 PMCID: PMC9322916 DOI: 10.3390/ijms23147859] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/12/2022] [Accepted: 07/14/2022] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies and leading causes of cancer-related deaths worldwide. Despite its complex pathogenesis and progression, CRC represents a well-fitting example of how the immune contexture can dictate the disease outcome. The presence of cytotoxic lymphocytes, both CD8+ T cells and natural killer (NK) cells, represents a relevant prognostic factor in CRC and is associated with a better overall survival. Together with NK cells, other innate lymphocytes, namely, innate lymphoid cells (ILCs), have been found both in biopsies of CRC patients and in murine models of intestinal cancer, playing both pro- and anti-tumor activities. In particular, several type 1 innate lymphoid cells (ILC1) with cytotoxic functions have been recently described, and evidence in mice shows a role for both NK cells and ILC1 in controlling CRC metastasis. In this review, we provide an overview of the features of NK cells and the expanding spectrum of innate lymphocytes with cytotoxic functions. We also comment on both the described and the potential roles these innate lymphocytes can play during the progression of intestinal cancer leading to metastasis. Finally, we discuss recent advances in the molecular mechanisms underlying the functional regulation of cytotoxic innate lymphocytes in CRC.
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Mansur A, Zhang F, Lu CY. Genetic Testing and/or Counseling for Colorectal Cancer by Health Insurance Type. J Pers Med 2022; 12:jpm12071146. [PMID: 35887643 PMCID: PMC9317363 DOI: 10.3390/jpm12071146] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 07/03/2022] [Accepted: 07/13/2022] [Indexed: 12/18/2022] Open
Abstract
Genetic testing is increasingly used in clinical practice to assist with the diagnosis of genetic diseases and/or provide information about disease risk, and genetic counseling supports patient understanding of test results before and/or after genetic testing. Therefore, access to genetic testing and counseling is important for patient care. Health insurance coverage is a major determinant of access to health care in the United States. Uninsured individuals are less likely to have a regular source of health care than their insured counterparts. Different health insurance types and benefits also influence access to health care. Data on the association of health insurance and uptake of genetic testing and/or counseling for cancer risk are limited. Using data from the National Health Interview Survey, we examined the uptake of genetic testing and/or counseling for colorectal cancer (CRC) risk by health insurance type. We found that only a small proportion of individuals undergo genetic testing and/or counseling for CRC risk (0.8%), even among subgroups of individuals at risk due to family or personal history (3.7%). Insured individuals were more likely to undergo genetic testing and/or counseling for CRC risk, particularly those with Military and Private insurance plans, after adjusting for various demographic, socioeconomic, and health risk covariates. Further investigations are warranted to examine potential disparities in access and health inequities.
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Affiliation(s)
| | - Fang Zhang
- Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, 401 Park Drive, Suite 401 East, Boston, MA 02215, USA;
| | - Christine Y. Lu
- Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, 401 Park Drive, Suite 401 East, Boston, MA 02215, USA;
- Correspondence: ; Tel.: +1-617-867-4989
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Hopper AD. Role of endoscopy in patients with familial adenomatous polyposis. Frontline Gastroenterol 2022; 13:e72-e79. [PMID: 35812028 PMCID: PMC9234724 DOI: 10.1136/flgastro-2022-102125] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/03/2022] [Indexed: 02/04/2023] Open
Abstract
Familial adenomatous polyposis (FAP) is a hereditary disease that, without intervention, will cause nearly all patients to develop colorectal cancer by the age of 45. However, even after prophylactic colorectal surgery the eventual development of duodenal adenomas leads to an additional risk of duodenal and ampullary cancers. Endoscopy is an essential part of the multidisciplinary management of FAP to aid the early identification or prevention of advanced gastrointestinal malignancy. This review article details the current evidence and consensus guidance available regarding the role of endoscopic surveillance and treatment strategies for FAP.
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Affiliation(s)
- Andrew D Hopper
- Department of Infection, Immunity and Cardiovascular Disease, Sheffield University, and Academic Department of Gastroenterology Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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Russo M, Barchi A, Mannucci A, Puzzono M, Zuppardo RA, Biamonte P, Bencardino S, Leandro G, Cannizzaro R, Monica F, Zagari RM, Pasquale L, Goni E, Di Leo M, Ricciardiello L, Cavestro GM. Increased Number of Colorectal Interval Cancers in Lynch Syndrome after the SARS-CoV-2 Pandemic: A Survey-Based Study. Dig Dis 2022; 41:227-232. [PMID: 35468603 PMCID: PMC9393779 DOI: 10.1159/000524393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 02/28/2022] [Indexed: 02/02/2023]
Abstract
BACKGROUND Hereditary colorectal cancer syndromes require timely endoscopic surveillance. METHODS This study evaluated the approach of Italian gastroenterologists to the management of such patients. It then assessed the impact of SARS-CoV-2. All members affiliated with the leading Italian gastroenterology societies (AIGO, SIED, and SIGE) received an online questionnaire. RESULTS One hundred and twenty-one clinicians from 96 centers answered, not necessarily experts in the field (mean age 50.26 ± 11.22 years). Many collected family history for genetic risk assessment (74.4%), but only 14.0% used an online predictive software. 65.6% discussed cases in multidisciplinary units. Genetic analysis was available to most centers, but only a few hospitals offered dedicated endoscopy (19.0%), outpatient clinics (33.9%), or surgeries (23.1%). Since the start of the SARS-CoV-2 pandemic, the number of clinicians with a high volume of patients decreased (from 38.8% to 28.1%). Almost half of the responders (45.5%) reported a delay in the surveillance (median: 4-12 months). Ultimately, 30.6% detected one interval colorectal cancer in at least one of their patients. CONCLUSION The SARS-CoV-2 pandemic directly affected the surveillance of hereditary colorectal cancer syndromes in Italy. Endoscopic surveillance should resume in all centers to avoid the possible long-term consequences of its interruption, especially for inherited colorectal cancer syndromes.
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Affiliation(s)
- Michele Russo
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Alberto Barchi
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Alessandro Mannucci
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Marta Puzzono
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy,Medical Biotechnologies Department, University of Siena, Siena, Italy
| | - Raffaella Alessia Zuppardo
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Paolo Biamonte
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Sarah Bencardino
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Gioacchino Leandro
- Gastroenterology Unit 1, Gastroenterological Hospital “S. De Bellis” IRCCS, Castellana Grotte, Italy
| | | | - Fabio Monica
- Gastroenterology and Digestive Endoscopy, Ospedale di Cattinara, Trieste, Italy
| | - Rocco Maurizio Zagari
- Gastroenterology Unit, IRCCS Azienda Ospedaliero-Universitaria, S. Orsola Hospital, Bologna, Italy,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Luigi Pasquale
- Gastroenterology Unit, S.O. Frangipane Hospital, Ariano Irpino, Italy
| | - Elisabetta Goni
- Medical Department II, University Hospital, Ludwig Maximilians-University, Munich, Germany
| | - Milena Di Leo
- Digestive Endoscopy Unit, ASST Santi Paolo e Carlo, Milan, Italy
| | - Luigi Ricciardiello
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy,IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giulia Martina Cavestro
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy,*Giulia Martina Cavestro,
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Toss A, Quarello P, Mascarin M, Banna GL, Zecca M, Cinieri S, Peccatori FA, Ferrari A. Cancer Predisposition Genes in Adolescents and Young Adults (AYAs): a Review Paper from the Italian AYA Working Group. Curr Oncol Rep 2022; 24:843-860. [PMID: 35320498 PMCID: PMC9170630 DOI: 10.1007/s11912-022-01213-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/18/2021] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW The present narrative systematic review summarizes current knowledge on germline gene mutations predisposing to solid tumors in adolescents and young adults (AYAs). RECENT FINDINGS AYAs with cancer represent a particular group of patients with specific challenging characteristics and yet unmet needs. A significant percentage of AYA patients carry pathogenic or likely pathogenic variants (PV/LPVs) in cancer predisposition genes. Nevertheless, knowledge on spectrum, frequency, and clinical implications of germline variants in AYAs with solid tumors is limited. The identification of PV/LPV in AYA is especially critical given the need for appropriate communicative strategies, risk of second primary cancers, need for personalized long-term surveillance, potential reproductive implications, and cascade testing of at-risk family members. Moreover, these gene alterations may potentially provide novel biomarkers and therapeutic targets that are lacking in AYA patients. Among young adults with early-onset phenotypes of malignancies typically presenting at later ages, the increased prevalence of germline PV/LPVs supports a role for genetic counseling and testing irrespective of tumor type.
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Affiliation(s)
- Angela Toss
- Department of Oncology and Hematology, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Paola Quarello
- Paediatric Onco-Haematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital, Turin, Italy
- Department of Public Health and Paediatric Sciences, University of Torino, Turin, Italy
| | - Maurizio Mascarin
- AYA Oncology and Pediatric Radiotherapy Unit, Centro di Riferimento Oncologico IRCCS, Aviano, Italy
| | - Giuseppe Luigi Banna
- Candiolo Cancer Institute, FPO-IRCCS, SP142, km 3.95, 10060, Candiolo, Turin, Italy.
| | - Marco Zecca
- Department of Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Saverio Cinieri
- Medical Oncology Unit and Breast Unit Ospedale Perrino ASL, Brindisi, Italy
| | - Fedro Alessandro Peccatori
- Fertility and Procreation Unit, Gynecologic Oncology Program, European Institute of Oncology IRCCS, Milan, Italy
| | - Andrea Ferrari
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
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Wang L, Tu H, Zeng L, Gao R, Luo S, Xiong C. Identification and in silico Analysis of Nonsense SNPs of Human Colorectal Cancer Protein. J Oleo Sci 2022; 71:363-370. [PMID: 35236796 DOI: 10.5650/jos.ess21313] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Colorectal cancer (CRC) is the third most prevalent disease in the world, with an estimated 1.2 million new cases each year. Spontaneous CRCs account for around 70% of all CRCs, are caused by somatic mutations. Minor variations or single-nucleotide polymorphisms (SNPs) in oncogene or tumor-suppressor genes cause familial CRC. MSH2 and MSH6 genes are located on chromosome 2. These genes products are involved in the repair of DNA replication defects. If these proteins are changed, the replication errors are not rectified, resulting in damaged DNA leading to colorectal cancer. We employed a variety of computational methodologies to find nsSNPs that are harmful to the structure and function of the MSH6 protein and could be causing CRC in our study. SIFT, PROVEAN, Poly- Phen-2, PhD-SNP, and SNPs&GO were among the in silico methods used to do the computational research. According to the findings, mutations of G932Q, E1234Q, and F1104Q are important alterations in native MSH6 protein rs35717727 that may contribute to its dysfunction and, ultimately, disease. The study also provided three-dimensional structures of the native MSH6 protein and mutations. These nsSNPs should be considered as key target mutations in many disorders involving MSH6 dysfunction in future studies. This is the first thorough study to use in silico technologies to assess MSH6 gene variants, and it will be extremely useful in planning largescale investigations and developing precision medicines to treat disorders caused by these polymorphisms. Additionally, animal models of various autoimmune disorders with these mutations could aid in determining their precise involvement.
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Affiliation(s)
- Lu Wang
- Department of Oncology, First People's Hospital of Jiujiang City
| | - Huiyang Tu
- Department of Oncology, First People's Hospital of Jiujiang City
| | - Lingzhi Zeng
- Department of Oncology, First People's Hospital of Jiujiang City
| | - Ruichen Gao
- Department of Oncology, First People's Hospital of Jiujiang City
| | - Sumei Luo
- Department of Oncology, First People's Hospital of Jiujiang City
| | - Chao Xiong
- Department of Oncology, First People's Hospital of Jiujiang City
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