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Hekman L, Napierkowski E, Hartman NC, Ellis JL, Wagner RH, Bova D, Picken MM, Flanigan RC. Incidental Discovery of Hepatocellular Carcinoma on 18F-PSMA PET CT Performed for Prostate Cancer Reassessment. Case Rep Surg 2023; 2023:1458175. [PMID: 38125746 PMCID: PMC10733019 DOI: 10.1155/2023/1458175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 11/01/2023] [Accepted: 11/06/2023] [Indexed: 12/23/2023] Open
Abstract
Prostate-specific membrane antigen positron emission tomography (PSMA PET) has been approved by the Food and Drug Administration (FDA) to identify prostate cancer in the setting of biochemical recurrence but can also identify other malignancies. 18F-PSMA PET has not been studied as a potential tool for hepatocellular carcinoma (HCC). We describe the case of a 76-year-old male with a rising prostate-specific antigen (PSA) after definitive prostate cancer treatment and no prior liver pathology who was incidentally found to have HCC on 18F-PSMA PET.
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Affiliation(s)
- Lauren Hekman
- Loyola University Medical Center, Department of Urology, USA
| | | | | | | | - Robert H. Wagner
- Loyola University Medical Center, Department of Nuclear Medicine, USA
| | - Davide Bova
- Loyola University Medical Center, Department of Radiology, USA
| | - Maria M. Picken
- Loyola University Medical Center, Department of Pathology, USA
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2
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Youssef ASED, Zekri ARN, Mohanad M, Loutfy SA, Abdel Fattah NF, Elberry MH, El Leithy AA, El-Touny A, Rabie AS, Shalaby M, Hanafy A, Lotfy MM, El-Sisi ER, El-Sayyad GS, Nassar A. Deleterious and ethnic-related BRCA1/2 mutations in tissue and blood of Egyptian colorectal cancer patients and its correlation with human papillomavirus. Clin Exp Med 2023; 23:5063-5088. [PMID: 37804357 PMCID: PMC10725364 DOI: 10.1007/s10238-023-01207-w] [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: 07/21/2023] [Accepted: 09/22/2023] [Indexed: 10/09/2023]
Abstract
This study aimed to identify BRCA1/2 mutational patterns in the tissue and blood of Egyptian colorectal cancer (CRC) patients and to study the possible correlation of this mutational pattern with Human papillomavirus (HPV) infection. Eighty-two colonoscopic biopsies and forty-six blood samples were collected from Egyptian CRC patients, as well as blood samples of age and sex-matched healthy controls (n = 43) were enrolled. The libraries were performed using Qiaseq Human BRCA1 and BRCA2 targeted DNA panel and sequenced via Ion proton sequencer. Also, the CRC tissues were subjected to conventional PCR targeting the HPV Late 1 (L1) region. Our analysis revealed that the BRCA-DNA damage pathway had been altered in more than 65% of the CRC patients. Comparing tissue and blood samples from CRC patients, 25 somatic mutations were found exclusively in tissue, while 41 germline mutations were found exclusively in blood. Additionally, we identified 23 shared BRCA1/2 pathogenic (PVs) mutations in both blood and tissue samples, with a significantly higher frequency in blood samples compared to tissue samples. The most affected exon in BRCA1 was exon 10, while the most affected exons in BRCA2 were 11, 14, 18, 24, and 27 exons. Notably, we revealed an ethnic-related cluster of polymorphism variants in our population closely related to South Asian and African ethnicities. Novel PVs were identified and submitted to the ClinVar database. HPV was found in 23.8% of the CRC tissues, and 54% of HPV-positive cases had somatic BRCA1/2 PVs. The results of this research point to a possible connection between infection with HPV and BRCA1/2 mutations in the occurrence of colorectal cancer in the Egyptian population, which has a mixed ethnic background. Our data also indicate that liquid biopsy (blood samples) may be more representative than tissue samples for detecting BRCA1/2 mutations. These findings may have implications for cancer screening and the development of personalized, targeted therapies, such as PARP inhibitors, which can effectively target BRCA1/2 mutations.
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Affiliation(s)
- Amira Salah El-Din Youssef
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
| | - Abdel Rahman N Zekri
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Marwa Mohanad
- Department of Biochemistry, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, Giza, Egypt
| | - Samah A Loutfy
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
- Nanotechnology Research Center (NTRC), The British University in Egypt (BUE), El-Shorouk City, Suez Desert Road, P. O. Box 43, Cairo, Egypt
| | - Nasra F Abdel Fattah
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Mostafa H Elberry
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Asmaa A El Leithy
- Department of Medical Biotechnology, College of Biotechnology, Misr University for Science and Technology, Giza, Egypt
| | - Ahmed El-Touny
- Surgical Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Ahmed Samy Rabie
- Surgical Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Mohamed Shalaby
- Surgical Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Ayman Hanafy
- Surgical Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Mai M Lotfy
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Enas R El-Sisi
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Gharieb S El-Sayyad
- Department of Microbiology and Immunology, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt.
- Department of Microbiology and Immunology, Faculty of Pharmacy, Galala University, New Galala City, Suez, Egypt.
- Drug Microbiology Lab., Drug Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt.
| | - Auhood Nassar
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
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3
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De Marco K, Sanese P, Simone C, Grossi V. Histone and DNA Methylation as Epigenetic Regulators of DNA Damage Repair in Gastric Cancer and Emerging Therapeutic Opportunities. Cancers (Basel) 2023; 15:4976. [PMID: 37894343 PMCID: PMC10605360 DOI: 10.3390/cancers15204976] [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: 06/19/2023] [Revised: 09/25/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
Gastric cancer (GC), one of the most common malignancies worldwide, is a heterogeneous disease developing from the accumulation of genetic and epigenetic changes. One of the most critical epigenetic alterations in GC is DNA and histone methylation, which affects multiple processes in the cell nucleus, including gene expression and DNA damage repair (DDR). Indeed, the aberrant expression of histone methyltransferases and demethylases influences chromatin accessibility to the DNA repair machinery; moreover, overexpression of DNA methyltransferases results in promoter hypermethylation, which can suppress the transcription of genes involved in DNA repair. Several DDR mechanisms have been recognized so far, with homologous recombination (HR) being the main pathway involved in the repair of double-strand breaks. An increasing number of defective HR genes are emerging in GC, resulting in the identification of important determinants of therapeutic response to DDR inhibitors. This review describes how both histone and DNA methylation affect DDR in the context of GC and discusses how alterations in DDR can help identify new molecular targets to devise more effective therapeutic strategies for GC, with a particular focus on HR-deficient tumors.
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Affiliation(s)
- Katia De Marco
- Medical Genetics, National Institute of Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (K.D.M.); (P.S.)
| | - Paola Sanese
- Medical Genetics, National Institute of Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (K.D.M.); (P.S.)
| | - Cristiano Simone
- Medical Genetics, National Institute of Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (K.D.M.); (P.S.)
- Medical Genetics, Department of Precision and Regenerative Medicine and Jonic Area (DiMePRe-J), University of Bari Aldo Moro, 70124 Bari, Italy
| | - Valentina Grossi
- Medical Genetics, National Institute of Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (K.D.M.); (P.S.)
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4
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Zhunussova G, Omarbayeva N, Kaidarova D, Abdikerim S, Mit N, Kisselev I, Yergali K, Zhunussova A, Goncharova T, Abdrakhmanova A, Djansugurova L. Determination of genetic predisposition to early breast cancer in women of Kazakh ethnicity. Oncotarget 2023; 14:860-877. [PMID: 37791908 PMCID: PMC10549772 DOI: 10.18632/oncotarget.28518] [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: 05/06/2023] [Accepted: 09/21/2023] [Indexed: 10/05/2023] Open
Abstract
Breast cancer (BC) is the most common type of cancer among women in Kazakhstan. To date, little data are available on the spectrum of genetic variation in Kazakh women with BC. We aimed to identify population-specific genetic markers associated with the risk of developing early-onset BC and test their association with clinical and prognostic factors. The study included 224 Kazakh women diagnosed with BC (≤40 age). Entire coding regions (>1700 exons) and the flanking noncoding regions of 94 cancer-associated genes were sequenced from blood DNA using MiSeq platform. We identified 38 unique pathogenic variants (PVs) in 13 different cancer-predisposing genes among 57 patients (25.4%), of which 6 variants were novel. In total, 12 of the 38 distinct PVs were detected recurrently, including BRCA1 c.5266dup, c.5278-2del, and c.2T>C, and BRCA2 c.9409dup and c.9253del that may be founder in this population. BRCA1 carriers were significantly more likely to develop triple-negative BC (OR = 6.61, 95% CI 2.44-17.91, p = 0.0002) and have family history of BC (OR = 3.17, 95% CI 1.14-8.76, p = 0.03) compared to non-carriers. This study allowed the identification of PVs specific to early-onset BC, which may be used as a foundation to develop regional expertise and diagnostic tools for early detection of BC in young Kazakh women.
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Affiliation(s)
- Gulnur Zhunussova
- Laboratory of Molecular Genetics, Institute of Genetics and Physiology, Almaty 050060, Kazakhstan
- Al-Farabi Kazakh National University, Almaty 050060, Kazakhstan
| | - Nazgul Omarbayeva
- Kazakh Institute of Oncology and Radiology, Almaty 050060, Kazakhstan
- Asfendiyarov Kazakh National Medical University, Almaty 050060, Kazakhstan
| | - Dilyara Kaidarova
- Kazakh Institute of Oncology and Radiology, Almaty 050060, Kazakhstan
- Asfendiyarov Kazakh National Medical University, Almaty 050060, Kazakhstan
| | - Saltanat Abdikerim
- Laboratory of Molecular Genetics, Institute of Genetics and Physiology, Almaty 050060, Kazakhstan
- Al-Farabi Kazakh National University, Almaty 050060, Kazakhstan
| | - Natalya Mit
- Laboratory of Molecular Genetics, Institute of Genetics and Physiology, Almaty 050060, Kazakhstan
| | - Ilya Kisselev
- Laboratory of Molecular Genetics, Institute of Genetics and Physiology, Almaty 050060, Kazakhstan
| | - Kanagat Yergali
- Laboratory of Molecular Genetics, Institute of Genetics and Physiology, Almaty 050060, Kazakhstan
| | - Aigul Zhunussova
- Laboratory of Molecular Genetics, Institute of Genetics and Physiology, Almaty 050060, Kazakhstan
| | | | - Aliya Abdrakhmanova
- Kazakh Institute of Oncology and Radiology, Almaty 050060, Kazakhstan
- Asfendiyarov Kazakh National Medical University, Almaty 050060, Kazakhstan
| | - Leyla Djansugurova
- Laboratory of Molecular Genetics, Institute of Genetics and Physiology, Almaty 050060, Kazakhstan
- Al-Farabi Kazakh National University, Almaty 050060, Kazakhstan
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5
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Bilyalov A, Nikolaev S, Danishevich A, Khatkov I, Makhmudov K, Isakova Z, Bakirov N, Omurbaev E, Osipova A, Ramaldanov R, Shagimardanova E, Kiyasov A, Gusev O, Bodunova N. The Spectrum of Germline Nucleotide Variants in Gastric Cancer Patients in the Kyrgyz Republic. Curr Issues Mol Biol 2023; 45:6383-6394. [PMID: 37623222 PMCID: PMC10453583 DOI: 10.3390/cimb45080403] [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: 06/08/2023] [Revised: 07/11/2023] [Accepted: 07/30/2023] [Indexed: 08/26/2023] Open
Abstract
Gastric cancer is a major challenge in modern oncology due to its high detection rate and prevalence. While sporadic cases make up the majority of gastric cancer, hereditary gastric cancer is caused by germline mutations in several genes linked to different syndromes. Thus, identifying hereditary forms of gastric cancer is considered crucial globally. A survey study using NGS-based analysis was conducted to determine the frequency of different types of hereditary gastric cancer in the yet-unstudied Kyrgyz population. The study cohort included 113 patients with diagnosed gastric cancer from Kyrgyzstan. The age of patients was 57.6 ± 8.9. Next-generation sequencing analysis of genomic DNA was performed using a custom Roche NimbleGen enrichment panel. The results showed that 6.2% (7/113) of the patients had pathogenic or likely pathogenic genetic variants. Additionally, 3.5% (4/113) of the patients carried heterozygous pathogenic/likely pathogenic variants in high penetrance genes, such as TP53, POLD1, RET, and BRCA2. Moreover, 2.7% (3/113) of the patients carried heterozygous mutations in genes linked to autosomal recessive conditions, specifically PALB2, FANCA, and FANCD2. We have not identified any genetic variants in hereditary GC-associated genes: CDH1, STK11, SMAD4, BMPRIA, APC, MLH1, and others. Our study included patients with sporadic features of GC. The use of recognized criteria (NCCN, Gastric Cancer, Version 2.2022) would increase the number of identified genetic variants in hereditary GC-associated genes. Further research is required to determine the clinical relevance of the genetic variants identified in the current study.
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Affiliation(s)
- Airat Bilyalov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (K.M.); (E.S.); (A.K.); (O.G.)
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia; (S.N.); (A.D.); (I.K.); (A.O.); (N.B.)
| | - Sergey Nikolaev
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia; (S.N.); (A.D.); (I.K.); (A.O.); (N.B.)
| | - Anastasiia Danishevich
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia; (S.N.); (A.D.); (I.K.); (A.O.); (N.B.)
| | - Igor Khatkov
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia; (S.N.); (A.D.); (I.K.); (A.O.); (N.B.)
| | - Komron Makhmudov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (K.M.); (E.S.); (A.K.); (O.G.)
| | - Zhainagul Isakova
- Research Institute of Molecular Biology and Medicine, Bishkek 720005, Kyrgyzstan;
| | - Nurbek Bakirov
- National Center of Oncology and Hematology of the Ministry of Health of the Kyrgyz Republic, Bishkek 720055, Kyrgyzstan; (N.B.); (E.O.); (R.R.)
| | - Ernis Omurbaev
- National Center of Oncology and Hematology of the Ministry of Health of the Kyrgyz Republic, Bishkek 720055, Kyrgyzstan; (N.B.); (E.O.); (R.R.)
| | - Alena Osipova
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia; (S.N.); (A.D.); (I.K.); (A.O.); (N.B.)
- Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
| | - Ramaldan Ramaldanov
- National Center of Oncology and Hematology of the Ministry of Health of the Kyrgyz Republic, Bishkek 720055, Kyrgyzstan; (N.B.); (E.O.); (R.R.)
| | - Elena Shagimardanova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (K.M.); (E.S.); (A.K.); (O.G.)
| | - Andrey Kiyasov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (K.M.); (E.S.); (A.K.); (O.G.)
| | - Oleg Gusev
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (K.M.); (E.S.); (A.K.); (O.G.)
- Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
- Endocrinology Research Centre, 117036 Moscow, Russia
| | - Natalia Bodunova
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia; (S.N.); (A.D.); (I.K.); (A.O.); (N.B.)
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6
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Tsang ES, Csizmok V, Williamson LM, Pleasance E, Topham JT, Karasinska JM, Titmuss E, Schrader I, Yip S, Tessier-Cloutier B, Mungall K, Ng T, Sun S, Lim HJ, Loree JM, Laskin J, Marra MA, Jones SJM, Schaeffer DF, Renouf DJ. Homologous recombination deficiency signatures in gastrointestinal and thoracic cancers correlate with platinum therapy duration. NPJ Precis Oncol 2023; 7:31. [PMID: 36964191 PMCID: PMC10039042 DOI: 10.1038/s41698-023-00368-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 03/08/2023] [Indexed: 03/26/2023] Open
Abstract
There is emerging evidence about the predictive role of homologous recombination deficiency (HRD), but this is less defined in gastrointestinal (GI) and thoracic malignancies. We reviewed whole genome (WGS) and transcriptomic (RNA-Seq) data from advanced GI and thoracic cancers in the Personalized OncoGenomics trial (NCT02155621) to evaluate HRD scores and single base substitution (SBS)3, which is associated with BRCA1/2 mutations and potentially predictive of defective HRD. HRD scores were calculated by sum of loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions scores. Regression analyses examined the association between HRD and time to progression on platinum (TTPp). We included 223 patients with GI (n = 154) or thoracic (n = 69) malignancies. TTPp was associated with SBS3 (p < 0.01) but not HRD score in patients with GI malignancies, whereas neither was associated with TTPp in thoracic malignancies. Tumors with gBRCA1/2 mutations and a somatic second alteration exhibited high SBS3 and HRD scores, but these signatures were also present in several tumors with germline but no somatic second alterations, suggesting silencing of the wild-type allele or BRCA1/2 haploinsufficiency. Biallelic inactivation of an HR gene, including loss of XRCC2 and BARD1, was identified in BRCA1/2 wild-type HRD tumors and these patients had prolonged response to platinum. Thoracic cases with high HRD score were associated with high RECQL5 expression (p ≤ 0.025), indicating another potential mechanism of HRD. SBS3 was more strongly associated with TTPp in patients with GI malignancies and may be complementary to using HRD and BRCA status in identifying patients who benefit from platinum therapy.
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Affiliation(s)
- Erica S Tsang
- Department of Medical Oncology, BC Cancer, Vancouver, BC, Canada
- Pancreas Centre BC, Vancouver, BC, Canada
| | - Veronika Csizmok
- Canada's Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, BC, Canada
| | - Laura M Williamson
- Canada's Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, BC, Canada
| | - Erin Pleasance
- Canada's Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, BC, Canada
| | | | | | - Emma Titmuss
- Canada's Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, BC, Canada
| | - Intan Schrader
- Canada's Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, BC, Canada
| | - Stephen Yip
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Basile Tessier-Cloutier
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Karen Mungall
- Canada's Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, BC, Canada
| | - Tony Ng
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Sophie Sun
- Department of Medical Oncology, BC Cancer, Vancouver, BC, Canada
| | - Howard J Lim
- Department of Medical Oncology, BC Cancer, Vancouver, BC, Canada
| | - Jonathan M Loree
- Department of Medical Oncology, BC Cancer, Vancouver, BC, Canada
| | - Janessa Laskin
- Department of Medical Oncology, BC Cancer, Vancouver, BC, Canada
| | - Marco A Marra
- Canada's Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, BC, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Steven J M Jones
- Canada's Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, BC, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, BC, Canada
| | - David F Schaeffer
- Pancreas Centre BC, Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Daniel J Renouf
- Department of Medical Oncology, BC Cancer, Vancouver, BC, Canada.
- Pancreas Centre BC, Vancouver, BC, Canada.
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Wang N, Yang Y, Jin D, Zhang Z, Shen K, Yang J, Chen H, Zhao X, Yang L, Lu H. PARP inhibitor resistance in breast and gynecological cancer: Resistance mechanisms and combination therapy strategies. Front Pharmacol 2022; 13:967633. [PMID: 36091750 PMCID: PMC9455597 DOI: 10.3389/fphar.2022.967633] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/04/2022] [Indexed: 12/02/2022] Open
Abstract
Breast cancer and gynecological tumors seriously endanger women’s physical and mental health, fertility, and quality of life. Due to standardized surgical treatment, chemotherapy, and radiotherapy, the prognosis and overall survival of cancer patients have improved compared to earlier, but the management of advanced disease still faces great challenges. Recently, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) have been clinically approved for breast and gynecological cancer patients, significantly improving their quality of life, especially of patients with BRCA1/2 mutations. However, drug resistance faced by PARPi therapy has hindered its clinical promotion. Therefore, developing new drug strategies to resensitize cancers affecting women to PARPi therapy is the direction of our future research. Currently, the effects of PARPi in combination with other drugs to overcome drug resistance are being studied. In this article, we review the mechanisms of PARPi resistance and summarize the current combination of clinical trials that can improve its resistance, with a view to identify the best clinical treatment to save the lives of patients.
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Affiliation(s)
- Nannan Wang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yan Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Dongdong Jin
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Zhengzhou Key Laboratory of Endometrial Disease Prevention and Treatment, Zhengzhou, China
| | - Zhenan Zhang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ke Shen
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jing Yang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Huanhuan Chen
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xinyue Zhao
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Li Yang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Zhengzhou Key Laboratory of Endometrial Disease Prevention and Treatment, Zhengzhou, China
- *Correspondence: Li Yang, ; Huaiwu Lu,
| | - Huaiwu Lu
- Department of Gynaecological Oncology, Sun Yat Sen Memorial Hospital, Guangzhou, China
- *Correspondence: Li Yang, ; Huaiwu Lu,
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8
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Silva-Veiga FM, Miranda CS, Vasques-Monteiro IML, Souza-Tavares H, Martins FF, Daleprane JB, Souza-Mello V. Peroxisome proliferator-activated receptor-alpha activation and dipeptidyl peptidase-4 inhibition target dysbiosis to treat fatty liver in obese mice. World J Gastroenterol 2022; 28:1814-1829. [PMID: 35633911 PMCID: PMC9099201 DOI: 10.3748/wjg.v28.i17.1814] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/04/2022] [Accepted: 03/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Obesity and comorbidities onset encompass gut dysbiosis, altered intestinal permeability, and endotoxemia. Treatments that target gut dysbiosis can cope with obesity and nonalcoholic fatty liver disease (NAFLD) management. Peroxisome proliferator-activated receptor (PPAR)-alpha activation and dipeptidyl-peptidase-4 (DPP-4) inhibition alleviate NAFLD, but the mechanism may involve gut microbiota modulation and merits further investigation. AIM To address the effects of PPAR-alpha activation and DPP-4 inhibition (isolated or combined) upon the gut-liver axis, emphasizing inflammatory pathways in NAFLD management in high-fat-fed C57BL/6J mice. METHODS Male C57BL/6J mice were fed a control diet (C, 10% of energy as lipids) or a high-fat diet (HFD, 50% of energy as lipids) for 12 wk, when treatments started, forming the groups: C, HF, HFA (HFD + PPAR-alpha agonist WY14643, 2.5 mg/kg body mass), HFL (HFD + DPP-4 inhibitor linagliptin, 15 mg/kg body mass), and HFC (HFD + the combination of WY14643 and linagliptin). RESULTS The HFD was obesogenic compared to the C diet. All treatments elicited significant body mass loss, and the HFC group showed similar body mass to the C group. All treatments tackled oral glucose intolerance and raised plasma glucagon-like peptide-1 concentrations. These metabolic benefits restored Bacteroidetes/Firmicutes ratio, resulting in increased goblet cells per area of the large intestine and reduced lipopolysaccharides concentrations in treated groups. At the gene level, treated groups showed higher intestinal Mucin 2, Occludin, and Zo-1 expression than the HFD group. The reduced endotoxemia suppressed inflammasome and macrophage gene expression in the liver of treated animals. These observations complied with the mitigation of liver steatosis and reduced hepatic triacylglycerol, reassuring the role of the proposed treatments on NAFLD mitigation. CONCLUSION PPAR alpha activation and DPP-4 inhibition (isolated or combined) tackled NAFLD in diet-induced obese mice by restoration of gut-liver axis. The reestablishment of the intestinal barrier and the rescued phylogenetic gut bacteria distribution mitigated liver steatosis through anti-inflammatory signals. These results can cope with NAFLD management by providing pre-clinical evidence that drugs used to treat obesity comorbidities can help to alleviate this silent and harmful liver disease.
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Affiliation(s)
- Flavia Maria Silva-Veiga
- Department of Anatomy, Institute of Biology, State University of Rio de Janeiro, Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Rio de Janeiro 20551-030, Brazil
| | - Carolline Santos Miranda
- Department of Anatomy, Institute of Biology, State University of Rio de Janeiro, Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Rio de Janeiro 20551-030, Brazil
| | - Isabela Macedo Lopes Vasques-Monteiro
- Department of Anatomy, Institute of Biology, State University of Rio de Janeiro, Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Rio de Janeiro 20551-030, Brazil
| | - Henrique Souza-Tavares
- Department of Anatomy, Institute of Biology, State University of Rio de Janeiro, Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Rio de Janeiro 20551-030, Brazil
| | - Fabiane Ferreira Martins
- Department of Anatomy, Institute of Biology, State University of Rio de Janeiro, Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Rio de Janeiro 20551-030, Brazil
| | - Julio Beltrame Daleprane
- Department of Clinical and Toxicology Analysis, State University of Rio de Janeiro, Nutrition Institute, State University of Rio de Janeiro, Nutrition Institute, University of Sao Paulo, Rio de Janeiro 20551-030, Brazil
| | - Vanessa Souza-Mello
- Department of Anatomy, Institute of Biology, State University of Rio de Janeiro, Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Rio de Janeiro 20551-030, Brazil
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9
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Kim W, Kidambi T, Lin J, Idos G. Genetic Syndromes Associated with Gastric Cancer. Gastrointest Endosc Clin N Am 2022; 32:147-162. [PMID: 34798983 DOI: 10.1016/j.giec.2021.08.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Although environmental factors such as Helicobacter pylori, tobacco, and diet are major contributors to the development of gastric cancer (GC) worldwide, it is estimated that up to 5% to 10% of GC cases are due to an underlying hereditary susceptibility caused by germline pathogenic variants. Hereditary diffuse gastric cancer (HDGC) caused by germline pathogenic variants in the CDH1 gene is the principal familial GC syndrome. However, other well-established hereditary gastrointestinal syndromes have been associated with an increased risk of GC. In this review, we will discuss the latest insights and advances in our understanding of GC associated with Lynch syndrome (LS), familial adenomatous polyposis (FAP), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), Li-Fraumeni syndrome (LFS), Peutz-Jeghers syndrome (PJS), and juvenile polyposis syndrome (JPS). We will also discuss the emergence of new associations of the homologous recombination pathway genes (BRCA1, BRCA2) with GC.
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Affiliation(s)
- Woojin Kim
- City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Trilokesh Kidambi
- City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - James Lin
- City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Gregory Idos
- City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA.
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10
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Dahlmann M, Gambara G, Brzezicha B, Popp O, Pachmayr E, Wedeken L, Pflaume A, Mokritzkij M, Gül-Klein S, Brandl A, Schweiger-Eisbacher C, Mertins P, Hoffmann J, Keilholz U, Walther W, Regenbrecht C, Rau B, Stein U. Peritoneal metastasis of colorectal cancer (pmCRC): identification of predictive molecular signatures by a novel preclinical platform of matching pmCRC PDX/PD3D models. Mol Cancer 2021; 20:129. [PMID: 34670579 PMCID: PMC8529724 DOI: 10.1186/s12943-021-01430-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 09/16/2021] [Indexed: 01/14/2023] Open
Affiliation(s)
- Mathias Dahlmann
- Translational Oncology of Solid Tumors, Experimental and Clinical Research Center, Charité - University Medicine Berlin, and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Str. 10, 13125, Berlin, Germany.,German Cancer Consortium (DKTK), Heidelberg, im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Guido Gambara
- German Cancer Consortium (DKTK), Heidelberg, im Neuenheimer Feld 280, 69120, Heidelberg, Germany.,Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, Invalidenstr. 80, 10117, Berlin, Germany
| | | | - Oliver Popp
- Proteomics Platform, Max-Delbrück-Center for Molecular Medicine and Berlin Institute of Health, Robert-Rössle-Str. 10, 13125, Berlin, Germany
| | - Eva Pachmayr
- Department of Surgery, Charité - University Medicine Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Lena Wedeken
- CELLphenomics GmbH, Robert-Rössle-Str. 10, 13125, Berlin, Germany
| | - Alina Pflaume
- CELLphenomics GmbH, Robert-Rössle-Str. 10, 13125, Berlin, Germany
| | - Margarita Mokritzkij
- Translational Oncology of Solid Tumors, Experimental and Clinical Research Center, Charité - University Medicine Berlin, and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Str. 10, 13125, Berlin, Germany
| | - Safak Gül-Klein
- Department of Surgery, Charité - University Medicine Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Andreas Brandl
- Department of Surgery, Charité - University Medicine Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Caroline Schweiger-Eisbacher
- German Cancer Consortium (DKTK), Heidelberg, im Neuenheimer Feld 280, 69120, Heidelberg, Germany.,Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, Invalidenstr. 80, 10117, Berlin, Germany
| | - Philipp Mertins
- Proteomics Platform, Max-Delbrück-Center for Molecular Medicine and Berlin Institute of Health, Robert-Rössle-Str. 10, 13125, Berlin, Germany
| | - Jens Hoffmann
- EPO GmbH Berlin-Buch, Robert-Rössle-Str. 10, 13125, Berlin, Germany
| | - Ulrich Keilholz
- German Cancer Consortium (DKTK), Heidelberg, im Neuenheimer Feld 280, 69120, Heidelberg, Germany.,Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, Invalidenstr. 80, 10117, Berlin, Germany
| | - Wolfgang Walther
- Translational Oncology of Solid Tumors, Experimental and Clinical Research Center, Charité - University Medicine Berlin, and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Str. 10, 13125, Berlin, Germany
| | - Christian Regenbrecht
- CELLphenomics GmbH, Robert-Rössle-Str. 10, 13125, Berlin, Germany.,Institute of Pathology, University Medicine Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany
| | - Beate Rau
- Department of Surgery, Charité - University Medicine Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Ulrike Stein
- Translational Oncology of Solid Tumors, Experimental and Clinical Research Center, Charité - University Medicine Berlin, and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Str. 10, 13125, Berlin, Germany. .,German Cancer Consortium (DKTK), Heidelberg, im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
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11
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Playing on the Dark Side: SMYD3 Acts as a Cancer Genome Keeper in Gastrointestinal Malignancies. Cancers (Basel) 2021; 13:cancers13174427. [PMID: 34503239 PMCID: PMC8430692 DOI: 10.3390/cancers13174427] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/29/2021] [Accepted: 08/30/2021] [Indexed: 01/17/2023] Open
Abstract
Simple Summary The activity of SMYD3 in promoting carcinogenesis is currently under debate. Growing evidence seems to confirm that SMYD3 overexpression correlates with poor prognosis, cancer growth and invasion, especially in gastrointestinal tumors. In this review, we dissect the emerging role played by SMYD3 in the regulation of cell cycle and DNA damage response by promoting homologous recombination (HR) repair and hence cancer cell genomic stability. Considering the crucial role of PARP1 in other DNA repair mechanisms, we also discuss a recently evaluated synthetic lethality approach based on the combined use of SMYD3 and PARP inhibitors. Interestingly, a significant proportion of HR-proficient gastrointestinal tumors expressing high levels of SMYD3 from the PanCanAtlas dataset seem to be eligible for this innovative strategy. This promising approach could be taken advantage of for therapeutic applications of SMYD3 inhibitors in cancer treatment. Abstract The SMYD3 methyltransferase has been found overexpressed in several types of cancers of the gastrointestinal (GI) tract. While high levels of SMYD3 have been positively correlated with cancer progression in cellular and advanced mice models, suggesting it as a potential risk and prognosis factor, its activity seems dispensable for autonomous in vitro cancer cell proliferation. Here, we present an in-depth analysis of SMYD3 functional role in the regulation of GI cancer progression. We first describe the oncogenic activity of SMYD3 as a transcriptional activator of genes involved in tumorigenesis, cancer development and transformation and as a co-regulator of key cancer-related pathways. Then, we dissect its role in orchestrating cell cycle regulation and DNA damage response (DDR) to genotoxic stress by promoting homologous recombination (HR) repair, thereby sustaining cancer cell genomic stability and tumor progression. Based on this evidence and on the involvement of PARP1 in other DDR mechanisms, we also outline a synthetic lethality approach consisting of the combined use of SMYD3 and PARP inhibitors, which recently showed promising therapeutic potential in HR-proficient GI tumors expressing high levels of SMYD3. Overall, these findings identify SMYD3 as a promising target for drug discovery.
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