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1
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Mancuso FM, Higareda-Almaraz JC, Canal-Noguer P, Bertossi A, Perera-Lluna A, Roehrl MHA, Kruusmaa K. Colorectal Adenoma Subtypes Exhibit Signature Molecular Profiles: Unique Insights into the Microenvironment of Advanced Precancerous Lesions for Early Detection Applications. Cancers (Basel) 2025; 17:654. [PMID: 40002249 PMCID: PMC11852906 DOI: 10.3390/cancers17040654] [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: 12/17/2024] [Revised: 01/24/2025] [Accepted: 02/08/2025] [Indexed: 02/27/2025] Open
Abstract
Background: Colorectal cancer (CRC) is characterized by the uncontrolled growth of malignant colonic or rectal crypt epithelium. About 85% of CRCs evolve through a stepwise progression from advanced precancerous adenoma lesions. A better understanding of the evolution from adenoma to carcinoma can provide a window of opportunity not only for early detection and therapeutic intervention but potentially also for cancer prevention strategies. Methods: This study investigates the heterogeneous methylation, copy-number alteration (CNA), and mutation signals of histological adenoma subtypes in the context of progression from normal colon to advanced precancerous lesions (APLs) and early-stage CRC. Results: Differential methylation analysis revealed 2321 significantly altered regions among APLs: 137 hypermethylated regions in serrated vs. tubular, 2093 in serrated vs. tubulovillous, and 91 in tubular vs. tubulovillous adenoma subtypes. The most differentiating pathways for serrated adenomas belonged to cAMP signaling and the regulation of pluripotency of stem cells, while regions separating tubular and tubulovillous subtypes were enriched for WNT signaling. CNA events were mostly present in tubular or tubulovillous adenomas, with the most frequent signals being seen in chromosomes 7, 12, 19, and 20. In contrast, early-stage CRC exhibited signals in chromosomes 7, 8, and 20, indicating different processes between APL and early-stage CRC. Mutations reinforce subtype-level differences, showing specific alterations in each subtype. Conclusions: These findings are especially important for developing early detection or cancer prevention tests trying to capture adenoma signatures.
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Affiliation(s)
| | | | - Pol Canal-Noguer
- Universal Diagnostics S.A., 41013 Seville, Spain; (F.M.M.); (J.C.H.-A.); (P.C.-N.)
| | - Arianna Bertossi
- Research & Development, Universal Diagnostics d.o.o., 1000 Ljubljana, Slovenia;
| | - Alexandre Perera-Lluna
- B2SLab, Institute for Research and Innovation in Health (IRIS), Universitat Politècnica de Catalunya—BarcelonaTech, 08028 Barcelona, Spain;
- Networking Biomedical Research Centre in the Subject Area of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029 Madrid, Spain
| | | | - Kristi Kruusmaa
- Research & Development, Universal Diagnostics d.o.o., 1000 Ljubljana, Slovenia;
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2
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Sutherland RL, Boyne DJ, Brenner DR, Cheung WY. The Impact of BRAF Mutation Status on Survival Outcomes and Treatment Patterns among Metastatic Colorectal Cancer Patients in Alberta, Canada. Cancers (Basel) 2023; 15:5748. [PMID: 38136294 PMCID: PMC10741517 DOI: 10.3390/cancers15245748] [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: 10/19/2023] [Revised: 11/27/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
Colorectal cancer presents via multiple different clinical phenotypes that can arise from a variety of different genetic and molecular alterations. The aim of this study was to describe survival outcomes and treatment patterns of metastatic colorectal cancer (mCRC) patients by v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation status. The Alberta Cancer Registry was used to identify all patients >18 years old who had been diagnosed with mCRC in Alberta between 1 January 2017 and 31 December 2019 and had received at least one cycle of systemic therapy. Treatment patterns were compared between wild-type and mutant BRAF mCRC patients. Cox regression models and Kaplan-Meier curves were created to assess survival differences by both treatment pattern and BRAF status. A total of 488 patients were identified with mCRC, of which 42 (11.4%) were confirmed to have a BRAF mutation. The most common first-line treatment regimen was either capecitabine and oxaliplatin (CAPOX) or leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (FOLFOX). The median overall survival for mCRC patients was 20.01 months. Mutant BRAF patients had a median survival of 8.21 months compared to 20.03 months among those with wild-type BRAF. BRAF mutations among mCRC patients are associated with a considerably poor prognosis, reinforcing the need for clinical BRAF testing among newly diagnosed patients to better understand their prognosis.
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Affiliation(s)
- R. Liam Sutherland
- Department of Community Health Sciences, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Devon J. Boyne
- Department of Oncology, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Darren R. Brenner
- Department of Community Health Sciences, University of Calgary, Calgary, AB T2N 4N1, Canada
- Department of Oncology, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Winson Y. Cheung
- Department of Community Health Sciences, University of Calgary, Calgary, AB T2N 4N1, Canada
- Department of Oncology, University of Calgary, Calgary, AB T2N 4N1, Canada
- Department of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
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3
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Katagiri A, Suzuki N, Nakatani S, Kikuchi K, Fujiwara T, Gocho T, Konda K, Inoki K, Yamamura F, Yoshida H. Submucosal Injection Using Epinephrine-Added Saline in Cold Snare Polypectomy for Colorectal Polyps Shortens Time Required for Resection: A Randomized Controlled Study. Cureus 2023; 15:e39164. [PMID: 37332405 PMCID: PMC10276175 DOI: 10.7759/cureus.39164] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/17/2023] [Indexed: 06/20/2023] Open
Abstract
AIMS Immediate bleeding after cold snare polypectomy (CSP) for colorectal polyps might interfere with confirmation of residuals and prolong the time required for resection. We investigated whether submucosal epinephrine-added saline injection reduces the time required for the CSP procedure. METHODS We conducted a single-center, prospective, randomized controlled trial (clinical trial registration number: UMIN000046770). Patients with colorectal polyps ≤ 10 mm were randomly allocated to either CSP with epinephrine-added submucosal injection (CEMR group) or conventional CSP (CSP group). The primary outcome was the time required for resection defined as the time from the initiation of resection (the first insertion of the snare in the CSP group or the injection needle in the CEMR group) to the end of resection (confirming complete resection endoscopically after recognizing the cessation of immediate bleeding) in each lesion, and the secondary outcome was the time to spontaneous cessation of immediate bleeding after resection defined as the time from ensnaring the lesion to confirming the spontaneous cessation of immediate bleeding. RESULTS A total of 126 patients were randomly assigned. Finally, 261 lesions in 118 patients (CEMR group, n = 59; CSP group, n = 59) were analyzed. The time required for resection calculated using the least-square mean was significantly shorter in the CEMR group (106.3 s, 95% CI 97.5 to 115.4 s) than in the CSP group (130.9 s, 95% CI 121.2 to 140.7 s) (P < 0.001). The time to spontaneous cessation of immediate bleeding was also significantly shorter in the CEMR group (20.4 s, 95% CI 14.3 to 26.5 s) than in the CSP group (74.2 s, 95% CI 67.6 to 80.7 s) (P < 0.001). Neither group had cases requiring hemostasis, perforation, or delayed bleeding. CONCLUSIONS CEMR shortened the time for resection by shortening the time to cessation of immediate bleeding compared with conventional CSP in colorectal polyps ≤ 10 mm.
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Affiliation(s)
- Atsushi Katagiri
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, JPN
| | - Norihiro Suzuki
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, JPN
| | - Shinya Nakatani
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, JPN
| | - Kazuo Kikuchi
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, JPN
| | - Takahisa Fujiwara
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, JPN
| | - Toshihiko Gocho
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, JPN
| | - Kenichi Konda
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, JPN
| | - Kazuya Inoki
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, JPN
| | - Fuyuhiko Yamamura
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, JPN
| | - Hitoshi Yoshida
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, JPN
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4
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Van Herck Y, Feyaerts A, Alibhai S, Papamichael D, Decoster L, Lambrechts Y, Pinchuk M, Bechter O, Herrera-Caceres J, Bibeau F, Desmedt C, Hatse S, Wildiers H. Is cancer biology different in older patients? THE LANCET HEALTHY LONGEVITY 2021; 2:e663-e677. [DOI: 10.1016/s2666-7568(21)00179-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/14/2021] [Accepted: 07/15/2021] [Indexed: 12/13/2022]
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Abstract
Mortality from colorectal cancer is reduced through screening and early detection; moreover, removal of neoplastic lesions can reduce cancer incidence. While understanding of the risk factors, pathogenesis, and precursor lesions of colorectal cancer has advanced, the cause of the recent increase in cancer among young adults is largely unknown. Multiple invasive, semi- and non-invasive screening modalities have emerged over the past decade. The current emphasis on quality of colonoscopy has improved the effectiveness of screening and prevention, and the role of new technologies in detection of neoplasia, such as artificial intelligence, is rapidly emerging. The overall screening rates in the US, however, are suboptimal, and few interventions have been shown to increase screening uptake. This review provides an overview of colorectal cancer, the current status of screening efforts, and the tools available to reduce mortality from colorectal cancer.
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Affiliation(s)
- Priyanka Kanth
- Division of Gastroenterology, University of Utah, Salt Lake City, UT, USA
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - John M Inadomi
- Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA
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6
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Annexin A10 and HES-1 Immunohistochemistry in Right-sided Traditional Serrated Adenomas Suggests an Origin From Sessile Serrated Adenoma. Appl Immunohistochem Mol Morphol 2021; 28:296-302. [PMID: 30653033 DOI: 10.1097/pai.0000000000000740] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
There is increasing body of evidence to suggest that some colonic serrated polyps do not fit morphologically with any of the proposed categories for serrated polyps recommended by the World Health Organization. Most of these polyps have morphologic features of traditional serrated adenoma (TSA) admixed with areas resembling sessile serrated adenoma (SSA) or hyperplastic polyp (HP). Based on these findings it has been suggested that at least some TSAs may arise in association with precursor HP or SSA lesions, particularly those that develop in right colon. To further evaluate this hypothesis, 39 serrated polyps from right side of the colon (cecum, ascending, and transverse colon) with mixed features of TSA and SSA were evaluated by 2 immunostains previously shown to represent markers of SSA. One is Annexin A10 which shows upregulated expression in SSA and the other is Hes-1 which is shown to be down regulated in SSA. The expression patterns of these markers were evaluated in SSA and TSA components of hybrid polyps and compared with control groups (pure SSAs and TSAs of right colon). SSA component in hybrid polyps did not show any significant difference in staining pattern compared with that seen in TSA component of hybrid polyps or in pure TSA polyps. These findings further support the hypothesis that recognizes SSA as a precursor lesion for TSA in the right colon.
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Ahmad R, Singh JK, Wunnava A, Al-Obeed O, Abdulla M, Srivastava SK. Emerging trends in colorectal cancer: Dysregulated signaling pathways (Review). Int J Mol Med 2021; 47:14. [PMID: 33655327 PMCID: PMC7834960 DOI: 10.3892/ijmm.2021.4847] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 12/14/2020] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third most frequently detected type of cancer, and the second most common cause of cancer‑related mortality globally. The American Cancer Society predicted that approximately 147,950 individuals would be diagnosed with CRC, out of which 53,200 individuals would succumb to the disease in the USA alone in 2020. CRC‑related mortality ranks third among both males and females in the USA. CRC arises from 3 major pathways: i) The adenoma‑carcinoma sequence; ii) serrated pathway; and iii) the inflammatory pathway. The majority of cases of CRC are sporadic and result from risk factors, such as a sedentary lifestyle, obesity, processed diets, alcohol consumption and smoking. CRC is also a common preventable cancer. With widespread CRC screening, the incidence and mortality from CRC have decreased in developed countries. However, over the past few decades, CRC cases and mortality have been on the rise in young adults (age, <50 years). In addition, CRC cases are increasing in developing countries with a low gross domestic product (GDP) due to lifestyle changes. CRC is an etiologically heterogeneous disease classified by tumor location and alterations in global gene expression. Accumulating genetic and epigenetic perturbations and aberrations over time in tumor suppressor genes, oncogenes and DNA mismatch repair genes could be a precursor to the onset of colorectal cancer. CRC can be divided as sporadic, familial, and inherited depending on the origin of the mutation. Germline mutations in APC and MLH1 have been proven to play an etiological role, resulting in the predisposition of individuals to CRC. Genetic alterations cause the dysregulation of signaling pathways leading to drug resistance, the inhibition of apoptosis and the induction of proliferation, invasion and migration, resulting in CRC development and metastasis. Timely detection and effective precision therapies based on the present knowledge of CRC is essential for successful treatment and patient survival. The present review presents the CRC incidence, risk factors, dysregulated signaling pathways and targeted therapies.
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Affiliation(s)
- Rehan Ahmad
- Colorectal Research Chair, Department of Surgery, King Saud University College of Medicine, Riyadh 11472, Saudi Arabia
| | - Jaikee Kumar Singh
- Department of Biosciences, Manipal University Jaipur, Jaipur, Rajasthan 303007, India
| | - Amoolya Wunnava
- Department of Biosciences, Manipal University Jaipur, Jaipur, Rajasthan 303007, India
| | - Omar Al-Obeed
- Colorectal Research Chair, Department of Surgery, King Saud University College of Medicine, Riyadh 11472, Saudi Arabia
| | - Maha Abdulla
- Colorectal Research Chair, Department of Surgery, King Saud University College of Medicine, Riyadh 11472, Saudi Arabia
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8
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Pitchumoni CS. Colorectal Cancer. GERIATRIC GASTROENTEROLOGY 2021:1963-1989. [DOI: 10.1007/978-3-030-30192-7_80] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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9
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You T, Song K, Guo W, Fu Y, Wang K, Zheng H, Yang J, Jin L, Qi L, Guo Z, Zhao W. A Qualitative Transcriptional Signature for Predicting CpG Island Methylator Phenotype Status of the Right-Sided Colon Cancer. Front Genet 2020; 11:971. [PMID: 33193579 PMCID: PMC7658404 DOI: 10.3389/fgene.2020.00971] [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: 05/17/2020] [Accepted: 07/31/2020] [Indexed: 12/24/2022] Open
Abstract
A part of colorectal cancer which is characterized by simultaneous numerous hypermethylation CpG islands sites is defined as CpG island methylator phenotype (CIMP) status. Stage II and III CIMP−positive (CIMP+) right-sided colon cancer (RCC) patients have a better prognosis than CIMP−negative (CIMP−) RCC treated with surgery alone. However, there is no gold standard available in defining CIMP status. In this work, we selected the gene pairs whose relative expression orderings (REOs) were associated with the CIMP status, to develop a qualitative transcriptional signature to individually predict CIMP status for stage II and III RCC. Based on the REOs of gene pairs, a signature composed of 19 gene pairs was developed to predict the CIMP status of RCC through a feature selection process. A sample is predicted as CIMP+ when the gene expression orderings of at least 12 gene pairs vote for CIMP+; otherwise the CIMP−. The difference of prognosis between the predicted CIMP+ and CIMP− groups was more significantly different than the original CIMP status groups. There were more differential methylation and expression characteristics between the two predicted groups. The hierarchical clustering analysis showed that the signature could perform better for predicting CIMP status of RCC than current methods. In conclusion, the qualitative transcriptional signature for classifying CIMP status at the individualized level can predict outcome and guide therapy for RCC patients.
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Affiliation(s)
- Tianyi You
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Kai Song
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Wenbing Guo
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Yelin Fu
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Kai Wang
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Hailong Zheng
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Jing Yang
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Liangliang Jin
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Lishuang Qi
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Zheng Guo
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.,Department of Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.,Fujian Provincial Key Laboratory on Hematology, Fujian Medical University, Fuzhou, China
| | - Wenyuan Zhao
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
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10
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Chino A, Kawachi H, Takamatsu M, Hatamori H, Ide D, Saito S, Igarashi M, Fujisaki J, Nagayama S. Macroscopic and microscopic morphology and molecular profiling to distinguish heterogeneous traditional serrated adenomas of the colorectum. Dig Endosc 2020; 32:921-931. [PMID: 31833094 DOI: 10.1111/den.13603] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 12/05/2019] [Indexed: 12/25/2022]
Abstract
OBJECTIVES Serrated lesions of the colorectum often have complex histological morphology, and some groups include subtypes with different molecular biology. This study aimed to characterize serrated lesions with heterogeneous histology that was dominated by a traditional serrated adenoma (TSA) component. METHODS Representative lesions were selected based on both endoscopic and histological features. If a lesion had more than one component, each of the different structural parts was considered as a separate sample. DNA was extracted from 177 samples of 60 lesions and amplified to screen for BRAF and K/NRAS mutations. RESULTS Heterogeneous TSA samples were classified into four categories: sessile serrated lesion with TSA (SA-1); TSAs with microvesicular hyperplastic polyp (SA-2); TSAs with unclassified adenoma, characterized by tubulo-serrated histology (SA-3); and TSAs with conventional adenomas (SA-4). On endoscopy, SA-1 lesions had sessile-elevated morphology with the small reddish elevations; SA-2 lesions had a pedunculated appearance with a whitish mucosal component at the stalk; SA-3 lesions had a sessile-elevated component surrounded by flat spreading margins; and SA-4 lesions had mixed adenomatous morphology. Eighteen of the 19 category SA-1 and -2 lesions (95%) had BRAF mutations, and all of the SA-3 and -4 lesions had K/NRAS mutations. CONCLUSIONS Traditional serrated adenomas were classified into two phenotypes according to their molecular characteristics: microvesicular serrated subtypes with BRAF mutations (SA-1 and -2 lesions) and subtypes containing tubulo-serrated/conventional adenoma with K/NRAS mutations (SA-3 and -4 lesions). Each subtype had characteristic macroscopic and microscopic morphologies and was distinct on endoscopy.
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Affiliation(s)
- Akiko Chino
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese for Cancer Research, Tokyo, Japan
| | - Hiroshi Kawachi
- Department of Pathology, The Cancer Institute Hospital of Japanese for Cancer Research, Tokyo, Japan
| | - Manabu Takamatsu
- Department of Pathology, The Cancer Institute Hospital of Japanese for Cancer Research, Tokyo, Japan
| | - Hiroyuki Hatamori
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese for Cancer Research, Tokyo, Japan
| | - Daisuke Ide
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese for Cancer Research, Tokyo, Japan
| | - Shoichi Saito
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese for Cancer Research, Tokyo, Japan
| | - Masahiro Igarashi
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese for Cancer Research, Tokyo, Japan
| | - Junko Fujisaki
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese for Cancer Research, Tokyo, Japan
| | - Satoshi Nagayama
- Department of Digestive Surgery, The Cancer Institute Hospital of Japanese for Cancer Research, Tokyo, Japan
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11
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Molina-Cerrillo J, San Román M, Pozas J, Alonso-Gordoa T, Pozas M, Conde E, Rosas M, Grande E, García-Bermejo ML, Carrato A. BRAF Mutated Colorectal Cancer: New Treatment Approaches. Cancers (Basel) 2020; 12:cancers12061571. [PMID: 32545884 PMCID: PMC7353017 DOI: 10.3390/cancers12061571] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 06/09/2020] [Accepted: 06/10/2020] [Indexed: 12/14/2022] Open
Abstract
Colon cancer is one of the most frequently diagnosed malignancies in adults, considering both its incidence and prevalence. Anatomically, the right colon is considered as being from the cecum to the splenic flexure, and the left colon is from the splenic flexure to the rectum. Sidedness is a surrogate of a wide spectrum of colorectal cancer (CRC) biology features (embryology, microbiome, methylation, microsatellite instability (MSI), BRAF, aging, KRAS, consensus molecular subtypes (CMS), etc.), which result in prognostic factors. Different molecular subtypes have been identified, according to genomic and transcriptomic criteria. A subgroup harboring a BRAF mutation has been described, and represents approximately 10% of the patients diagnosed with colon cancer. This subgroup has morphological, clinical, and therapeutic characteristics that differ substantially from patients who do not carry this genetic alteration. Unfortunately, there is no established standard of care for this particular cohort of patients. This manuscript aims to study the biology of this subgroup of colon cancer, to understand the current approach in clinical research.
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Affiliation(s)
- Javier Molina-Cerrillo
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (M.S.R.); (J.P.); (T.A.-G.); (M.P.); (A.C.)
- CIBERONC, The Ramón y Cajal Health Research Institute (IRYCIS), 28034 Madrid, Spain
- Medicine School, Alcalá University, 28805 Madrid, Spain
- Correspondence: or
| | - María San Román
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (M.S.R.); (J.P.); (T.A.-G.); (M.P.); (A.C.)
| | - Javier Pozas
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (M.S.R.); (J.P.); (T.A.-G.); (M.P.); (A.C.)
| | - Teresa Alonso-Gordoa
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (M.S.R.); (J.P.); (T.A.-G.); (M.P.); (A.C.)
- CIBERONC, The Ramón y Cajal Health Research Institute (IRYCIS), 28034 Madrid, Spain
- Medicine School, Alcalá University, 28805 Madrid, Spain
| | - Miguel Pozas
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (M.S.R.); (J.P.); (T.A.-G.); (M.P.); (A.C.)
| | - Elisa Conde
- Biomarkers and Therapeutic Targets Group and Core Facility, The Ramón y Cajal Health Research Institute (IRYCIS), CIBERONC, 28034 Madrid, Spain; (E.C.); (M.L.G.-B.)
| | - Marta Rosas
- Pathology department, University Hospital Ramon y Cajal, 28034 Madrid, Spain;
| | - Enrique Grande
- Department of Medical Oncology, MD Anderson Cancer Center, 28033 Madrid, Spain;
| | - María Laura García-Bermejo
- Biomarkers and Therapeutic Targets Group and Core Facility, The Ramón y Cajal Health Research Institute (IRYCIS), CIBERONC, 28034 Madrid, Spain; (E.C.); (M.L.G.-B.)
| | - Alfredo Carrato
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (M.S.R.); (J.P.); (T.A.-G.); (M.P.); (A.C.)
- CIBERONC, The Ramón y Cajal Health Research Institute (IRYCIS), 28034 Madrid, Spain
- Medicine School, Alcalá University, 28805 Madrid, Spain
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12
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Grazioso TP, Brandt M, Djouder N. Diet, Microbiota, and Colorectal Cancer. iScience 2019; 21:168-187. [PMID: 31669832 PMCID: PMC6889474 DOI: 10.1016/j.isci.2019.10.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 07/03/2019] [Accepted: 10/02/2019] [Indexed: 02/07/2023] Open
Abstract
The intestinal epithelium is a very dynamic tissue under a high regenerative pressure, which makes it susceptible to malignant transformation. Proper integration of various cell signaling pathways and a balanced cross talk between different cell types composing the organ are required to maintain intestinal homeostasis. Dysregulation of this balance can lead to colorectal cancer (CRC). Here, we review important insights into molecular and cellular mechanisms of CRC. We discuss how perturbation in complex regulatory networks, including the Wnt, Notch, BMP, and Hedgehog pathways; and how variations in inflammatory signaling, nutrients, and microbiota can affect intestinal homeostasis contributing to the malignant transformation of intestinal cells.
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Affiliation(s)
- Tatiana P Grazioso
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional Investigaciones Oncológicas, CNIO, Madrid 28029, Spain
| | - Marta Brandt
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional Investigaciones Oncológicas, CNIO, Madrid 28029, Spain
| | - Nabil Djouder
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional Investigaciones Oncológicas, CNIO, Madrid 28029, Spain.
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13
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Nourbakhsh M, Mansoor A, Koro K, Zhang Q, Minoo P. Expression Profiling Reveals Involvement of WNT Pathway in the Malignant Progression of Sessile Serrated Adenomas. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:1732-1743. [PMID: 31199922 DOI: 10.1016/j.ajpath.2019.05.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 05/03/2019] [Accepted: 05/07/2019] [Indexed: 02/07/2023]
Abstract
Approximately 15% to 20% of colorectal cancers are developed through the serrated pathway of tumorigenesis, which is associated with BRAF mutation, CpG island methylation phenotype, and MLH1 methylation. However, the detailed process of progression from sessile serrated adenoma (SSA) to dysplasia and carcinoma has not been elucidated. To further characterize mechanisms involved in the dysplastic progression of SSA, we investigated differential expressions of mRNAs between areas with and without dysplasia within the same SSA polyps. Significantly dysregulated genes in paired samples were applied for functional annotation and biological significance. The same lysates from a subset of matched samples were subjected for miRNA expression profiling. Differentially expressed miRNAs were determined, and their targeted mRNAs were compared in parallel to the list of differentially expressed mRNAs from an RNA sequencing study. Fourteen common mRNA targets were identified, which include AXIN2, a known indicator of WNT/β-catenin pathway activation. Together, in this study, different genes, pathways, and biological processes involved in the initiation and progression of dysplasia in the serrated pathway are documented. One of the most significant findings is the involvement of the WNT/β-catenin pathway in the dysplastic progression of SSAs with different genes being targeted in early versus advanced dysplasia.
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Affiliation(s)
- Mahra Nourbakhsh
- Department of Pathology, Cumming School of Medicine and Alberta Public Laboratories, University of Calgary, Calgary, Alberta, Canada; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
| | - Adnan Mansoor
- Department of Pathology, Cumming School of Medicine and Alberta Public Laboratories, University of Calgary, Calgary, Alberta, Canada; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
| | - Konstantin Koro
- Department of Pathology, Cumming School of Medicine and Alberta Public Laboratories, University of Calgary, Calgary, Alberta, Canada; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
| | - Qingrun Zhang
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
| | - Parham Minoo
- Department of Pathology, Cumming School of Medicine and Alberta Public Laboratories, University of Calgary, Calgary, Alberta, Canada; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
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14
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Cassese G, Amendola A, Maione F, Giglio MC, Pagano G, Milone M, Aprea G, Luglio G, De Palma GD. Serrated Lesions of the Colon-Rectum: A Focus on New Diagnostic Tools and Current Management. Gastroenterol Res Pract 2019; 2019:9179718. [PMID: 30774654 PMCID: PMC6350577 DOI: 10.1155/2019/9179718] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 12/23/2018] [Indexed: 02/07/2023] Open
Abstract
Prompt diagnosis and correct management of the so called "serrated lesions" (SLs) of the colon-rectum are generally considered of crucial importance in the past years, mainly due to their histological heterogeneity and peculiar clinical and molecular patterns; sometimes, they are missed at conventional endoscopy and are possibly implicated in the genesis of interval cancers. The aim of this review is to focus on the diagnostic challenges of serrated lesions, underlying the role of both conventional endoscopy and novel technologies. We will show how an accurate and precise diagnosis should immediately prompt the most appropriate therapy other than defining a proper follow-up program. It will be emphasized how novel endoscopic techniques may provide better visualization of mucosal microsurface structures other than enhancing the microvascular architecture, in order to better define and characterize specific patterns of mucosal lesions of the gastrointestinal tract. Standard therapy of SLs of the colon-rectum is still very debated, also due to the relatively lack of studies focusing on treatment issues. The high risk of incomplete resection, together with the high rate of postcolonoscopy interval cancers, suggests the need of an extra care when facing this kind of lesions. Given this background, we will outline useful technical tips and tricks in the resection of SLs, taking aspects such as the size and location of the lesions, as well as novel available techniques and technologies, other than future perspectives, including confocal laser endomicroscopy into consideration. Follow-up of SLs is another hot topic, also considering that their clinical impact has been misunderstood for a long time. The incidence of the so called interval colorectal cancer underlines how some weaknesses exist in current screening and follow-up programs. Considering the lack of wide consensus for the management of some SLs, we will try to summarize and clarify the best strategies for their optimal management.
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Affiliation(s)
- Gianluca Cassese
- University of Naples “Federico II”, Department of Clinical Medicine and Surgery, Italy
| | - Alfonso Amendola
- University of Naples “Federico II”, Department of Clinical Medicine and Surgery, Italy
| | - Francesco Maione
- University of Naples “Federico II”, Department of Clinical Medicine and Surgery, Italy
| | - Mariano Cesare Giglio
- University of Naples “Federico II”, Department of Clinical Medicine and Surgery, Italy
| | - Gianluca Pagano
- University of Naples “Federico II”, Department of Clinical Medicine and Surgery, Italy
| | - Marco Milone
- University of Naples “Federico II”, Department of Clinical Medicine and Surgery, Italy
| | - Giovanni Aprea
- University of Naples “Federico II”, Department of Clinical Medicine and Surgery, Italy
| | - Gaetano Luglio
- University of Naples “Federico II”, Department of Clinical Medicine and Surgery, Italy
| | - Giovanni Domenico De Palma
- University of Naples “Federico II”, Department of Clinical Medicine and Surgery, Italy
- Center of Excellence for Technological Innovation in Surgery, University of Naples “Federico II”, Italy
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15
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Parker HR, Orjuela S, Martinho Oliveira A, Cereatti F, Sauter M, Heinrich H, Tanzi G, Weber A, Komminoth P, Vavricka S, Albanese L, Buffoli F, Robinson MD, Marra G. The proto CpG island methylator phenotype of sessile serrated adenomas/polyps. Epigenetics 2018; 13:1088-1105. [PMID: 30398409 PMCID: PMC6342079 DOI: 10.1080/15592294.2018.1543504] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Sessile serrated adenomas/polyps (SSA/Ps) are the putative precursors of the ~20% of colon cancers with the CpG island methylator phenotype (CIMP). To investigate the epigenetic phenotype of these precancers, we prospectively collected fresh-tissue samples of 17 SSA/Ps and 15 conventional adenomas (cADNs), each with a matched sample of normal mucosa. Their DNA was subjected to bisulfite next-generation sequencing to assess methylation levels at ~2.7 million CpGs located predominantly in gene regulatory regions and spanning 80.5Mb; RNA was sequenced to define the samples' transcriptomes. Compared with normal mucosa, SSA/Ps and cADNs exhibited markedly remodeled methylomes. In cADNs, hypomethylated regions were far more numerous (18,417 vs 4288 in SSA/Ps) and rarely affected CpG islands/shores. SSA/Ps seemed to have escaped this wave of demethylation. Cytosine hypermethylation in SSA/Ps was more pervasive (hypermethylated regions: 22,147 vs 15,965 in cADNs; hypermethylated genes: 4938 vs 3443 in cADNs) and more extensive (region for region), and it occurred mainly within CpG islands and shores. Given its resemblance to the CIMP typical of SSA/Ps' putative descendant colon cancers, we refer to the SSA/P methylation phenotype as proto-CIMP. Verification studies of six hypermethylated regions in an independent series of precancers demonstrated DNA methylation markers' high potential for predicting the diagnosis of SSA/Ps and cADNs. Surprisingly, proto-CIMP in SSA/Ps was associated with upregulated gene expression; downregulation was more common in cADNs. In conclusion, the epigenetic landscape of SSA/Ps differs markedly from that of cADNs. These differences are a potentially rich source of novel tissue-based and noninvasive biomarkers.
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Affiliation(s)
- Hannah R Parker
- a Institute of Molecular Cancer Research , University of Zurich , Zurich , Switzerland
| | - Stephany Orjuela
- a Institute of Molecular Cancer Research , University of Zurich , Zurich , Switzerland.,b Institute of Molecular Life Sciences and SIB Swiss Institute of Bioinformatics , University of Zurich , Zurich , Switzerland
| | | | - Fabrizio Cereatti
- c Gastroenterology and Endoscopy Unit , Hospital of Cremona , Cremona , Italy
| | - Matthias Sauter
- d Division of Gastroenterology , Triemli Hospital , Zurich , Switzerland
| | - Henriette Heinrich
- d Division of Gastroenterology , Triemli Hospital , Zurich , Switzerland
| | - Giulia Tanzi
- e Division of Pathology , Hospital of Cremona , Cremona , Italy
| | - Achim Weber
- f Institute of Surgical Pathology , University of Zurich , Zurich , Switzerland
| | - Paul Komminoth
- g Division of Pathology , Triemli Hospital , Zurich , Switzerland
| | - Stephan Vavricka
- d Division of Gastroenterology , Triemli Hospital , Zurich , Switzerland
| | - Luca Albanese
- a Institute of Molecular Cancer Research , University of Zurich , Zurich , Switzerland
| | - Federico Buffoli
- c Gastroenterology and Endoscopy Unit , Hospital of Cremona , Cremona , Italy
| | - Mark D Robinson
- b Institute of Molecular Life Sciences and SIB Swiss Institute of Bioinformatics , University of Zurich , Zurich , Switzerland
| | - Giancarlo Marra
- a Institute of Molecular Cancer Research , University of Zurich , Zurich , Switzerland
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16
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Kaneko M, Tanaka K, Kobayashi K. An Unusual Lesion in the Ascending Colon. Gastroenterology 2018; 154:2037-2038. [PMID: 28947350 DOI: 10.1053/j.gastro.2017.09.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 09/13/2017] [Indexed: 12/02/2022]
Affiliation(s)
- Masabumi Kaneko
- Department of Gastroenterology, Matsusaka Central Hospital, Matsusaka, Japan
| | - Kyosuke Tanaka
- Department of Endoscopy, Mie University Hospital, Tsu, Japan
| | - Kazuhiko Kobayashi
- Department of Gastroenterology, Matsusaka Central Hospital, Matsusaka, Japan
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17
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Nagata S, Mitsuyama K, Kawano H, Noda T, Maeyama Y, Mukasa M, Takedatsu H, Yoshioka S, Kuwaki K, Akiba J, Tsuruta O, Torimura T. Endoscopic analysis of colorectal serrated lesions with cancer. Oncol Lett 2018; 15:8655-8662. [PMID: 29805602 DOI: 10.3892/ol.2018.8386] [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: 02/11/2016] [Accepted: 07/07/2017] [Indexed: 11/06/2022] Open
Abstract
Serrated lesions, including hyperplastic polyps (HPs), traditional serrated adenomas (TSAs) and sessile serrated adenomas/polyps (SSA/Ps), are important contributors to colorectal carcinogenesis. The aim of the present study was to analyze the potential of conventional endoscopy and advanced endoscopic imaging techniques to delineate the characteristic features of serrated lesions with cancer. The present study was a retrospective analysis of the data of 168 patients who had undergone colonoscopy, and a total of 228 serrated lesions (77 HPs, 58 TSAs, 84 SSA/Ps, 9 SSA/P plus TSAs) have been identified in these patients. A cancer component was identified in 2.6% of HPs, 13.8% of TSAs and 10.7% of SSA/Ps, but none of SSA/P plus TSAs. Compared with the lesions without cancer, the lesions with cancer exhibited a larger size (HP, TSA and SSA/P), a reddish appearance (SSA/P), a two-tier raised appearance (HP and SSA/P), a central depression (HP, TSA and SSA/P), the type V pit pattern (HP, TSA and SSA/P), and/or the type III capillary pattern (TSA and SSA/P). Deep invasion was identified in 50.0% of HPs, 12.5% of TSAs and 55.6% of SSA/Ps with cancer. The Ki-67 proliferative zone was distributed diffusely within the area of the cancer, but partially within the non-cancer area of HPs, TSAs and SSA/Ps. The lesion types were also analyzed on the basis of mucin phenotype. The present study suggested that a detailed endoscopic analysis of serrated lesions with cancer is useful for delineating characteristic features, and the analysis aids treatment selection.
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Affiliation(s)
- Shuichiro Nagata
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Keiichi Mitsuyama
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Hiroshi Kawano
- Department of Gastroenterology, St. Mary's Hospital, Kurume, Fukuoka 830-8543, Japan
| | - Tetsuhiro Noda
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Yasuhiko Maeyama
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Michita Mukasa
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Hidetoshi Takedatsu
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Shinichiro Yoshioka
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Kotaro Kuwaki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Jun Akiba
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Osamu Tsuruta
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
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18
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Nguyen HT, Duong HQ. The molecular characteristics of colorectal cancer: Implications for diagnosis and therapy. Oncol Lett 2018; 16:9-18. [PMID: 29928381 DOI: 10.3892/ol.2018.8679] [Citation(s) in RCA: 126] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 02/22/2018] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) results from the progressive accumulation of multiple genetic and epigenetic aberrations within cells. The progression from colorectal adenoma to carcinoma is caused by three major pathways: Microsatellite instability, chromosomal instability and CpG island methylator phenotype. A growing body of scientific evidences suggests that CRC is a heterogeneous disease, and genetic characteristics of the tumors determine their prognostic outcome and response to targeted therapies. Early diagnosis and effective targeted therapies based on a current knowledge of the molecular characteristics of CRC are essential to the successful treatment of CRC. Therefore, the present review summarized the current understanding of the molecular characteristics of CRC, and discussed its implications for diagnosis and targeted therapy.
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Affiliation(s)
- Ha Thi Nguyen
- Center for Molecular Biology, Institute of Research and Development, Duy Tan University, Danang 550000, Vietnam
| | - Hong-Quan Duong
- Department of Cancer Research, Vinmec Research Institute of Stem Cell and Gene Technology, Hanoi 100000, Vietnam
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19
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mTORC1 Inactivation Promotes Colitis-Induced Colorectal Cancer but Protects from APC Loss-Dependent Tumorigenesis. Cell Metab 2018; 27:118-135.e8. [PMID: 29275959 DOI: 10.1016/j.cmet.2017.11.006] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 08/21/2017] [Accepted: 11/15/2017] [Indexed: 01/17/2023]
Abstract
Dietary habits that can induce inflammatory bowel disease (IBD) are major colorectal cancer (CRC) risk factors, but mechanisms linking nutrients, IBD, and CRC are unknown. Using human data and mouse models, we show that mTORC1 inactivation-induced chromosomal instability impairs intestinal crypt proliferation and regeneration, CDK4/6 dependently. This triggers interleukin (IL)-6-associated reparative inflammation, inducing crypt hyper-proliferation, wound healing, and CRC. Blocking IL-6 signaling or reactivating mTORC1 reduces inflammation-induced CRC, so mTORC1 activation suppresses tumorigenesis in IBD. Conversely, mTORC1 inactivation is beneficial in APC loss-dependent CRC. Thus, IL-6 blockers or protein-rich-diet-linked mTORC1 activation may prevent IBD-associated CRC. However, abolishing mTORC1 can mitigate CRC in predisposed patients with APC mutations. Our work reveals mTORC1 oncogenic and tumor-suppressive roles in intestinal epithelium and avenues to optimized and personalized therapeutic regimens for CRC.
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20
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Hisamatsu K, Noguchi K, Tomita H, Muto A, Yamada N, Kobayashi K, Hirata A, Kanayama T, Niwa A, Ishida K, Nakashima T, Hatano Y, Suzui N, Miyazaki T, Hara A. Distinctive crypt shape in a sessile serrated adenoma/polyp: Distribution of Ki67-, p16INK4a-, WNT5A-positive cells and intraepithelial lymphocytes. Oncol Rep 2017. [PMID: 28627675 PMCID: PMC5561931 DOI: 10.3892/or.2017.5725] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Serrated lesions in the colorectum are currently predominantly classified as hyperplastic polyps (HPs), sessile serrated adenomas/polyps (SSA/Ps), and traditional serrated adenomas (TSAs) according to their morphology. However, the histological morphology and the molecular changes in the serrated lesions are still unclear. We performed immunohistochemistry for Ki67, p16INK4a, and WNT5A in human HPs (n=22), SSA/Ps (n=41), and TSAs (n=19). The distribution of Ki67 and p16INK4a positive cells in TSAs was different from that in HPs and SSA/Ps. Co-expression of Ki67 and P16INK4a was infrequent in HPs and SSA/Ps; p16INK4a-positive cells were found in the crypt cleft and stromal WNT5A-positive stromal cells were localized near the cleft in SSA/Ps, while intraepithelial lymphocytes (IELs) in SSA/Ps were more abundant than HPs. In conclusion, our study provides evidence that HPs branch because of the increase in and patchy distribution of senescent and proliferative cells, with increased and misdistributed stromal and inflammatory cells, which might contribute to creation of L- and/or T-shaped crypts, which are of distinctive shapes in SSA/Ps. Our findings may facilitate better understanding and therapy in the serrated lesions.
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Affiliation(s)
- Kenji Hisamatsu
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Kei Noguchi
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Hiroyuki Tomita
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Aoi Muto
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Natsumi Yamada
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Kazuhiro Kobayashi
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Akihiro Hirata
- Division of Animal Experiment, Life Science Research Center, Gifu University, Gifu 501-1194, Japan
| | - Tomohiro Kanayama
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Ayumi Niwa
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Kazuhisa Ishida
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Takayuki Nakashima
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Yuichiro Hatano
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Natsuko Suzui
- Pathology Division, Gifu University Hospital, Gifu 501-1194, Japan
| | | | - Akira Hara
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
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21
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Eiró N, González LO, Cid S, Andicoechea A, Vizoso FJ. Matrix metalloproteases expression in different histological types of colorectal polyps. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2017; 109:414-420. [PMID: 28376625 DOI: 10.17235/reed.2017.4551/2016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
INTRODUCTION Colorectal carcinoma (CC) may begin as benign polyps, which may be classified in different histological types with a different risk to develop cancer. Matrix metalloproteases (MMPs) are able to degrade all components in the extracellular matrix and are important tissue-remodeling enzymes and key elements in tumor invasion and metastasis. The aim of this study was to investigate the expression and clinical relevance of MMPs in different histological types of colorectal polyps. METHODS The expression levels of MMP-1, 2, 7, 9, 11, 13 and 14 were analyzed by real-time PCR, Western-blot and immunohistochemistry in 50 patients with different histological types of colorectal polyps, 28 of which developed CC. RESULTS The results indicate that hyperplastic polyps had the lowest levels of MMP-1 and MMP-7, tubular polyps showed higher levels of both MMP-7 and MMP-14, and tubulovillous adenoma showed higher levels of MMP-1, MMP-7 and MMP-14. CONCLUSION MMP expression was decreased in hyperplastic, tubular and tubulovillous adenoma polyps from patients who developed CC. Our findings suggest that MMP expression may be a pathological marker of colorectal polyps and for cancer susceptibility, which may improve strategies for CC prevention based on screening colonoscopy.
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Affiliation(s)
- Noemi Eiró
- Unidad de Investigación, Fundación Hospital de Jove
| | - Luis O González
- Unidad de Investigación y Servicio de Anatomía Pat, Fundación Hospital de Jove
| | - Sandra Cid
- Unidad de Investigación, Fundación Hospital de Jove
| | | | - Francisco J Vizoso
- Unidad de Investigación y Servicio de Cirugía Gene, Fundación Hospital de Jove, España
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22
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Thorlacius H, Takeuchi Y, Kanesaka T, Ljungberg O, Uedo N, Toth E. Serrated polyps - a concealed but prevalent precursor of colorectal cancer. Scand J Gastroenterol 2017; 52:654-661. [PMID: 28277895 DOI: 10.1080/00365521.2017.1298154] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 02/14/2017] [Accepted: 02/18/2017] [Indexed: 02/04/2023]
Abstract
Serrated polyps have long been considered to lack malignant potential but accumulating data suggest that these lesions may cause up to one-third of all sporadic colorectal cancer. Serrated polyps are classified into three subtypes, including sessile serrated adenomas/polyps (SSA/Ps), traditional serrated adenomas (TSAs), and hyperplastic polyps (HPs). SSA/P and TSA harbour malignant potential but TSA represents only 1-2%, wheras SSA/P constitute up to 20% of all serrated lesions. HPs are most common (80%) of all serrated polyps but are considered to have a low potential of developing colorectal cancer. Due to their subtle appearence, detection and removal of serrated polyps pose a major challenge to endoscopists. Considering that precancerous serrated polyps are predominately located in the right colon could explain why interval cancers most frequently appear in the proximal colon and why colonoscopy is less protective against colon cancer in the proximal compared to the distal colon. Despite the significant impact on colorectal cancer incidence, the aetiology, incidence, prevalence, and natural history of serrated polyps is incompletely known. To effectively detect, remove, and follow-up serrated polyps, endoscopists and pathologists should be well-informed about serrated polyps. This review highlights colorectal serrated polyps in terms of biology, types, diagnosis, therapy, and follow-up.
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Affiliation(s)
- Henrik Thorlacius
- a Department of Clinical Sciences, Section, of Surgery , Skåne University Hospital, Lund University , Malmö , Sweden
| | - Yoji Takeuchi
- b Department of Gastrointestinal Oncology , Osaka Medical Center for Cancer and Cardiovascular Diseases , Osaka , Japan
| | - Takashi Kanesaka
- b Department of Gastrointestinal Oncology , Osaka Medical Center for Cancer and Cardiovascular Diseases , Osaka , Japan
| | - Otto Ljungberg
- c Department of Clinical Sciences, Section, of Gastroenterology , Skåne University Hospital, Lund University , Malmö , Sweden
| | - Noriya Uedo
- b Department of Gastrointestinal Oncology , Osaka Medical Center for Cancer and Cardiovascular Diseases , Osaka , Japan
| | - Ervin Toth
- d Department of Clinical Sciences, Section, of Pathology , Skåne University Hospital, Lund University , Malmö , Sweden
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23
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Jayasekara H, MacInnis RJ, Williamson EJ, Hodge AM, Clendenning M, Rosty C, Walters R, Room R, Southey MC, Jenkins MA, Milne RL, Hopper JL, Giles GG, Buchanan DD, English DR. Lifetime alcohol intake is associated with an increased risk of KRAS+ and BRAF-/KRAS- but not BRAF+ colorectal cancer. Int J Cancer 2017; 140:1485-1493. [PMID: 27943267 DOI: 10.1002/ijc.30568] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 10/14/2016] [Accepted: 11/24/2016] [Indexed: 12/16/2022]
Abstract
Ethanol in alcoholic beverages is a causative agent for colorectal cancer. Colorectal cancer is a biologically heterogeneous disease, and molecular subtypes defined by the presence of somatic mutations in BRAF and KRAS are known to exist. We examined associations between lifetime alcohol intake and molecular and anatomic subtypes of colorectal cancer. We calculated usual alcohol intake for 10-year periods from age 20 using recalled frequency and quantity of beverage-specific consumption for 38,149 participants aged 40-69 years from the Melbourne Collaborative Cohort Study. Cox regression was performed to derive hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between lifetime alcohol intake and colorectal cancer risk. Heterogeneity in the HRs across subtypes of colorectal cancer was assessed. A positive dose-dependent association between lifetime alcohol intake and overall colorectal cancer risk (mean follow-up = 14.6 years; n = 596 colon and n = 326 rectal cancer) was observed (HR = 1.08, 95% CI: 1.04-1.12 per 10 g/day increment). The risk was greater for rectal than colon cancer (phomogeneity = 0.02). Alcohol intake was associated with increased risks of KRAS+ (HR = 1.07, 95% CI: 1.00-1.15) and BRAF-/KRAS- (HR = 1.05, 95% CI: 1.00-1.11) but not BRAF+ tumors (HR = 0.89, 95% CI: 0.78-1.01; phomogeneity = 0.01). Alcohol intake is associated with an increased risk of KRAS+ and BRAF-/KRAS- tumors originating via specific molecular pathways including the traditional adenoma-carcinoma pathway but not with BRAF+ tumors originating via the serrated pathway. Therefore, limiting alcohol intake from a young age might reduce colorectal cancer originating via the traditional adenoma-carcinoma pathway.
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Affiliation(s)
- Harindra Jayasekara
- Cancer Council Victoria, Cancer Epidemiology Centre, 615 St Kilda Road, Melbourne, VIC, 3004, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, 207 Bouverie Street, Melbourne, VIC, 3010, Australia
| | - Robert J MacInnis
- Cancer Council Victoria, Cancer Epidemiology Centre, 615 St Kilda Road, Melbourne, VIC, 3004, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, 207 Bouverie Street, Melbourne, VIC, 3010, Australia
| | - Elizabeth J Williamson
- Farr Institute of Health Informatics Research, London, NW1 2DA, United Kingdom
- Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, United Kingdom
| | - Allison M Hodge
- Cancer Council Victoria, Cancer Epidemiology Centre, 615 St Kilda Road, Melbourne, VIC, 3004, Australia
| | - Mark Clendenning
- Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia
| | - Christophe Rosty
- Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia
- Envoi Specialist Pathologists, Brisbane, QLD, Australia
- School of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Rhiannon Walters
- Cancer and Population Studies Group, Queensland Institute of Medical Research, Herston, QLD, Australia
| | - Robin Room
- Centre for Alcohol Policy Research, La Trobe University, Melbourne, VIC, 3000, Australia
- Centre for Health Equity, Melbourne School of Population and Global Health, The University of Melbourne, Carlton, VIC, 3010, Australia
- Centre for Social Research on Alcohol and Drugs, Stockholm University, Stockholm, SE-106 91, Sweden
| | - Melissa C Southey
- Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, VIC, Australia
| | - Mark A Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, 207 Bouverie Street, Melbourne, VIC, 3010, Australia
| | - Roger L Milne
- Cancer Council Victoria, Cancer Epidemiology Centre, 615 St Kilda Road, Melbourne, VIC, 3004, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, 207 Bouverie Street, Melbourne, VIC, 3010, Australia
| | - John L Hopper
- Cancer Council Victoria, Cancer Epidemiology Centre, 615 St Kilda Road, Melbourne, VIC, 3004, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, 207 Bouverie Street, Melbourne, VIC, 3010, Australia
| | - Graham G Giles
- Cancer Council Victoria, Cancer Epidemiology Centre, 615 St Kilda Road, Melbourne, VIC, 3004, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, 207 Bouverie Street, Melbourne, VIC, 3010, Australia
| | - Daniel D Buchanan
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, 207 Bouverie Street, Melbourne, VIC, 3010, Australia
- Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia
| | - Dallas R English
- Cancer Council Victoria, Cancer Epidemiology Centre, 615 St Kilda Road, Melbourne, VIC, 3004, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, 207 Bouverie Street, Melbourne, VIC, 3010, Australia
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Okamoto K, Kitamura S, Kimura T, Nakagawa T, Sogabe M, Miyamoto H, Muguruma N, Takayama T. Clinicopathological characteristics of serrated polyps as precursors to colorectal cancer: Current status and management. J Gastroenterol Hepatol 2017; 32:358-367. [PMID: 27376251 DOI: 10.1111/jgh.13482] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/28/2016] [Indexed: 12/13/2022]
Abstract
Serrated polyps have long been thought to lack malignant potential in the human colorectum. However, identification of the serrated pathway to colorectal cancer based on molecular biology has improved our understanding of the pathogenesis of colorectal cancers. Accordingly, serrated polyps such as traditional serrated adenoma and sessile serrated adenoma/polyps (SSA/P) are now considered to be precursor lesions of the serrated pathway. Recently, serrated polyps were classified into three subtypes, consisting of hyperplastic polyp, SSA/P, and traditional serrated adenoma, according to the World Health Organization classification. It has been suggested that SSA/P in the proximal colon are a precursor lesion of pathogenesis of colorectal cancer and are characterized by BRAF mutation and a CpG island methylator phenotype with or without microsatellite instability. However, SSA/P is more challenging to detect by colonoscopy and is likely to account for some interval cancers, particularly in the proximal colon because it presents flat or sessile, isochroous appearance, and occasionally has a mucous cap. Furthermore, the possibility has been raised that pathologists misclassify SSA/P as hyperplastic polyp. It is important for gastroenterologists to recognize the endoscopic features of serrated polyps to facilitate their detection and removal and also to establish postpolypectomy surveillance guidelines. In this review, we discuss the recent classification of serrated polyps; the molecular characteristics of the serrated pathway; appropriate diagnostic methods using endoscopy, including a new image-enhanced endoscopic technique; and management of these lesions.
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Affiliation(s)
- Koichi Okamoto
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Shinji Kitamura
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Tetsuo Kimura
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Tadahiko Nakagawa
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Masahiro Sogabe
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Naoki Muguruma
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
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25
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Ashburn JH, Plesec TP, Kalady MF. Serrated Polyps and Serrated Polyposis Syndrome. Clin Colon Rectal Surg 2016; 29:336-344. [PMID: 31777465 DOI: 10.1055/s-0036-1584088] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Colorectal serrated polyps are intermediate lesions in the serrated neoplastic pathway, which account for up to 30% of colorectal cancers. This pathway is biologically distinct from the adenoma-to-carcinoma sequence, with associated cancers exhibiting mutations in the BRAF oncogene, DNA promoter hypermethylation, and microsatellite instability. An evolving understanding of these unique lesions has led to the development of a more accurate classification, improved endoscopic identification, and tailored clinical management guidelines. This article reviews serrated polyps and serrated polyposis syndrome.
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Affiliation(s)
- Jean H Ashburn
- Department of Colorectal Surgery, Sanford R. Weiss, MD, Center for Inherited Colorectal Neoplasia, Digestive Diseases Institute, Cleveland Clinic, Cleveland, Ohio
| | - Thomas P Plesec
- Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio
| | - Matthew F Kalady
- Department of Colorectal Surgery, Sanford R. Weiss, MD, Center for Inherited Colorectal Neoplasia, Digestive Diseases Institute, Cleveland Clinic, Cleveland, Ohio
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26
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Johnson CD. Serrated colonic polyps: dispelling myths. Abdom Radiol (NY) 2016; 41:781-2. [PMID: 27072932 DOI: 10.1007/s00261-016-0720-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Greuter MJE, Demirel E, Lew JB, Berkhof J, Xu XM, Canfell K, Dekker E, Meijer GA, Coupé VMH. Long-Term Impact of the Dutch Colorectal Cancer Screening Program on Cancer Incidence and Mortality-Model-Based Exploration of the Serrated Pathway. Cancer Epidemiol Biomarkers Prev 2015; 25:135-44. [PMID: 26598535 DOI: 10.1158/1055-9965.epi-15-0592] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Accepted: 10/28/2015] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND We aimed to predict the long-term colorectal cancer incidence, mortality, and colonoscopy demand of the recently implemented Dutch colorectal cancer screening program. METHODS The Adenoma and Serrated pathway to Colorectal Cancer model was set up to simulate the Dutch screening program consisting of biennial fecal immunochemical testing combined with the new Dutch surveillance guidelines, between 2014 and 2044. The impact of screening and surveillance was evaluated under three sets of natural history assumptions differing in the contribution of the serrated pathway to colorectal cancer incidence. In sensitivity analyses, other assumptions concerning the serrated pathway were varied. Model-predicted outcomes were yearly colorectal cancer incidence, mortality, and colonoscopy demand per year. RESULTS Assuming an aging population, colorectal cancer incidence under 30 years of screening is predicted to decrease by 35% and 31% for a contribution of 0% and 30% of the serrated pathway to colorectal cancer, respectively. For colorectal cancer mortality, reductions are 47% and 45%. In 2044, 110,000 colonoscopies will be required annually assuming no contribution of the serrated pathway (27 per 1,000 individuals in the screening age range). Including the serrated pathway influences predicted screening effectiveness if serrated lesions are neither detected nor treated at colonoscopy, and/or if colorectal cancers arising from serrated lesions have substantially lower survival rates than those arising from adenomas. CONCLUSIONS The Dutch screening program will markedly decrease colorectal cancer incidence and mortality but considerable colonoscopy resources will be required. IMPACT Predictions of long-term screening effectiveness are preferably based on both pathways to colorectal cancer to transparently describe the impact of uncertainties regarding the serrated pathway on long-term predictions.
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Affiliation(s)
- Marjolein J E Greuter
- Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands.
| | - Erhan Demirel
- Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands
| | - Jie-Bin Lew
- Lowy Cancer Research Centre, The University of NSW, New South Wales, Australia. Lowy Cancer Research Centre, Prince of Wales Clinical School, The University of NSW, New South Wales, Australia
| | - Johannes Berkhof
- Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands
| | - Xiang-Ming Xu
- Lowy Cancer Research Centre, The University of NSW, New South Wales, Australia. Lowy Cancer Research Centre, Prince of Wales Clinical School, The University of NSW, New South Wales, Australia
| | - Karen Canfell
- Lowy Cancer Research Centre, The University of NSW, New South Wales, Australia. Lowy Cancer Research Centre, Prince of Wales Clinical School, The University of NSW, New South Wales, Australia
| | - Evelien Dekker
- Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, the Netherlands
| | - Gerrit A Meijer
- Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands
| | - Veerle M H Coupé
- Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands
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Yamada M, Sakamoto T, Otake Y, Nakajima T, Kuchiba A, Taniguchi H, Sekine S, Kushima R, Ramberan H, Parra-Blanco A, Fujii T, Matsuda T, Saito Y. Investigating endoscopic features of sessile serrated adenomas/polyps by using narrow-band imaging with optical magnification. Gastrointest Endosc 2015; 82:108-17. [PMID: 25840928 DOI: 10.1016/j.gie.2014.12.037] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2014] [Accepted: 12/07/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND A sessile serrated adenoma/polyp (SSA/P) is a common type of colorectal polyp that possesses malignant potential. Although narrow-band imaging (NBI) can easily differentiate neoplastic lesions from hyperplastic polyps (HPs), SSA/Ps can be a challenge to distinguish from HPs. OBJECTIVE To investigate specific endoscopic features of SSA/Ps by using NBI with optical magnification. DESIGN Retrospective study. SETTING Single high-volume referral center. PATIENTS A total of 289 patients with histopathologically proven SSA/Ps or HPs obtained from colonoscopic polypectomy. INTERVENTION Endoscopic images obtained by using NBI with optical magnification of 242 lesions (124 HPs, 118 SSA/Ps) removed between January 2010 and December 2012 were independently evaluated by 2 experienced endoscopists. Three external experienced endoscopists systematically validated the diagnostic accuracies by using 40 lesions (21 HPs and 19 SSA/Ps) removed between January and March 2013. MAIN OUTCOME MEASUREMENTS Specific endoscopic features of SSA/Ps by using 5 potential characteristics: dilated and branching vessels (DBVs), irregular dark spots, a regular network pattern, a disorganized network pattern, and a dense pattern. RESULTS Multivariate analysis demonstrated that DBV had a 2.3-fold odds ratio (95% confidence interval, 0.96-5.69) among SSA/Ps compared with HPs (sensitivity, 56%; specificity, 75%; accuracy, 65%). Interobserver and intraobserver agreement indicated almost perfect agreement for DBVs in both the evaluation and validation studies. When DBVs, proximal location, and tumor size (≥10 mm) were combined, the positive predictive value was 92% and the area under the curve was 0.783 in the receiver-operating characteristics by using the validation group. LIMITATIONS Retrospective study. CONCLUSIONS The current study suggests that a DBV is a potentially unique endoscopic feature of a colorectal SSA/P.
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Affiliation(s)
- Masayoshi Yamada
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Taku Sakamoto
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Yosuke Otake
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Takeshi Nakajima
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Aya Kuchiba
- Department of Biostatistics, National Cancer Center, Tokyo, Japan
| | - Hirokazu Taniguchi
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
| | - Shigeki Sekine
- Molecular Pathology Division, National Cancer Center Research Institute, Tokyo, Japan
| | - Ryoji Kushima
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
| | - Hemchand Ramberan
- Department of Gastroenterology, University of Tennessee College of Medicine, Erlanger Hospital, Chattanooga, TN, USA
| | - Adolfo Parra-Blanco
- Department of Gastroenterology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Takahisa Matsuda
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Yutaka Saito
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
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Sánchez-Tomé E, Rivera B, Perea J, Pita G, Rueda D, Mercadillo F, Canal A, Gonzalez-Neira A, Benitez J, Urioste M. Genome-wide linkage analysis and tumoral characterization reveal heterogeneity in familial colorectal cancer type X. J Gastroenterol 2015; 50:657-66. [PMID: 25381643 DOI: 10.1007/s00535-014-1009-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Accepted: 10/20/2014] [Indexed: 02/04/2023]
Abstract
BACKGROUND Familial colorectal cancer type X (FCCTX) fulfils clinical criteria defining Lynch syndrome (LS), but is not related to germline mutations in DNA mismatch-repair genes. Its aetiology remains unexplained and there is little evidence of involvement of the common colorectal carcinogenetic pathways. We aimed to identify susceptibility loci and gain insights into carcinogenic pathways involved FCCTX tumour development. METHODS We performed a linkage analysis in 22 FCCTX families. We also constructed a tissue microarray in order to define an immunohistochemical (IHC) profile for FCCTX tumours (N = 27) by comparing them to three other types of colorectal tumors: LS (N = 18), stable early-onset (N = 31) and other sporadic disease (N = 80). Additionally, we screened for BRAF/KRAS mutations and determined CpG island methylator phenotype (CIMP) status for all FCCTX tumours. RESULTS We found suggestive evidence of linkage at four chromosomal regions; 2p24.3, 4q13.1, 4q31.21 and 12q21.2-q21.31. We screened genes in 12q21 and ruled out the implication of RASSF9 and NTS, good candidates due to their potential involvement in carcinogenesis and colorectal epithelium development. Based on IHC profiles FCCTX tumours did not form a single, exclusive cluster. They were clearly different from LS, but very similar to stable early onset tumours. The CIMP and chromosomal instability pathways were implicated in one-third and one-quarter of FCCTX cases, respectively. The remaining cases did not have alterations in any known carcinogenic pathways. CONCLUSIONS Our results highlight the heterogeneity of FCCTX tumours and call into question the utility of using only clinical criteria to identify FCCTX cases.
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Affiliation(s)
- E Sánchez-Tomé
- Familial Cancer Clinical Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain,
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Prevalence and characteristics of serrated lesions of the colorectum in Italy: A multicentre prospective cohort study. Dig Liver Dis 2015; 47:512-7. [PMID: 25842183 DOI: 10.1016/j.dld.2015.03.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 03/02/2015] [Accepted: 03/08/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Serrated lesions are recognized as important contributors to colorectal cancer incidence. We aimed to prospectively assess the prevalence of serrated lesions and identify potential predictors of these lesions during colonoscopy in an Italian population. METHODS Prospective cross sectional study involving 8 endoscopy units from February 1st to July 31st 2012. RESULTS Out of 2468 colonoscopies, 886 precancerous lesions were detected in 567 patients. Of these, 173 SELs were diagnosed in 148 patients (140 serrated/hyperplastic polyps and 33 serrated adenomas). Prevalence was 7% (173/2468). Serrated lesions accounted for 19.5% of all precancerous lesions. Serrated polyps were prevalent in the left colon (42.1%) and serrated adenomas in the proximal colon (54.5%). Independent clinical predictors of serrated lesions were patient age (OR 0.98 [0.97-1.00]) and post-polypectomy surveillance (OR 1.87 [1.24-2.82]). Endoscopic predictors were right colon location (OR 2.65 [1.63-4.30] vs. rectum; and 1.53 [1.03-2.26] vs. left colon), polypoid shape (OR 0.41 [027-0.64]) and size <6 mm (OR 0.49 [0.33-0.72] vs. 6-10 mm; and 0.14 [0.07-0.28] vs. >10 mm). There was no independent predictor of serrated adenoma. CONCLUSION In our Italian study population, the prevalence of colorectal serrated lesions was 7%. Their diagnosis is associated with younger age and surveillance colonoscopy, right-sided colorectal location, non-polypoid shape and size <6 mm.
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31
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Taupin D, Lam W, Rangiah D, McCallum L, Whittle B, Zhang Y, Andrews D, Field M, Goodnow CC, Cook MC. A deleterious RNF43 germline mutation in a severely affected serrated polyposis kindred. Hum Genome Var 2015; 2:15013. [PMID: 27081527 PMCID: PMC4785559 DOI: 10.1038/hgv.2015.13] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Revised: 02/24/2015] [Accepted: 03/11/2015] [Indexed: 01/09/2023] Open
Abstract
We report a germline nonsense mutation within the extracellular domain of the RING finger ubiquitin ligase RNF43, segregating with a severe form of serrated polyposis within a kindred. The finding provides evidence that inherited RNF43 mutations define a familial cancer syndrome.
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Affiliation(s)
- Douglas Taupin
- Cancer Research, The Canberra Hospital, Canberra, ACT, Australia; Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, ACT, Australia
| | - Wesley Lam
- Translational Research Unit, Canberra Hospital , Canberra, ACT, Australia
| | - David Rangiah
- Department of Surgery, The Canberra Hospital , Canberra, ACT, Australia
| | - Larissa McCallum
- Gastroenterology and Hepatology Unit, The Canberra Hospital , Canberra, ACT, Australia
| | - Belinda Whittle
- Australian Phenomics Facility, Australian National University , Canberra, ACT, Australia
| | - Yafei Zhang
- Australian Phenomics Facility, Australian National University , Canberra, ACT, Australia
| | - Daniel Andrews
- Australian Phenomics Facility, Australian National University, Canberra, ACT, Australia; Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
| | - Matthew Field
- Australian Phenomics Facility, Australian National University, Canberra, ACT, Australia; Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
| | - Christopher C Goodnow
- Australian Phenomics Facility, Australian National University, Canberra, ACT, Australia; Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
| | - Matthew C Cook
- Translational Research Unit, Canberra Hospital, Canberra, ACT, Australia; Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
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Tsai JH, Lin YL, Cheng YC, Chen CC, Lin LI, Tseng LH, Cheng ML, Liau JY, Jeng YM. Aberrant expression of annexin A10 is closely related to gastric phenotype in serrated pathway to colorectal carcinoma. Mod Pathol 2015; 28:268-78. [PMID: 25081749 DOI: 10.1038/modpathol.2014.96] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Revised: 05/20/2014] [Accepted: 05/21/2014] [Indexed: 02/07/2023]
Abstract
Annexin A10 (ANXA10) is a member of the ANX family that is normally expressed in gastric mucosa. ANXA10 was recently observed to be upregulated in sessile serrated adenoma, a precursor to microsatellite-unstable colorectal cancer. We investigated the use of ANXA10 in diagnosing colorectal carcinoma. In an immunohistochemical analysis, the intensity and quantity of ANXA10, MUC5AC, MUC6 and CDX2 in 123 colorectal carcinomas were graded. We determined the molecular status of BRAF and KRAS mutations, as well as the microsatellite instability status and the CpG island methylator phenotype in all colorectal carcinomas, and subcategorized into four molecular subgroups according to the molecular derangements. Nuclear ANXA10 staining was present in 36 colorectal carcinomas, exhibiting a strong significant association with the BRAF mutation status (P<0.0001) and positive CpG island methylator phenotype (P<0.0001), and a borderline significant association with high levels of microsatellite instability (P=0.072). The ANXA10-positive colorectal carcinomas were frequently positive for MUC5AC and MUC6, and were associated with absent or reduced CDX2 expression (all P<0.0001). According to a classification and regression tree analysis, ANXA10 is a superior marker for the molecular subtyping of colorectal carcinomas and represents a specific marker for colorectal cancers of the serrated pathway. Our results indicated that ANXA10 expression is implicated in gastric programming in serrated-pathway-associated colorectal carcinoma. ANXA10-positive colorectal carcinoma is highly associated with the molecular features of the serrated neoplasia pathway.
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Affiliation(s)
- Jia-Huei Tsai
- 1] Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan [2] Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yu-Lin Lin
- 1] Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan [2] Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yi-Chen Cheng
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chien-Chuan Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Liang-In Lin
- 1] Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan [2] Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Li-Hui Tseng
- Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
| | - Mei-Ling Cheng
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - Jau-Yu Liau
- 1] Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan [2] Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yung-Ming Jeng
- 1] Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan [2] Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan
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Rahmi G, Lecomte T, Malka D, Maniere T, Le Rhun M, Guimbaud R, Lapalus MG, Le Sidaner A, Moussata D, Caron O, Barbieux JP, Gaudric M, Coron E, Barange K, Ponchon T, Sautereau D, Samaha E, Saurin JC, Chaussade S, Laurent-Puig P, Chatellier G, Cellier C. Impact of chromoscopy on adenoma detection in patients with Lynch syndrome: a prospective, multicenter, blinded, tandem colonoscopy study. Am J Gastroenterol 2015; 110:288-98. [PMID: 25601014 DOI: 10.1038/ajg.2014.423] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 12/02/2014] [Indexed: 02/08/2023]
Abstract
OBJECTIVES In Lynch syndrome, flat and diminutive adenomas are particularly prone to malignant transformation, but they can be missed by standard colonoscopy. It is not known whether chromocolonoscopy is able to detect more adenomas than standard colonoscopy in patients with Lynch syndrome. METHODS We conducted a prospective, multicenter, randomized trial to compare standard colonoscopy with standard colonoscopy followed by pancolonic chromoscopy with indigo carmine in patients with a proven germline mutation in a mismatch-repair gene related to Lynch syndrome and who were undergoing screening or surveillance colonoscopy. Standard colonoscopy was used first to detect visible lesions. Colonoscopy with chromoscopy was then performed by a second gastroenterologist (blinded to the findings of the first colonoscopy) to detect additional lesions. The primary end point was the number of patients in whom at least one adenoma was detected. RESULTS A total of 78 eligible patients (median age, 45 years) were enrolled at 10 centers from July 2008 to August 2009. Significantly more patients with at least one adenoma were identified by chromocolonoscopy (32/78 (41%)) than by standard colonoscopy (18/78 (23%); P<0.001). The percentage of patients in whom at least one additional adenoma was detected during the chromoscopy was 31% (24/78). Overall, chromocolonoscopy plus colonoscopy detected a total of 55 adenomas in 32 patients (mean number of adenomas detected per patient: 0.7 vs. standard colonoscopy alone: 0.3; P<0.001). CONCLUSION The results support the proposition that chromocolonoscopy may significantly improve the detection rate of colorectal adenomas in patients undergoing screening or surveillance colonoscopy for Lynch syndrome.
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Affiliation(s)
- Gabriel Rahmi
- 1] Université Paris Descartes, Paris, France; Paris Sorbonne Cité, Paris, France [2] Assistance Publique des Hôpitaux de Paris, Service de Gastroentérologie, Hôpital Européen Georges Pompidou, Paris, France
| | - Thierry Lecomte
- 1] Université François-Rabelais, Paris, France [2] Service d'Hépato-gastroentérologie et de Cancérologie digestive, CHRU de Tours, Paris, France
| | - David Malka
- Département de Médecine Oncologique, Unité d'oncologie digestive, Institut Gustave Roussy, Villejuif, France
| | - Thibault Maniere
- 1] Université Paris Descartes, Paris, France; Paris Sorbonne Cité, Paris, France [2] Assistance Publique des Hôpitaux de Paris, Service de Gastroentérologie, Hôpital Européen Georges Pompidou, Paris, France
| | - Marc Le Rhun
- Service d'Hépato-gastroentérologie, CHU de Nantes, Nantes, France
| | - Rosine Guimbaud
- 1] Service d'oncologie, Hôpital Purpan, Toulouse, France [2] Université de Toulouse 3 University, Toulouse, France
| | | | - Anne Le Sidaner
- Service d'Hépato-gastroentérologie, CHU Dupuytren, Limoges, France
| | - Driffa Moussata
- Service de Gastroentérologie, Hôpital Lyon Sud, Lyon, France
| | - Olivier Caron
- Service d'oncogénétique, Institut Gustave Roussy, Villejuif, France
| | - Jean-Pierre Barbieux
- Service d'Hépato-gastroentérologie et de Cancérologie digestive, CHRU de Tours, Paris, France
| | - Marianne Gaudric
- Assistance Publique des Hôpitaux de Paris, Service de Gastroentérologie, Hôpital Cochin, Paris, France
| | - Emmanuel Coron
- Service d'Hépato-gastroentérologie, CHU de Nantes, Nantes, France
| | - Karl Barange
- Service d'Hépato-gastroentérologie, Hôpital Purpan, Toulouse, France
| | - Thierry Ponchon
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Lyon, France
| | - Denis Sautereau
- Service d'Hépato-gastroentérologie, CHU Dupuytren, Limoges, France
| | - Elia Samaha
- Assistance Publique des Hôpitaux de Paris, Service de Gastroentérologie, Hôpital Européen Georges Pompidou, Paris, France
| | | | - Stanislas Chaussade
- 1] Université Paris Descartes, Paris, France; Paris Sorbonne Cité, Paris, France [2] Assistance Publique des Hôpitaux de Paris, Service de Gastroentérologie, Hôpital Cochin, Paris, France
| | - Pierre Laurent-Puig
- 1] Université Paris Descartes, Paris, France; Paris Sorbonne Cité, Paris, France [2] Assistance Publique des Hôpitaux de Paris, Unité d'oncogénétique, Hôpital Européen Georges Pompidou, Paris, France
| | - Gilles Chatellier
- 1] Université Paris Descartes, Paris, France; Paris Sorbonne Cité, Paris, France [2] Assistance Publique des Hôpitaux de Paris, Unité d'épidémiologie et de recherche clinique, Hôpital européen Georges Pompidou, Paris, France
| | - Christophe Cellier
- 1] Université Paris Descartes, Paris, France; Paris Sorbonne Cité, Paris, France [2] Assistance Publique des Hôpitaux de Paris, Service de Gastroentérologie, Hôpital Européen Georges Pompidou, Paris, France
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Crockett SD, Snover DC, Ahnen DJ, Baron JA. Sessile serrated adenomas: an evidence-based guide to management. Clin Gastroenterol Hepatol 2015; 13:11-26.e1. [PMID: 24216467 DOI: 10.1016/j.cgh.2013.10.035] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Revised: 10/29/2013] [Accepted: 10/31/2013] [Indexed: 02/07/2023]
Abstract
The concept of serrated colorectal neoplasia and a serrated pathway to colorectal cancer (CRC) is relatively new and continuing to evolve, but it has become highly relevant to gastroenterologists, pathologist, and oncologists alike. Sessile serrated adenomas (SSA) are now thought to be the major precursor lesion of serrated pathway cancers, which represent up to one-third of all sporadic CRC cases. However, despite their increasingly recognized importance, relatively little is known about the epidemiology and natural history of SSAs, and the molecular and epigenetic aspects are incompletely understood. Endoscopists must be aware of the unique features of SSAs so that the practice of colonoscopic screening for CRC can include optimized detection, removal, and appropriate surveillance of SSAs and other serrated precursor lesions. In this review, we discuss the history, epidemiology, and pathologic aspects of SSAs, as well as a recommended management approach and a discussion of uncertainties and opportunities for future research.
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Affiliation(s)
- Seth D Crockett
- Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
| | - Dale C Snover
- Department of Pathology, Fairview Southdale Hospital, Edina, Minnesota
| | - Dennis J Ahnen
- Division of Gastroenterology, Department of Veterans Affairs Eastern Colorado Health Care System and University of Colorado School of Medicine, Denver, Colorado
| | - John A Baron
- Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina
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Abstract
Colonoscopy offers incomplete protection from colorectal cancer, particularly in the right colon. Part of this inadequacy may be related to serrated neoplasia. Serrated polyps of the colorectum are now understood to be a heterogeneous group of polyps, some of which are cancer precursors, such as the sessile serrated adenoma (SSA) and the traditional serrated adenoma (TSA). In contrast to conventional adenomas, there is limited published literature on the epidemiology and natural history of these lesions. Furthermore, existing guidelines regarding screening and surveillance practices for these polyps are based largely on expert opinion without firm evidence. In this review, we describe the current understanding of the molecular biology, histopathology, and endoscopic features of serrated neoplasia of the colorectum, with an emphasis on aspects relevant to the practicing gastroenterologist.
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Luo Y, Wong CJ, Kaz AM, Dzieciatkowski S, Carter KT, Morris SM, Wang J, Willis JE, Makar KW, Ulrich CM, Lutterbaugh JD, Shrubsole MJ, Zheng W, Markowitz SD, Grady WM. Differences in DNA methylation signatures reveal multiple pathways of progression from adenoma to colorectal cancer. Gastroenterology 2014; 147:418-29.e8. [PMID: 24793120 PMCID: PMC4107146 DOI: 10.1053/j.gastro.2014.04.039] [Citation(s) in RCA: 145] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2013] [Revised: 04/15/2014] [Accepted: 04/23/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Genetic and epigenetic alterations contribute to the pathogenesis of colorectal cancer (CRC). There is considerable molecular heterogeneity among colorectal tumors, which appears to arise as polyps progress to cancer. This heterogeneity results in different pathways to tumorigenesis. Although epigenetic and genetic alterations have been detected in conventional tubular adenomas, little is known about how these affect progression to CRC. We compared methylomes of normal colon mucosa, tubular adenomas, and colorectal cancers to determine how epigenetic alterations might contribute to cancer formation. METHODS We conducted genome-wide array-based studies and comprehensive data analyses of aberrantly methylated loci in 41 normal colon tissue, 42 colon adenomas, and 64 cancers using HumanMethylation450 arrays. RESULTS We found genome-wide alterations in DNA methylation in the nontumor colon mucosa and cancers. Three classes of cancers and 2 classes of adenomas were identified based on their DNA methylation patterns. The adenomas separated into classes of high-frequency methylation and low-frequency methylation. Within the high-frequency methylation adenoma class a subset of adenomas had mutant KRAS. Additionally, the high-frequency methylation adenoma class had DNA methylation signatures similar to those of cancers with low or intermediate levels of methylation, and the low-frequency methylation adenoma class had methylation signatures similar to that of nontumor colon tissue. The CpG sites that were differentially methylated in these signatures are located in intragenic and intergenic regions. CONCLUSIONS Genome-wide alterations in DNA methylation occur during early stages of progression of tubular adenomas to cancer. These findings reveal heterogeneity in the pathogenesis of colorectal cancer, even at the adenoma step of the process.
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Affiliation(s)
- Yanxin Luo
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
| | - Chao-Jen Wong
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Andrew M Kaz
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Research and Development Service, VA Puget Sound Health Care System, Seattle, Washington; Department of Medicine, University of Washington School of Medicine, Seattle, Washington
| | | | - Kelly T Carter
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Shelli M Morris
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Jianping Wang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
| | - Joseph E Willis
- Department of Pathology, Case Medical Center, Case Comprehensive Cancer Center and Case Western Reserve University, Cleveland, Ohio
| | - Karen W Makar
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Cornelia M Ulrich
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), University of Heidelberg, Heidelberg, Germany GDR
| | - James D Lutterbaugh
- Department of Medicine and Ireland Cancer Center, Case Western Reserve University School of Medicine and Case Medical Center, Cleveland, Ohio
| | - Martha J Shrubsole
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Sanford D Markowitz
- Department of Medicine and Ireland Cancer Center, Case Western Reserve University School of Medicine and Case Medical Center, Cleveland, Ohio
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
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Greuter MJE, Xu XM, Lew JB, Dekker E, Kuipers EJ, Canfell K, Meijer GA, Coupé VMH. Modeling the Adenoma and Serrated pathway to Colorectal CAncer (ASCCA). RISK ANALYSIS : AN OFFICIAL PUBLICATION OF THE SOCIETY FOR RISK ANALYSIS 2014; 34:889-910. [PMID: 24172539 DOI: 10.1111/risa.12137] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Several colorectal cancer (CRC) screening models have been developed describing the progression of adenomas to CRC. Currently, there is increasing evidence that serrated lesions can also develop into CRC. It is not clear whether screening tests have the same test characteristics for serrated lesions as for adenomas, but lower sensitivities have been suggested. Models that ignore this type of colorectal lesions may provide overly optimistic predictions of the screen-induced reduction in CRC incidence. To address this issue, we have developed the Adenoma and Serrated pathway to Colorectal CAncer (ASCCA) model that includes the adenoma-carcinoma pathway and the serrated pathway to CRC as well as characteristics of colorectal lesions. The model structure and the calibration procedure are described in detail. Calibration resulted in 19 parameter sets for the adenoma-carcinoma pathway and 13 for the serrated pathway that match the age- and sex-specific adenoma and serrated lesion prevalence in the COlonoscopy versus COlonography Screening (COCOS) trial, Dutch CRC incidence and mortality rates, and a number of other intermediate outcomes concerning characteristics of colorectal lesions. As an example, we simulated outcomes for a biennial fecal immunochemical test screening program and a hypothetical one-time colonoscopy screening program. Inclusion of the serrated pathway influenced the predicted effectiveness of screening when serrated lesions are associated with lower screening test sensitivity or when they are not removed. To our knowledge, this is the first model that explicitly includes the serrated pathway and characteristics of colorectal lesions. It is suitable for the evaluation of the (cost)effectiveness of potential screening strategies for CRC.
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Wada R, Morimoto T, Inayoshi T. Pathological features of the sessile serrated adenoma/polyp with special references of its carcinogenesis. Med Mol Morphol 2014; 47:123-9. [PMID: 24748273 DOI: 10.1007/s00795-014-0075-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 03/18/2014] [Indexed: 12/16/2022]
Abstract
The sessile serrated adenoma/polyp (SSA/P) has been thought as the relatively new precursor for the colorectal cancer. In the current review, the well-known pathological features including the histological definition of the SSA/P are described using the previous reports. Although the SSA/P is thought one of pre-cancerous lesions of the colorectal carcinoma, the decisive or documentary lesion like "carcinoma in adenoma" is very rare. In this review, the strict case of the carcinoma derived from the SSA/P is demonstrated using our cases. Although the genetic investigations of the SSA/P have shown the new pathway of colorectal carcinogenesis and these concepts are thought to be almost right, the verification for them should be performed using "the carcinoma in SSA/P" like the present case.
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Affiliation(s)
- Ryo Wada
- Division of Diagnostic Pathology, Juntendo University, Shizuoka Hospital, Izunokuni, 1129 Nagaoka, Izunokuni, Shizuoka, 410-2295, Japan,
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Davies EJ, Marsh Durban V, Meniel V, Williams GT, Clarke AR. PTEN loss and KRAS activation leads to the formation of serrated adenomas and metastatic carcinoma in the mouse intestine. J Pathol 2014; 233:27-38. [PMID: 24293351 DOI: 10.1002/path.4312] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Revised: 11/22/2013] [Accepted: 11/26/2013] [Indexed: 12/15/2022]
Abstract
Mutation or loss of the genes PTEN and KRAS have been implicated in human colorectal cancer (CRC), and have been shown to co-occur despite both playing a role in the PI3' kinase (PI3'K) pathway. We investigated the role of these genes in intestinal tumour progression in vivo, using genetically engineered mouse models, with the aim of generating more representative models of human CRC. Intestinal-specific deletion of Pten and activation of an oncogenic allele of Kras was induced in wild-type (WT) mice and mice with a predisposition to adenoma development (Apc(fl/+) ). The animals were euthanized when they became symptomatic of a high tumour burden. Histopathological examination of the tissues was carried out, and immunohistochemistry used to characterize signalling pathway activation. Mutation of Pten and Kras resulted in a significant life-span reduction of mice predisposed to adenomas. Invasive adenocarcinoma was observed in these animals, with evidence of activation of the PI3'K pathway but no metastasis. However, mutation of Pten and Kras in WT animals not predisposed to adenomas led to perturbed homeostasis of the intestinal epithelium and the development of hyperplastic polyps, dysplastic sessile serrated adenomas and metastasizing adenocarcinomas with serrated features. These studies demonstrate synergism between Pten and Kras mutations in intestinal tumour progression, in an autochthonous and immunocompetent murine model, with potential application to preclinical drug testing. In particular, they show that Pten and Kras mutations alone predispose mice to the spectrum of serrated lesions that reflect the serrated pathway of CRC progression in humans.
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Affiliation(s)
- Emma J Davies
- Cardiff School of Biosciences, Cardiff University, UK
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Heigh RI, Yab TC, Taylor WR, Hussain FTN, Smyrk TC, Mahoney DW, Domanico MJ, Berger BM, Lidgard GP, Ahlquist DA. Detection of colorectal serrated polyps by stool DNA testing: comparison with fecal immunochemical testing for occult blood (FIT). PLoS One 2014; 9:e85659. [PMID: 24465639 PMCID: PMC3896420 DOI: 10.1371/journal.pone.0085659] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Accepted: 11/29/2013] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES Precursors to 1/3 of colorectal cancer (CRC), serrated polyps have been under-detected by screening due to their inconspicuous, non-hemorrhagic, and proximal nature. A new multi-target stool DNA test (multi-target sDNA) shows high sensitivity for both CRC and advanced adenomas. Screen detection of serrated polyps by this approach requires further validation. We sought to assess and compare noninvasive detection of sessile serrated polyps (SSP) ≥ 1 cm by sDNA and an occult blood fecal immunochemical test (FIT). METHODS In a blinded prospective study, a single stool sample used for both tests was collected from 456 asymptomatic adults prior to screening or surveillance colonoscopy (criterion standard). All 29 patients with SSP ≥ 1 cm were included as cases and all 232 with no neoplastic findings as controls. Buffered stool samples were processed and frozen on receipt; Exact Sciences performed sDNA in batches using optimized analytical methods. The sDNA multi-marker panel targets methylated BMP3 (mBMP3) and NDRG4, mutant KRAS, β-actin, and hemoglobin. FIT (Polymedco OC-FIT Check) was performed in separate lab ≤ 2 days post defecation and evaluated at cutoffs of 50 (FIT-50) and 100 ng/ml (FIT-100). RESULTS MEDIAN AGES: cases 61 (range 57-77), controls 62 (52-70), p = NS. Women comprised 59% and 51%, p = NS, respectively. SSP median size was 1.2 cm (1-3 cm), 93% were proximal, and 64% had synchronous diminutive polyps. Among multi-target sDNA markers, mBMP3 proved highly discriminant for detection of SSP ≥ 1 cm (AUC = 0.87, p<0.00001); other DNA markers provided no incremental sensitivity. Hemoglobin alone showed no discrimination (AUC = 0.50, p = NS). At matched specificities, detection of SSP ≥ 1 cm by stool mBMP3 was significantly greater than by FIT-50 (66% vs 10%, p = 0.0003) or FIT-100 (63% vs 0%, p<0.0001). CONCLUSIONS In a screening and surveillance setting, SSP ≥ 1 cm can be detected noninvasively by stool assay of exfoliated DNA markers, especially mBMP3. FIT appears to have no value in SSP detection.
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Affiliation(s)
- Russell I. Heigh
- Division of Gastroenterology at Mayo Clinic, Scottsdale, Arizona, United States of America
- * E-mail:
| | - Tracy C. Yab
- Division of Gastroenterology and Hepatology at Mayo Clinic, Rochester, Minnesota, United States of America
| | - William R. Taylor
- Division of Gastroenterology and Hepatology at Mayo Clinic, Rochester, Minnesota, United States of America
| | | | - Thomas C. Smyrk
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester Minnesota, United States of America
| | - Douglas W. Mahoney
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester Minnesota, United States of America
| | | | - Barry M. Berger
- Exact Sciences Corporation, Madison, Wisconsin, United States of America
| | - Graham P. Lidgard
- Exact Sciences Corporation, Madison, Wisconsin, United States of America
| | - David A. Ahlquist
- Division of Gastroenterology and Hepatology at Mayo Clinic, Rochester, Minnesota, United States of America
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Metachronous serrated neoplasia is uncommon after right colectomy in patients with methylator colon cancers with a high degree of microsatellite instability. Dis Colon Rectum 2014; 57:39-46. [PMID: 24316944 DOI: 10.1097/01.dcr.0000437690.18709.76] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Right-sided serrated polyps are precursors to sporadic microsatellite unstable colon cancers via the methylator pathway and have a high rate of synchronous and metachronous lesions. Serrated polyps also occur in Lynch syndrome, where right-sided microsatellite unstable cancers arise from germline mutations in mismatch repair genes. OBJECTIVE The aim of this study was to compare serrated neoplasia in patients with sporadic and hereditary microsatellite unstable colon cancer and to examine the effect of right colectomy on the risk of metachronous polyps and cancers. DESIGN This is a retrospective, descriptive, cohort study from database and chart review. SETTING This study was conducted at a tertiary care hospital with a center for hereditary colorectal cancer. PATIENTS Patients who had colon cancers with a high degree of microsatellite instability, methylator cancers, and Lynch syndrome cancers, were included. INTERVENTIONS Interventions included colectomy, surveillance colonoscopy, and polypectomy. MAIN OUTCOME MEASURES The primary outcomes measured were the incidence and location of metachronous polyps and cancers. RESULTS Eighty-five patients were included: 47 with methylator cancers and 38 with Lynch syndrome. Median ages at surgery were 75 years (range, 41-90) and 48 years (range, 27-77), p < 0.0001. Forty-six (98%) patients with methylator cancers and 17 (45%) patients with Lynch syndrome underwent a right colectomy, p < 0.0001. Metachronous cancers occurred in 19/60 (32%) of patients with Lynch syndrome and no patients with methylator cancers, p < 0.0001. Thirty-four patients with methylator cancers had colonoscopic follow-up, with a median of 2 colonoscopies per patient over a 32-month follow-up (range, 1-136). Sixty-three percent of patients with Lynch syndrome had colonoscopic follow-up, median of 4 colonoscopies per patient over 102 months (range, 1-462), p < 0.0001. Four (9%) patients with methylator cancers each had 1 metachronous serrated polyp, compared with 10/37 (27%) patients with Lynch syndrome (p = 0.049), whose median number of polyps was 2 (range, 1-8). Characteristics of other associated polyps were similar between cohorts. LIMITATIONS This study is somewhat limited by potential inherent bias from its retrospective design. Also, a high number of deaths in the CIMP+ cohort could have contributed to the low number of serrated polyps detected on colonoscopy surveillance, but given current understanding of serrated polyp growth, this may truly represent the left colon's tendency not to develop serrated polyps. CONCLUSIONS Cancers with a high degree of microsatellite instability arise through 2 different molecular mechanisms. Metachronous serrated neoplasia, benign and malignant, following right colectomy in patients with the CpG-island methylator phenotype of colorectal cancer is uncommon. However, the colons of patients with Lynch syndrome are at high risk after segmental colectomy.
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Improved molecular classification of serrated lesions of the colon by immunohistochemical detection of BRAF V600E. Mod Pathol 2014; 27:135-44. [PMID: 23887306 DOI: 10.1038/modpathol.2013.126] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2012] [Accepted: 06/03/2013] [Indexed: 01/12/2023]
Abstract
BRAF V600E mutation in serrated lesions of the colon has been implicated as an important mutation and as a specific marker for the serrated carcinogenic pathway. Recent findings point to microvesicular hyperplastic polyps that have similar histologic and molecular features to sessile serrated adenomas/polyps, as potential colorectal carcinoma precursors. The aim of this study was to evaluate BRAF V600E mutation status by immunohistochemistry in serrated lesions of the colon with regard to histomorphology. We investigated 194 serrated lesions of the colon, comprising 42 sessile serrated adenomas/polyps, 16 traditional serrated adenomas, 136 hyperplastic polyps and 20 tubular/tubulovillous adenomas (conventional adenomas) with the novel BRAF V600E mutation-specific antibody VE1. In addition, BRAF exon 15 and KRAS exon 2 status was investigated by capillary sequencing in selected cases. All sessile serrated adenomas/polyps (42/42, 100%), 15/16 (94%) traditional serrated adenomas and 84/136 (62%) hyperplastic polyps were VE1+. None of the VE1- serrated lesions showed BRAF V600E mutation. Forty out of 42 (95%) sessile serrated adenomas/polyps displayed areas with microvesicular hyperplastic polyp-like features. In microvesicular hyperplastic polyps, VE1 positivity was significantly associated with nuclear atypia (P=0.003); however, nuclear atypia was also present in VE1- cases. Immunostaining with VE1 allows not only the detection of BRAF V600E mutation but also the correlation with histomorphology on a cellular level in serrated lesions. VE1 enables a subclassification of microvesicular hyperplastic polyps according to the mutation status. This improved classification of serrated lesions including immunohistochemical evaluation of BRAF V600E mutation may be the key to identify lesions with higher potential to progression into sessile serrated adenoma/polyp, and further to BRAF V600E-mutated colorectal cancer.
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Okamoto K, Fujimori T, Yamaguchi T, Ichikawa K, Tomita S, Sugai T, Imura J, Ohkura Y, Yao T, Fujii S, Kusaka T, Sekikawa A, Fukui H, Chiba T, Kato H, Mitomi H. Overexpression of regenerating gene Iα appears to reflect aberration of crypt cell compartmentalization in sessile serrated adenoma/polyps of the colon. Diagn Pathol 2013; 8:187. [PMID: 24225137 PMCID: PMC4225863 DOI: 10.1186/1746-1596-8-187] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Accepted: 10/29/2013] [Indexed: 12/26/2022] Open
Abstract
Background Colorectal sessile serrated adenoma/polyps (SSA/Ps) are characterized by asymmetrical distribution of Ki67-positive cells, which varies among crypts and involves the crypt length to a variable extent; the pattern has been designated as aberration of crypt cell compartmentalization. The regenerating gene (REG) Iα is a cell growth and/or anti-apoptotic factor and its overexpression might be associated with aberration of crypt cell compartmentalization in SSA/Ps. We investigated REG Iα expression in SSA/Ps in comparison to hyperplastic polyps (HPs). Methods A total of 64 cases of serrated polyps (≥10 mm in size), including 53 SSA/Ps and 11 HPs, were included in the present study. Immunostaining was performed using a labeled streptavidin-biotin method. REG Iα expression was classified as follows: (i) expression of endocrine cells: grade 0 (a few positive cells) to 3 (marked increase in positive cells); (ii) expression of goblet cells: grade 0 (negative) to 2 (positive for crypts and surface epithelial cells); (iii) staining intensity of goblet cells: grade 0 (negative) to 2 (strong); (iv) staining intensity of crypt (absorptive) cell membranes: grade 0 (negative) to 2 (strong). The presence of aberration of crypt cell compartmentalization was assessed using Ki67 immunostaining. Results With regard to the REG Iα expression of endocrine cells, 8 out of 11 HPs (73%) were grade 0, whereas 51 of 53 SSA/Ps (96%) were grade 1 or higher (p < 0.001). With regard to the distribution of REG Iα-immunoreactive goblet cells, 10 of 11 HPs (91%) were grade 1, whereas 50 of 53 SSA/Ps (94%) were grade 2 (p < 0.001). A similar trend was found in the staining intensity of goblet cells or crypt cell membranes (p = 0.011). Aberration of crypt cell compartmentalization was more frequently identified in SSA/Ps (72%) than in HPs (18%; p = 0.002). A significant association was observed between REG Iα overexpression and the aberration of crypt cell compartmentalization in serrated polyps (p = 0.037). Conclusions REG Iα overexpression is a characteristic of SSA/Ps, which appears to reflect aberration of crypt cell compartmentalization. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7240956081100040
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Hiroyuki Mitomi
- Department of Surgical and Molecular Pathology, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, Japan.
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Minoo P. Toward a Molecular Classification of Colorectal Cancer: The Role of MGMT. Front Oncol 2013; 3:266. [PMID: 24151575 PMCID: PMC3798865 DOI: 10.3389/fonc.2013.00266] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Accepted: 10/04/2013] [Indexed: 11/23/2022] Open
Abstract
O6-methylguanine DNA methyltransferase (MGMT) is a DNA repair enzyme with the ability to protect cells from DNA mutations by removing alkyl groups from the O6 position of guanine. Colon mucosa is exposed to the direct effects of environmental carcinogens and therefore maintaining a proficient DNA repair system is very important to stay protected against DNA mutagenesis. Loss of MGMT expression is almost exclusively associated with methylation of CpG islands in the MGMT gene promoter region which is found in approximately 40% of colorectal cancers. The role of MGMT loss in colorectal tumorigenesis is complex but numerous studies have documented methylation of this gene even in the normal appearing mucosa as well as in aberrant crypt foci, suggesting that MGMT methylation can be regarded as an early event or “field defect” in colon cancer neoplasia. The focus of this perspective is the role of MGMT in different pathways of colorectal carcinogenesis as well as the implication of this molecule in treatment decisions in colorectal cancer patients.
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Affiliation(s)
- Parham Minoo
- Calgary Laboratory Services, Department of Pathology, University of Calgary , Calgary, AB , Canada
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Kim CJ, Tambe Y, Mukaisho KI, Sugihara H, Isono T, Sonoda H, Shimizu T, Kondoh G, Inoue H. Female-specific rectal carcinogenesis in cyclin D1b transgenic mice. Carcinogenesis 2013; 35:227-36. [PMID: 23975835 DOI: 10.1093/carcin/bgt293] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Human cyclin D1 generates two major isoforms via alternative splicing: cyclin D1a and cyclin D1b. Cyclin D1b is hardly expressed in normal tissues but is frequently expressed in certain types of cancer tissues. To clarify the oncogenic potential of cyclin D1b variant, we developed cyclin D1b transgenic (Tg) mice and analyzed their phenotypes. We detected rectal tumors in 63% (15/24) of the female Tg mice. All rectal tumors had the histological characteristics similar to human sessile serrated adenoma/polyps (SSA/Ps). Adenocarcinomas were also found in 53% (8/15) of the rectal tumors, suggesting that these adenocarcinomas originated from the SSA/P-like lesions. No rectal tumors were found in the ovariectomized female cyclin D1b Tg mice (0/10), indicating that ovarian hormones played a critical role in rectal carcinogenesis in these Tg mice. Both phosphorylation of Erk, without activating MEK, and expression of estrogen receptor β were elevated in the rectal tumors of female cyclin D1b Tg mice compared with normal rectums of female wild-type mice. In addition, we established a cell line, D1bTgRT, derived from a rectal cancer of female Tg mouse. Small interfering RNA-induced cyclin D1b knockdown in this cell line suppressed Erk phosphorylation, anchorage-independent growth, cell invasiveness and tumorigenicity in nude mice. In humans, expression of cyclin D1b messenger RNA was detected in 17% (1/6) of colorectal cancer cell lines and 9.7% (3/31) of colorectal cancer tissues. Taken together, these results indicate that cyclin D1b expression contributes to the female- specific rectal carcinogenesis in mouse model.
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Affiliation(s)
- Chul Jang Kim
- Department of Urology, Kohka Public Hospital, Minakuchi-cho, Kohka, Shiga 528-0014, Japan
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Steele SR, Johnson EK, Champagne B, Davis B, Lee S, Rivadeneira D, Ross H, Hayden DA, Maykel JA. Endoscopy and polyps-diagnostic and therapeutic advances in management. World J Gastroenterol 2013; 19:4277-4288. [PMID: 23885138 PMCID: PMC3718895 DOI: 10.3748/wjg.v19.i27.4277] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2013] [Revised: 05/30/2013] [Accepted: 06/10/2013] [Indexed: 02/06/2023] Open
Abstract
Despite multiple efforts aimed at early detection through screening, colon cancer remains the third leading cause of cancer-related deaths in the United States, with an estimated 51000 deaths during 2013 alone. The goal remains to identify and remove benign neoplastic polyps prior to becoming invasive cancers. Polypoid lesions of the colon vary widely from hyperplastic, hamartomatous and inflammatory to neoplastic adenomatous growths. Although these lesions are all benign, they are common, with up to one-quarter of patients over 60 years old will develop pre-malignant adenomatous polyps. Colonoscopy is the most effective screening tool to detect polyps and colon cancer, although several studies have demonstrated missed polyp rates from 6%-29%, largely due to variations in polyp size. This number can be as high as 40%, even with advanced (> 1 cm) adenomas. Other factors including sub-optimal bowel preparation, experience of the endoscopist, and patient anatomical variations all affect the detection rate. Additional challenges in decision-making exist when dealing with more advanced, and typically larger, polyps that have traditionally required formal resection. In this brief review, we will explore the recent advances in polyp detection and therapeutic options.
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Sweetser S, Smyrk TC, Sinicrope FA. Serrated colon polyps as precursors to colorectal cancer. Clin Gastroenterol Hepatol 2013; 11:760-7; quiz e54-5. [PMID: 23267866 PMCID: PMC3628288 DOI: 10.1016/j.cgh.2012.12.004] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Revised: 11/27/2012] [Accepted: 12/07/2012] [Indexed: 02/07/2023]
Abstract
Identification of the serrated neoplasia pathway has improved our understanding of the pathogenesis of colorectal cancer (CRC). Insights include an increased recognition of the malignant potential of different types of serrated polyps such as sessile and traditional serrated adenomas. Sessile serrated adenomas share molecular features with colon tumors that have microsatellite instability and a methylator phenotype, indicating that these lesions are precursors that progress via the serrated neoplasia pathway. These data have important implications for clinical practice and CRC prevention, because hyperplastic polyps were previously regarded as having no malignant potential. There is also evidence that the serrated pathway contributes to interval or missed cancers. Endoscopic detection of serrated polyps is a challenge because they are often inconspicuous with indistinct margins and are frequently covered by adherent mucus. It is important for gastroenterologists to recognize the subtle endoscopic features of serrated polyps to facilitate their detection and removal, and thereby ensure a high-quality colonoscopic examination. Recognition of the role of serrated polyps in colon carcinogenesis has led to the inclusion of these lesions in postpolypectomy surveillance guidelines. However, an enhanced effort is needed to identify and completely remove serrated adenomas, with the goal of increasing the effectiveness of colonoscopy to reduce CRC incidence.
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Affiliation(s)
- Seth Sweetser
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
| | - Thomas C. Smyrk
- Division of Anatomic Pathology, Mayo Clinic College of Medicine, Rochester, MN
| | - Frank A. Sinicrope
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
- Division of Oncology, Mayo Clinic College of Medicine, Rochester, MN
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Naini BV, Odze RD. Advanced precancerous lesions (APL) in the colonic mucosa. Best Pract Res Clin Gastroenterol 2013; 27:235-56. [PMID: 23809243 DOI: 10.1016/j.bpg.2013.03.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Accepted: 03/08/2013] [Indexed: 01/31/2023]
Abstract
Colorectal cancer is a leading cause of cancer death worldwide. Most colorectal cancers are preventable. Surveillance colonoscopy is used to detect and remove precancerous lesions. Although the majority of precancerous lesions develop sporadically, some have an inherited component. In this review, we summarize the clinical, pathologic, and molecular features of advanced precancerous lesions of the colon. The most common and clinically important intestinal polyposis syndromes, and their genetics, are also discussed. Finally, current recommendations regarding the treatment and surveillance of precancerous lesions, both in the sporadic and in inherited setting, are reviewed.
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Affiliation(s)
- Bita V Naini
- David Geffen School of Medicine at UCLA, Department of Pathology & Lab Medicine, Box 951732, 1P-172 CHS, 10833 Le Conte Ave, Los Angeles, CA 90095-1732, USA.
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A correlation of the endoscopic characteristics of colonic laterally spreading tumours with genetic alterations. Eur J Gastroenterol Hepatol 2013; 25:319-26. [PMID: 23354161 DOI: 10.1097/meg.0b013e32835b57e7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
OBJECTIVES Laterally spreading tumours (LSTs) are a heterogeneous group of adenomas that are emerging as important precursors of colorectal cancer and in which the risk for cancer is related to their endoscopically definable morphology. It is currently unclear whether different molecular alterations determine their morphologies. We aimed to assess this relationship in LSTs using strict morphological classifications. METHODS We characterized 135 sessile adenomatous lesions (≥ 20 mm) according to histopathology and the Paris classification. We investigated key molecular changes commonly found in colorectal neoplasms, namely mutation of KRAS, BRAF, APC and CTNNB1 and microsatellite instability, and determined their relationship with morphology. RESULTS The Paris classification revealed a heterogeneous cohort comprising Is/IIa+Is (41.5%), IIa/IIb (53.3%) and IIc/IIa+IIc (5.2%) lesions. Histopathological analysis showed that 19 (14.1%) of these were sessile serrated adenomas. Here, we defined a group of 58 lesions that showed either Paris IIa or IIb morphology with no serrated histopathology. These 'classical LSTs' showed the following molecular characteristics: microsatellite instability 0/56 (0%), APC mutation 29/30 (96.7%), CTNNB1 mutation 2/55 (3.6%), KRAS mutation 24/55 (43.6%) and BRAF mutation 2/55 (3.6%). Separation of lesions according to surface morphology showed that KRAS mutations occurred much more frequently in granular (56.4%, 22/39) than in nongranular LSTs (12.5%, 1/16, P=0.004). CONCLUSION The microsatellite instable pathway is not important in the development of LSTs, which are instead likely to develop along a divergent chromosomal instability pathway. We demonstrate the biological significance of endoscopic findings by showing that the morphological characteristics of LSTs are underpinned by distinctive molecular profiles.
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Matsunoki A, Kawakami K, Kotake M, Kaneko M, Kitamura H, Ooi A, Watanabe G, Minamoto T. LINE-1 methylation shows little intra-patient heterogeneity in primary and synchronous metastatic colorectal cancer. BMC Cancer 2012; 12:574. [PMID: 23216958 PMCID: PMC3534591 DOI: 10.1186/1471-2407-12-574] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2012] [Accepted: 11/28/2012] [Indexed: 01/29/2023] Open
Abstract
Background Long interspersed nucleotide element 1 (LINE-1) hypomethylation is suggested to play a role in the progression of colorectal cancer (CRC). To assess intra-patient heterogeneity of LINE-1 methylation in CRC and to understand its biological relevance in invasion and metastasis, we evaluated the LINE-1 methylation at multiple tumor sites. In addition, the influence of stromal cell content on the measurement of LINE-1 methylation in tumor tissue was analyzed. Methods Formalin-fixed paraffin-embedded primary tumor tissue was obtained from 48 CRC patients. Matched adjacent normal colon tissue, lymph node metastases and distant metastases were obtained from 12, 18 and 7 of these patients, respectively. Three different areas were microdissected from each primary tumor and included the tumor center and invasive front. Normal mucosal and stromal cells were also microdissected for comparison with the tumor cells. The microdissected samples were compared in LINE-1 methylation level measured by multicolor MethyLight assay. The assay results were also compared between microdissected and macrodissected tissue samples. Results LINE-1 methylation within primary tumors showed no significant intra-tumoral heterogeneity, with the tumor center and invasive front showing identical methylation levels. Moreover, no difference in LINE-1 methylation was observed between the primary tumor and lymph node and distant metastases from the same patient. Tumor cells showed significantly less LINE-1 methylation compared to adjacent stromal and normal mucosal epithelial cells. Consequently, LINE-1 methylation was significantly lower in microdissected samples compared to macrodissected samples. A trend for less LINE-1 methylation was also observed in more advanced stages of CRC. Conclusions LINE-1 methylation shows little intra-patient tumor heterogeneity, indicating the suitability of its use for molecular diagnosis in CRC. The methylation is relatively stable during CRC progression, leading us to propose a new concept for the association between LINE-1 methylation and disease stage.
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Affiliation(s)
- Aika Matsunoki
- Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan
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