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Capello Ingold G, Martins da Fonseca J, Kolenda Zloić S, Verdan Moreira S, Kago Marole K, Finnegan E, Yoshikawa MH, Daugėlaitė S, Souza E Silva TX, Soato Ratti MA. Preoperative radiomics models using CT and MRI for microsatellite instability in colorectal cancer: a systematic review and meta-analysis. Abdom Radiol (NY) 2025:10.1007/s00261-025-04981-1. [PMID: 40347255 DOI: 10.1007/s00261-025-04981-1] [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: 02/16/2025] [Revised: 04/25/2025] [Accepted: 04/29/2025] [Indexed: 05/12/2025]
Abstract
OBJECTIVE Microsatellite instability (MSI) is a novel predictive biomarker for chemotherapy and immunotherapy response, as well as prognostic indicator in colorectal cancer (CRC). The current standard for MSI identification is polymerase chain reaction (PCR) testing or the immunohistochemical analysis of tumor biopsy samples. However, tumor heterogeneity and procedure complications pose challenges to these techniques. CT and MRI-based radiomics models offer a promising non-invasive approach for this purpose. MATERIALS AND METHODS A systematic search of PubMed, Embase, Cochrane Library and Scopus was conducted to identify studies evaluating the diagnostic performance of CT and MRI-based radiomics models for detecting MSI status in CRC. Pooled area under the curve (AUC), sensitivity, and specificity were calculated in RStudio using a random-effects model. Forest plots and a summary ROC curve were generated. Heterogeneity was assessed using I² statistics and explored through sensitivity analyses, threshold effect assessment, subgroup analyses and meta-regression. RESULTS 17 studies with a total of 6,045 subjects were included in the analysis. All studies extracted radiomic features from CT or MRI images of CRC patients with confirmed MSI status to train machine learning models. The pooled AUC was 0.815 (95% CI: 0.784-0.840) for CT-based studies and 0.900 (95% CI: 0.819-0.943) for MRI-based studies. Significant heterogeneity was identified and addressed through extensive analysis. CONCLUSION Radiomics models represent a novel and promising tool for predicting MSI status in CRC patients. These findings may serve as a foundation for future studies aimed at developing and validating improved models, ultimately enhancing the diagnosis, treatment, and prognosis of colorectal cancer.
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Xiao G, Li J, Deng L, Gao S, Tan C, He G, Du R. Microsatellite instability evaluation by a novel PCR-based 8-loci test kit in colorectal cancer. Biotechnol Appl Biochem 2024; 71:860-867. [PMID: 38556769 DOI: 10.1002/bab.2582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 03/18/2024] [Indexed: 04/02/2024]
Abstract
Microsatellite instability (MSI) assessment is strongly recommended for colorectal cancer patients, as MSI status is crucial in determining optimal treatment and predicting prognosis. This study evaluated the reliability and accuracy of a novel polymerase chain reaction (PCR)-based 8-loci MSI test kit, a rapid test kit designed to detect MSI, by comparing its performance with immunohistochemistry (IHC) and the National Cancer Institute (NCI) 2B3D Panel. MSI status was determined in 186 formalin-fixed paraffin-embedded (FFPE) colorectal cancer tissue samples with known mismatch repair (MMR) status by IHC using the novel PCR-based 8-loci MSI test kit. Additionally, the consistency between the NCI 2B3D Panel and the novel PCR-based 8-loci panel was compared using 69 FFPE tumor tissues paired with adjacent non-cancerous tissue. The novel PCR-based 8-loci MSI test kit and IHC demonstrated high concordance (overall agreement: 97.8%). However, four samples displayed discordant results, exhibiting MMR deficiency using IHC and microsatellite stability using the novel PCR-based 8-loci MSI test kit. Of the 69 samples reanalyzed using the NCI 2B3D Panel, high concordance with the novel PCR-based 8-loci MSI test kit was observed in 67 of 69 cases (overall agreement: 97.1%). The novel PCR-based 8-loci MSI test kit is a rapid and reliable tool for accurately detecting MSI status in colorectal cancer.
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Affiliation(s)
- Gaofang Xiao
- Department of Pathology, Shantou University Affiliated Yuebei People's Hospital, Shaoguan, Guangdong, China
| | - Jing Li
- Department of Pathology, Shantou University Affiliated Yuebei People's Hospital, Shaoguan, Guangdong, China
| | - Lijun Deng
- Department of Medical Engineering, Shantou University Affiliated Yuebei People's Hospital, Shaoguan, Guangdong, China
| | - Shuangquan Gao
- Department of Pathology, Shantou University Affiliated Yuebei People's Hospital, Shaoguan, Guangdong, China
| | - Caiyun Tan
- Department of Pathology, Shantou University Affiliated Yuebei People's Hospital, Shaoguan, Guangdong, China
| | - Guiqing He
- Department of Pathology, Shantou University Affiliated Yuebei People's Hospital, Shaoguan, Guangdong, China
| | - Richang Du
- Department of Pathology, Shantou University Affiliated Yuebei People's Hospital, Shaoguan, Guangdong, China
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Waller J, Gu L, De Hoedt AM, Freedland SJ, Wang T, Amonkar M, Aurora-Garg D, Liaw KL, Wehn A, Klaassen Z. DNA mismatch repair and microsatellite instability in colorectal tumors: an observational study in the Veterans Affairs Health Care System. Future Oncol 2022; 18:649-660. [DOI: 10.2217/fon-2021-0874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Background: Challenges in identifying microsatellite instability (MSI)/mismatch repair (MMR)–tested colorectal carcinoma (CRC) patients in electronic health records have led to gaps in the understanding of MSI-high/deficient mismatch repair prevalence. Methods: An algorithm to identify MSI-/MMR-tested Veterans Affairs patients was developed and an observational study of adult CRC patients with MSI/MMR testing from 2010 to 2018 was undertaken. Results: An optimized model to identify MSI-/MMR-tested patients yielded high positive predictive value (89.0%) and specificity (97.8%). The authors observed MSI-high/deficient mismatch repair CRC in 54 of 291 patients (18.6%); highest frequencies were observed in Stages II (25.9%) and III (22.6%) and lowest in Stage IV (5.8%). Conclusions: In this real-world study, the authors proposed a novel method of identifying MSI-/MMR-tested patients. Further validation and refinement of this model, and study in a larger CRC cohort, is warranted.
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Affiliation(s)
- Justin Waller
- Durham Veterans Affairs Health Care System, Durham, NC 27705, USA
| | - Lin Gu
- Durham Veterans Affairs Health Care System, Durham, NC 27705, USA
- Duke Cancer Institute, Biostatistics Shared Resource, Durham, NC 27710, USA
| | | | - Stephen J Freedland
- Durham Veterans Affairs Health Care System, Durham, NC 27705, USA
- Center for Integrated Research on Cancer & Lifestyle, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Tongtong Wang
- Epidemiology, Merck & Co., Inc., Kenilworth, NJ 07033, USA
| | - Mayur Amonkar
- Center for Observational & Real-World Evidence, Merck & Co., Inc., Kenilworth, NJ 07033, USA
| | | | - Kai-Li Liaw
- Epidemiology, Merck & Co., Inc., Kenilworth, NJ 07033, USA
| | - Amy Wehn
- Research Science, Merck & Co., Inc., Kenilworth, NJ 07033, USA
| | - Zachary Klaassen
- Durham Veterans Affairs Health Care System, Durham, NC 27705, USA
- Georgia Cancer Center, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
- Department of Surgery, Division of Urology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
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Toh JWT, Phan K, Reza F, Chapuis P, Spring KJ. Rate of dissemination and prognosis in early and advanced stage colorectal cancer based on microsatellite instability status: systematic review and meta-analysis. Int J Colorectal Dis 2021; 36:1573-1596. [PMID: 33604737 DOI: 10.1007/s00384-021-03874-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/27/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION For the past two decades, microsatellite instability (MSI) has been reported as a robust clinical biomarker associated with survival advantage attributed to its immunogenicity. However, MSI is also associated with high-risk adverse pathological features (poorly differentiated, mucinous, signet cell, higher grade) and exhibits a double-edged sword phenomenon. We performed a systematic review and meta-analysis to evaluate the rate of dissemination and the prognosis of early and advanced stage colorectal cancer based on MSI status. METHODS A systematic literature search of original studies was performed on Ovid searching MEDLINE, Embase, Cochrane Database of Systematic Reviews, American College of Physicians ACP Journal Club, Database of Abstracts of Reviews of Effects DARE, Clinical Trials databases from inception of database to June 2019. Colorectal cancer, microsatellite instability, genomic instability and DNA mismatch repair were used as key words or MeSH terms. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Data were pooled using a random-effects model with odds ratio (OR) as the effect size. Statistical analysis was performed using RevMan ver 5.3 Cochrane Collaboration. RESULTS From 5288 studies, 136 met the inclusion criteria (n = 92,035; MSI-H 11,746 (13%)). Overall, MSI-H was associated with improved OS (OR, 0.81; 95% CI 0.73-0.90), DFS (OR, 0.73; 95% CI 0.66-0.81) and DSS (OR, 0.69; 95% CI 0.52-0.90). Importantly, MSI-H had a protective effect against dissemination with a significantly lower rate of lymph node and distant metastases. By stage, the protective effect of MSI-H in terms of OS and DFS was observed clearly in stage II and stage III. Survival in stage I CRC was excellent irrespective of MSI status. In stage IV CRC, without immunotherapy, MSI-H was not associated with any survival benefit. CONCLUSIONS MSI-H CRC was associated with an overall survival benefit with a lower rate of dissemination. Survival benefit was clearly evident in both stage II and III CRC, but MSI-H was neither a robust prognostic marker in stage I nor stage IV CRC without immunotherapy.
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Affiliation(s)
- James W T Toh
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia. .,Discipline of Surgery, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. .,Discipline of Surgery, The University of New South Wales, Sydney, NSW, Australia. .,Medical Oncology, Ingham Institute for Applied Medical Research, School of Medicine Western Sydney University and South Western Clinical School, University of New South Wales, NSW, Sydney, Australia.
| | - Kevin Phan
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia
| | - Faizur Reza
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia
| | - Pierre Chapuis
- Discipline of Surgery, Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Kevin J Spring
- Medical Oncology, Ingham Institute for Applied Medical Research, School of Medicine Western Sydney University and South Western Clinical School, University of New South Wales, NSW, Sydney, Australia
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Wang SM, Jiang B, Deng Y, Huang SL, Fang MZ, Wang Y. Clinical significance of MLH1/ MSH2 for stage II/III sporadic colorectal cancer. World J Gastrointest Oncol 2019; 11:1065-1080. [PMID: 31798786 PMCID: PMC6883179 DOI: 10.4251/wjgo.v11.i11.1065] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 08/10/2019] [Accepted: 09/10/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The development of colorectal cancer (CRC) is a complicated multistep process that involves an accumulation of mutations in tumor suppressor genes and oncogenes. In the process of DNA replication, base mismatch often occurs due to various factors leading to abnormal expression of mismatch repair genes (MMR), among which MLH1 and MSH2 are the most important. Recently, numerous studies indicated that MLH1/MSH2 phenotype is associated with CRC. We wanted to elucidate the role of MLH1/MSH2 in the prediction and prognosis of CRC through long-term clinical observation.
AIM To evaluate the prognostic and predictive significance of MLH1/MSH2 in patients with stage II-III CRC using immunohistochemical analysis and GeneScan.
METHODS Specimens from 681 patients with CRC (395 stage II and 286 stage III, 387 males and 294 females) who underwent curative surgical resection from 2013 to 2016 were tested. Immunohistochemistry was used to analyze MMR status and the microsatellite status of 133 patients was determined by GeneScan analysis.
RESULTS Five hundred and fifty (80.76%) patients were MLH1/MSH2 positive and 131 (19.24%) were negative by immunohistochemistry. MLH1/MSH2-positive tumors were significantly more frequent in the colon than in the rectum, and had poor differentiation and less mucin production (P < 0.05). Patients of different groups did not differ in terms of age, gender, tumor size, tumor stage, lymphocytic infiltration, or circumscribed margin. MLH1/MSH2-negative patients had a more favorable OS than MLH1/MSH2-positive patients (P < 0.001). Univariate and multivariate analyses demonstrated MLH1/MSH2 expression as an independent prognostic and predictive factor for stage II/III CRC. MLH1/MSH2 expression was a strong prognostic factor in all patients [P < 0.001, hazard ratio (HR) = 4.064, 95%CI: 2.241–7.369]. Adjuvant chemotherapy had a greater correlation with survival advantage in MLH1/MSH2-negative patients with stage III disease (P < 0.001, HR = 7.660, 95%CI: 2.974–15.883). However, patients with stage II disease or MLH1/MSH2-positive patients with stage III disease did not benefit from adjuvant chemotherapy. GeneScan analysis demonstrated that among 133 patients, 105 (78.95%) were microsatellite stable, and 28 (21.05%) had microsatellite instability (MSI), including 18 (13.53%) with high MSI and 10 (7.52%) with low MSI. This is consistent with the immunohistochemical results.
CONCLUSION MLH1/MSH2 phenotype constitutes a pathologically and clinically distinct subtype of sporadic CRC. MLH1/MSH2 is an independent prognostic and predictive factor for outcome of stage II-III CRC.
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Affiliation(s)
- Shui-Ming Wang
- National Center of Colorectal Disease, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu Province, China
| | - Bin Jiang
- National Center of Colorectal Disease, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu Province, China
| | - Youping Deng
- Bioinformatics Core, Department of Complementary and Integrative Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, HI 96813, United States
| | - Shu-Liang Huang
- Department of Pathology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu Province, China
| | - Ming-Zhi Fang
- Department of Oncology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu Province, China
| | - Yu Wang
- Bioinformatics Core, Department of Complementary and Integrative Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, HI 96813, United States
- Department of Oncology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu Province, China
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Wang B, Li F, Zhou X, Ma Y, Fu W. Is microsatellite instability-high really a favorable prognostic factor for advanced colorectal cancer? A meta-analysis. World J Surg Oncol 2019; 17:169. [PMID: 31639018 PMCID: PMC6805421 DOI: 10.1186/s12957-019-1706-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 09/09/2019] [Indexed: 01/08/2023] Open
Abstract
Background Stage II colorectal cancer with microsatellite instability-high (MSI-H) has been proven to have a better prognosis. However, in advanced stage, this trend remains controversial. This study aimed to explore the prognostic role of MSI-H in stage III and IV colorectal cancer (CRC) through meta-analysis. Methods A comprehensive search was performed in PubMed, Cochrane Central Library, and Embase databases. All randomized clinical trials and non-randomized studies were included based on inclusion and exclusion criteria and on survival after a radical operation with or without chemotherapy. The adjusted log hazard ratios (HRs) were used to estimate the prognostic value between MSI-H and microsatellite-stable CRCs. The random-effects model was used to estimate the pooled effect size. Results Thirty-six studies were included. Randomized controlled trials (RCT) and non-RCT were analyzed separately. For stage III CRCs, pooled HR for overall survival (OS) was 0.96 (95% confidence interval [CI] 0.75–.123) in the RCT subgroup and 0.89 (95% CI 0.62–1.28) in the non-RCT subgroup. For disease-free survival (DFS), the HR for the RCT group was 0.83 (95% CI 0.65–1.07), similar to the non-RCT subgroup (0.83, 95% CI 0.65–1.07). Disease-specific survival (DSS) was also calculated, which had an HR of 1.07 (95% CI 0.68–1.69) in the non-RCT subgroup. All these results showed that MSI-H has no beneficial effects in stage III CRC. For stage IV CRC, the HR for OS in the RCT subgroup was 1.23 (95% CI 0.92–1.64) but only two RCTs were included. For non-RCT study, the combined HR for OS and DFS was 1.10 (95% CI 0.77–1.51) and 0.72 (95% CI 0.53–0.98), respectively, suggesting the beneficial effect for DFS and non-beneficial effect for OS. Conclusion For stage III CRC, MSI-H had no prognostic effect for OS, DFS, and DSS. For stage IV CRC, DFS showed a beneficial result, whereas OS did not; however, the included studies were limited and needed further exploration.
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Affiliation(s)
- Bingyan Wang
- Department of General Surgery, Peking University Third Hospital, Beijing, China
| | - Fei Li
- Department of General Surgery, Peking University Third Hospital, Beijing, China
| | - Xin Zhou
- Department of General Surgery, Peking University Third Hospital, Beijing, China
| | - Yanpeng Ma
- Department of General Surgery, Peking University Third Hospital, Beijing, China
| | - Wei Fu
- Department of General Surgery, Peking University Third Hospital, Beijing, China.
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Deng Z, Qin Y, Wang J, Wang G, Lang X, Jiang J, Xie K, Zhang W, Xu H, Shu Y, Zhang Y. Prognostic and predictive role of DNA mismatch repair status in stage II‐III colorectal cancer: A systematic review and meta‐analysis. Clin Genet 2019; 97:25-38. [PMID: 31432497 DOI: 10.1111/cge.13628] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 08/15/2019] [Accepted: 08/20/2019] [Indexed: 12/21/2022]
Affiliation(s)
- Zhujun Deng
- Precision Medicine Center, State Key Laboratory of Biotherapy, and Precision Medicine Key Laboratory of Sichuan Province, West China HospitalSichuan University Chengdu Sichuan China
| | - Yun Qin
- Department of Radiology, West China HospitalSichuan University Chengdu Sichuan China
| | - Jing Wang
- Precision Medicine Center, State Key Laboratory of Biotherapy, and Precision Medicine Key Laboratory of Sichuan Province, West China HospitalSichuan University Chengdu Sichuan China
| | - Gang Wang
- Precision Medicine Center, State Key Laboratory of Biotherapy, and Precision Medicine Key Laboratory of Sichuan Province, West China HospitalSichuan University Chengdu Sichuan China
| | - Xiaoqiang Lang
- Precision Medicine Center, State Key Laboratory of Biotherapy, and Precision Medicine Key Laboratory of Sichuan Province, West China HospitalSichuan University Chengdu Sichuan China
| | - Juan Jiang
- Precision Medicine Center, State Key Laboratory of Biotherapy, and Precision Medicine Key Laboratory of Sichuan Province, West China HospitalSichuan University Chengdu Sichuan China
| | - Kang Xie
- Precision Medicine Center, State Key Laboratory of Biotherapy, and Precision Medicine Key Laboratory of Sichuan Province, West China HospitalSichuan University Chengdu Sichuan China
| | - Wengeng Zhang
- Precision Medicine Center, State Key Laboratory of Biotherapy, and Precision Medicine Key Laboratory of Sichuan Province, West China HospitalSichuan University Chengdu Sichuan China
| | - Heng Xu
- Precision Medicine Center, State Key Laboratory of Biotherapy, and Precision Medicine Key Laboratory of Sichuan Province, West China HospitalSichuan University Chengdu Sichuan China
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital, Sichuan University Chengdu Sichuan China
| | - Yang Shu
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital, Sichuan University Chengdu Sichuan China
| | - Yan Zhang
- Department of Thoracic Oncology, Cancer CenterWest China Hospital, Sichuan University Chengdu Sichuan China
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Evaluation of a Fully Automated Idylla Test System for Microsatellite Instability in Colorectal Cancer. Clin Colorectal Cancer 2019; 18:e316-e323. [PMID: 31375292 DOI: 10.1016/j.clcc.2019.05.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 04/05/2019] [Accepted: 05/28/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Microsatellite instability (MSI) is a phenotype commonly observed in colorectal cancer, and is caused by a deficient mismatch repair system. Determining MSI status greatly aids tumor prognosis and treatment plans in colorectal cancer, and plays a critical role in recent United States Food and Drug Administration-approved immunotherapies. As recognition of its importance grows, MSI has been identified in more types of cancers, underscoring the importance of accurate assays for determining MSI status in tumor cells. Currently, tumor MSI status is detected via polymerase chain reaction-based methods or immunohistochemistry. MATERIALS AND METHODS In this study, we tested a new, fully automated MSI detection system (Idylla MSI detection kit) released by Biocartis. We evaluated 42 formalin-fixed paraffin-embedded tumor tissues, which were clinically tested for MSI status using the polymerase chain reaction or immunohistochemistry method, with the Idylla MSI detection system. RESULTS The Idylla MSI detection system showed an overall 97.62% concordance rate with previously used methods. Moreover, this fully automated system requires less than 5 minutes "hands on" preparation time and 150 minutes total run time per sample. CONCLUSION The Biocartis Idylla MSI kit proves a powerful tool to accurately detect MSI status in tumor cells in a rapid and almost labor-free manner.
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Lang-Schwarz C, Melcher B, Haumaier F, Schneider-Fuchs A, Lang-Schwarz K, Krugmann J, Vieth M, Sterlacci W. Budding, tumor-infiltrating lymphocytes, gland formation: scoring leads to new prognostic groups in World Health Organization low-grade colorectal cancer with impact on survival. Hum Pathol 2019; 89:81-89. [PMID: 31054898 DOI: 10.1016/j.humpath.2019.04.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 04/11/2019] [Accepted: 04/25/2019] [Indexed: 01/27/2023]
Abstract
Grading for colorectal carcinoma (CRC) is traditionally based on the percentage of gland formation. In recent years, high-grade CRC has become subject to more precise molecular grading strategies. Most, however, are low-grade cases according to the World Health Organization (WHO) with inhomogenous outcomes due to still insufficient characterization. On the other hand, budding and tumor-infiltrating lymphocytes have developed as interesting additive prognostic factors in CRC. Especially budding has been very well defined by the International Tumor Budding Consensus Conference recently. We analyzed a large collective of 576 WHO low-grade CRC cases, stages I to IV, diagnosed between 2005 and 2016 in terms of gland formation, budding, and tumor-infiltrating lymphocytes and developed a new, morphology-based risk score, taking into account each of the 3 parameters. For each parameter, 1 to 2 points were given, resulting in a sum score, dividing the CRC cases into a low-, an intermediate-, and a high-risk group. By our score, 179 (34.9%) of the cases were grouped as low risk, 241 (53.5) as intermediate risk, and 92 (35.5%) as high risk. The 3 groups differed significantly in pT, pN, and M as well as tumor stages, lymphatic vessel invasion, venous invasion, and overall survival (0.;P < .001 for low risk versus high risk, P = .038 for low versus intermediate risk, and P = .036 for intermediate versus high risk; log rank: median, 94.0 months [95% confidence interval {CI}, 74.9-113.1] for low risk; median, 63.0 months [95% CI, 44.0-82.0] for intermediate risk; and median, 40.0 months [95% CI, 23.4-56.7] for high risk) in Kaplan-Meier-analysis. Our proposed Bayreuth score enables separating the large group of WHO low-grade CRC cases into subgroups, which differ significantly in outcome.
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Affiliation(s)
| | - Balint Melcher
- Institute of Pathology, Klinikum Bayreuth, 95445 Bayreuth, Germany
| | | | | | - Klaus Lang-Schwarz
- Department of Anesthesiology, Klinikum Bayreuth, 95445 Bayreuth, Germany
| | - Jens Krugmann
- Institute of Pathology, Klinikum Bayreuth, 95445 Bayreuth, Germany
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, 95445 Bayreuth, Germany
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Comprehensive analysis of PD-L1 expression, HER2 amplification, ALK/EML4 fusion, and mismatch repair deficiency as putative predictive and prognostic factors in ovarian carcinoma. Virchows Arch 2019; 474:599-608. [DOI: 10.1007/s00428-019-02528-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Revised: 12/26/2018] [Accepted: 01/17/2019] [Indexed: 12/11/2022]
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Otto W, Macrae F, Sierdziński J, Smaga J, Król M, Wilińska E, Zieniewicz K. Microsatellite instability and manifestations of angiogenesis in stage IV of sporadic colorectal carcinoma. Medicine (Baltimore) 2019; 98:e13956. [PMID: 30608431 PMCID: PMC6344194 DOI: 10.1097/md.0000000000013956] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 11/05/2018] [Accepted: 12/11/2018] [Indexed: 12/20/2022] Open
Abstract
Angiogenesis represents one of the critical mechanisms that facilitates carcinoma development. The study objective was to evaluate whether the microsatellite instability of colorectal carcinoma has impact on the angiogenesis activity in liver metastases.In a cohort of 80 randomly selected patients with stage IV colorectal carcinoma, 30% were recognized as microsatellite unstable (Microsatellite instability high-frequency (MSI-H)). The endothelial progenitor cell fraction (CD309+) was counted within the subpopulation of CD34+CD45+ cell and CD34+CD45- cells by flow cytometer. vascular endothelial growth factor (VEGF) factor levels were quantified in serum samples by enzyme-linked immunosorbent assay (ELISA). A control group consisted of 36 healthy volunteers. The relationship of genomic instability to angiogenesis activity was evaluated by multivariate analysis in comparison to the controls, adopting a P < .05 value as statistically significant.The expression of endothelial progenitor cells (EPCs) and VEGF was significantly higher in MSI-H compared to both microsatellite stability (MSS) patients and healthy controls (P < .008). Multi-parametric analysis showed microsatellite instability (OR=9.12, P < .01), metastases in both lobes (OR = 32.83, P < .001) and simultaneous metastases outside liver (OR = 8.32, P < .01), as independent factors associated with increased angiogenesis as assessed by measures of EPC and VEGF. A higher percentage of EPCs within the white blood cell fraction (total % EPCs / white blood cells (WBC)) and higher serum concentrations of VEGF were present in patients with MSI-H colorectal cancer, and not with MSS cancers (P < .001).MSI-H patients with colorectal cancer metastases are associated with the overexpression of circulating EPCs and VEGF, potentially driving angiogenesis. This should be considered in therapeutic decision-making.
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Affiliation(s)
| | - Finlay Macrae
- Department of Colorectal Medicine and Genetics, The Royal Melbourne Hospital, and Department of Medicine, The University of Melbourne, Australia
| | | | | | - Maria Król
- Department of Oncology, Hematology & Internal Medicine
| | - Ewa Wilińska
- Department of Pathology Central Teaching Hospital, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland
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Matevska-Geshkovska N, Staninova-Stojovska M, Kapedanovska-Nestorovska A, Petrushevska-Angelovska N, Panovski M, Grozdanovska B, Mitreski N, Dimovski A. Influence of MSI and 18q LOH markers on capecitabine adjuvant monotherapy in colon cancer patients. Pharmgenomics Pers Med 2018; 11:193-203. [PMID: 30464574 PMCID: PMC6219100 DOI: 10.2147/pgpm.s172467] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
PURPOSE The aim of this study was to evaluate whether pretreatment analysis of selected molecular markers can be used for the prediction of disease-free survival (DFS)/overall survival (OS) of capecitabine adjuvant monotherapy in colon cancer patients. PATIENTS AND METHODS A total of 126 patients enrolled in a capecitabine Phase IV clinical trial were analyzed for microsatellite instability (MSI), 18q loss of heterozygosity (LOH), thymidylate synthase (TYMS) 5' variable number of tandem repeat (VNTR), and methylene tetrahydrofolate reductase (MTHFR) C677T variants. The significance in predicting 5-year DFS/OS was assessed by Kaplan-Meier and Cox regression analyses. RESULTS The MSI-high (MSI-H) genotype was significantly associated with DFS (HR 0.205, 95% CI 0.05-0.88, P=0.033) and OS (HR 0.208, 95% CI 0.05-0.89, P=0.035) compared to the microsatellite stable genotype. In models stratified according to clinicopathologic characteristics, the MSI-H genotype remained a positive predictive factor for DFS/OS only in patients with stage III (P=0.023) and patients with tumors localized proximally to the splenic flexure (P=0.004). Distal colon cancers with 18q LOH have a greater survival rate when treated with capecitabine than patients with stable tumors (81.3% vs 50.0%, HR for relapse 0.348, 95% CI 0.13-0.97, P=0.043). TYMS 5'VNTR and MTHFR C677T variants were not associated with DFS or OS. CONCLUSION MSI and 18q LOH markers have the potential to be utilized in the selection of colon cancer patients eligible for capecitabine adjuvant monotherapy.
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Affiliation(s)
- Nadica Matevska-Geshkovska
- Center for Biomolecular Pharmaceutical Analyses, Faculty of Pharmacy, Ss. Cyril and Methodius University in Skopje, Skopje, Macedonia,
| | - Marija Staninova-Stojovska
- Center for Biomolecular Pharmaceutical Analyses, Faculty of Pharmacy, Ss. Cyril and Methodius University in Skopje, Skopje, Macedonia,
| | | | | | - Milco Panovski
- University Clinic for Abdominal Surgery, Ss. Cyril and Methodius University in Skopje, Skopje, Macedonia
| | - Biljana Grozdanovska
- University Clinic for Oncology and Radiotherapy, Ss. Cyril and Methodius University in Skopje, Skopje, Macedonia
| | - Nenad Mitreski
- University Clinic for Oncology and Radiotherapy, Ss. Cyril and Methodius University in Skopje, Skopje, Macedonia
| | - Aleksandar Dimovski
- Center for Biomolecular Pharmaceutical Analyses, Faculty of Pharmacy, Ss. Cyril and Methodius University in Skopje, Skopje, Macedonia,
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Microsatellite Instability in Mouse Models of Colorectal Cancer. Can J Gastroenterol Hepatol 2018; 2018:6152928. [PMID: 29686976 PMCID: PMC5852867 DOI: 10.1155/2018/6152928] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 01/20/2018] [Accepted: 01/29/2018] [Indexed: 02/08/2023] Open
Abstract
Microsatellite instability (MSI) is caused by DNA mismatch repair deficiency and is an important prognostic and predictive biomarker in colorectal cancer but relatively few studies have exploited mouse models in the study of its clinical utility. Furthermore, most previous studies have looked at MSI in the small intestine rather than the colon of mismatch repair deficient Msh2-knockout (KO) mice. Here we compared Msh2-KO, p53-KO, and wild type (WT) mice that were treated with the carcinogen azoxymethane (AOM) and the nonsteroidal anti-inflammatory drug sulindac or received no treatment. The induced tumors and normal tissue specimens from the colon were analysed with a panel of five mononucleotide repeat markers. MSI was detected throughout the normal colon in untreated Msh2-KO mice and this involved contraction of the repeat sequences compared to WT. The markers with longer mononucleotide repeats (37-59) were the most sensitive for MSI while the markers with shorter repeats (24) showed only minor change. AOM exposure caused further contraction of the Bat37 and Bat59 repeats in the distal colon of Msh2-KO mice which was reversed by sulindac. Thus AOM-induced carcinogenesis is associated with increased instability of mononucleotide repeats in the colon of Msh2-KO mice but not in WT or p53-KO mice. Chemoprevention of these tumors by sulindac treatment reversed or prevented the increased MSI.
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14
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Wang SC, Schulman-Marcus J, Fantauzzi J, Bevington T, Sayegh A, Lee E, Ata A, Kambam M, Sidhu M, Lyubarova R. Colon cancer laterality is associated with atherosclerosis and coronary artery disease. J Gastrointest Oncol 2018; 10:30-36. [PMID: 30788156 DOI: 10.21037/jgo.2018.09.18] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background Primary right-sided colon cancer (RCC) is associated with a higher mortality than left-sided colon cancer (LCC), but the etiology of this phenomenon remains unclear. We sought to study whether cancer laterality is associated with the prevalence of clinical coronary artery disease, calcific atherosclerosis as measured by computed tomography (CT), and cardiovascular risk factors. Methods We conducted a single center retrospective study of 546 participants who had previously been diagnosed with colon cancer between January 2005 and December 2014. The presence of coronary and aortic calcifications was assessed by CT in 486 of these patients. We examined the prevalence of clinical cardiovascular disease (CAD) (prior myocardial infarction or revascularization), comorbidities, coronary and aortic calcification in patients with RCC (n=261) and LCC (n=285). Logistic regression analysis was performed to assess the likelihood of clinical CAD and calcific atherosclerosis by cancer laterality. Results Compared to patients with LCC, patients with RCC were more likely to have hypertension, hyperlipidemia, hypothyroidism and clinical CAD. In the patients with available CT scans, RCC was associated with higher prevalence of coronary, thoracic, and abdominal calcifications than LCC. On univariate and multivariate analyses, RCC was associated with higher likelihood of clinical CAD (adjusted risk ratio 2.15, 95% CI, 1.37-3.38, P=0.001) as well as radiological evidence of calcific atherosclerosis compared to LCC. Conclusions we found that both clinical CAD and vascular calcifications are prevalent in patients with colon cancer, and are independently increased in patients with RCC compared to LCC.
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Affiliation(s)
- Stephani C Wang
- Department of Medicine, Albany Medical Center, Albany, NY, USA
| | | | - John Fantauzzi
- Department of Radiology, Albany Medical Center, Albany, NY, USA
| | | | - Anthony Sayegh
- Department of Radiology, Albany Medical Center, Albany, NY, USA
| | - Edward Lee
- Division of Colorectal Surgery, Department of Surgery, Albany Medical Center, Albany, NY, USA
| | - Ashar Ata
- Division of Colorectal Surgery, Department of Surgery, Albany Medical Center, Albany, NY, USA
| | | | - Mandeep Sidhu
- Division of Cardiology, Department of Medicine, Albany Medical Center, Albany, NY, USA
| | - Radmila Lyubarova
- Division of Cardiology, Department of Medicine, Albany Medical Center, Albany, NY, USA
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15
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Affiliation(s)
- D Lawes
- Academic Division of Surgical Specialties, Royal Free and University College Medical School, Charles Bell House, 67-73 Riding House Street, London W1W 7EJ, UK
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16
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Interleukin-8 mRNA Expression in Locally Advanced Colorectal Cancer Patients. CURRENT HEALTH SCIENCES JOURNAL 2017; 43:209-213. [PMID: 30595877 PMCID: PMC6284832 DOI: 10.12865/chsj.43.03.04] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 09/16/2017] [Indexed: 11/18/2022]
Abstract
Purpose: Interleukin-8 (IL-8) has been proven to promote progression of malignant tumours and control angiogenesis processes. We aim to determine and compare interleukin-8 (IL-8) gene expression level in colorectal tumors (CCR) and peritumoral samples obtained through endoscopic biopsy. Material and methods: Total mRNA was obtained from both tumoral and peritumoral tissue samples collected from patients diagnosed with colorectal cancer. Through Quantitative Real Time PCR, IL-8 gene expression was assessed in both pathologic tissue and adjacent normal mucosa. Results: In our cohort, IL8 expression was higher in adjacent normal mucosa than in tumoral tissue, in all the samples. Further studies on larger groups are required to validate our results.
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17
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Yan WY, Hu J, Xie L, Cheng L, Yang M, Li L, Shi J, Liu BR, Qian XP. Prediction of biological behavior and prognosis of colorectal cancer patients by tumor MSI/MMR in the Chinese population. Onco Targets Ther 2016; 9:7415-7424. [PMID: 27994472 PMCID: PMC5153316 DOI: 10.2147/ott.s117089] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Colorectal cancers (CRCs) exhibiting microsatellite instability (MSI) have special biological behavior. The clinical predictors for MSI and its survival relevance for the Chinese population were still unclear. Seven hundred ninety-five CRC patients were retrospectively assessed. Mismatch repair (MMR) proteins (MSH2, MSH6, PMS1, and MLH1) expression was detected by immunohistochemistry using tumor tissues of all patients. DNA MSI status was analyzed by polymerase chain reaction in 182 samples randomly selected from the 795 cases. Among all CRC tumor tissues, 97 cases (12.2%) were with an MMR protein-deficient (MMR-D) phenotype, whereas 698 cases (87.8%) were with an MMR proteins intact (MMR-I) phenotype. A total of 21 (11.5%) CRCs were identified as having high microsatellite instability, 156 (85.7%) tumors were having microsatellite stability (MSS), and five (2.7%) were having low microsatellite instability. Importantly, MMR status was demonstrated to be moderately consistent with MSI status (κ=0.845, 95% confidence interval [CI] 0.721, 0.969). Unconditional logistic regression analysis revealed age, number of lymph node, tumor diameter, and tumor site as predictors for MSI with a substantial ability to discriminate different MSI status by area under curve of 80.62% using receiver operation curve. Compared with MMR-I, MMR-D was an independent prognostic factor for longer overall survival (hazard ratio =0.340, 95% CI 0.126, 0.919; P=0.034). MMR-D is an independent prognostic factor for better outcome. Our results may provide evidence for individualized diagnosis and treatment of CRC, but this will require further validation in larger sample studies.
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Affiliation(s)
- Wen-Yue Yan
- The Comprehensive Cancer Center, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine
| | - Jing Hu
- The Comprehensive Cancer Center, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine; The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
| | - Li Xie
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
| | - Lei Cheng
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
| | - Mi Yang
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
| | - Li Li
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
| | - Jiong Shi
- Department of Pathology, Drum Tower Hospital, Medical School of Nanjing University, Jiangsu, People's Republic of China
| | - Bao-Rui Liu
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
| | - Xiao-Ping Qian
- The Comprehensive Cancer Center, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine; The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
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18
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Liu Q, Zhang B. Integrative Omics Analysis Reveals Post-Transcriptionally Enhanced Protective Host Response in Colorectal Cancers with Microsatellite Instability. J Proteome Res 2016; 15:766-76. [PMID: 26680540 PMCID: PMC4782175 DOI: 10.1021/acs.jproteome.5b00847] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Indexed: 12/19/2022]
Abstract
Microsatellite instability (MSI) is a frequent and clinically relevant molecular phenotype in colorectal cancer. MSI cancers have favorable survival compared with microsatellite stable cancers (MSS), possibly due to the pronounced tumor-infiltrating lymphocytes observed in MSI cancers. Consistent with the strong immune response that MSI cancers trigger in the host, previous transcriptome expression studies have identified mRNA signatures characteristic of immune response in MSI cancers. However, proteomics features of MSI cancers and the extent to which the mRNA signatures are reflected at the protein level remain largely unknown. Here, we performed a comprehensive comparison of global proteomics profiles between MSI and MSS colorectal cancers in The Cancer Genome Atlas (TCGA) cohort. We found that protein signatures of MSI are also associated with increased immunogenicity. To reliably quantify post-transcription regulation in MSI cancers, we developed a resampling-based regression method by integrative modeling of transcriptomics and proteomics data sets. Compared with the popular simple method, which detects post-transcriptional regulation by either identifying genes differentially expressed at the mRNA level but not at the protein level or vice versa, our method provided a quantitative, more sensitive, and accurate way to identify genes subject to differential post-transcriptional regulation. With this method, we demonstrated that post-transcriptional regulation, coordinating protein expression with key players, initiates de novo and enhances protective host response in MSI cancers.
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Affiliation(s)
- Qi Liu
- Department
of Biomedical Informatics, Vanderbilt University
School of Medicine, Nashville, Tennessee 37232, United States
- Center
for Quantitative Sciences, Vanderbilt University
School of Medicine, Nashville, Tennessee 37232, United States
| | - Bing Zhang
- Department
of Biomedical Informatics, Vanderbilt University
School of Medicine, Nashville, Tennessee 37232, United States
- Center
for Quantitative Sciences, Vanderbilt University
School of Medicine, Nashville, Tennessee 37232, United States
- Department
of Cancer Biology, Vanderbilt University
School of Medicine, Nashville, Tennessee 37232, United States
- Vanderbilt
Ingram Cancer Center, Vanderbilt University
School of Medicine, Nashville, Tennessee 37232, United States
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Abstract
PURPOSE Colorectal cancer has a distinct clinicopathologic presentation in younger patients. The aim of this paper was to evaluate the outcome of younger (age below 50 y) and older patients with stage IV (advanced) colorectal cancer in the modern era of combination chemotherapy. METHODS Cases of metastatic colorectal cancer reported in Surveillance, Epidemiology, and End Results registry (1973 to 2008) were reviewed. Demographics, tumor characteristics, and overall and cancer-specific survivals in patients below 50 and above 50 years of age were compared by Cox proportional hazard analyses. Joinpoint regression analysis was used to evaluate secular trends in 2-year survival. RESULTS Younger patients had a greater proportion of negative clinicopathologic features (male sex, African American ethnicity, and signet ring or mucinous histology). In multivariate analysis, older age, male sex, African American ethnicity, right-sided tumors, and signet ring histology were associated with higher mortality risk. Younger patients had improved survival (hazard ratio 0.72; 95% confidence interval: 0.70-0.75) compared with older patients, whereas all patients experienced increased 2-year survival by joinpoint analysis beginning in 1999-2000. CONCLUSIONS The results confirm decreased mortality from advanced colorectal cancer in the era of modern combination chemotherapy in younger and older patients. Younger age, non-right-sided tumors, and absence of signet ring histology significantly associate with better survival.
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20
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Neumann JHL, Jung A, Kirchner T. [Molecular pathology of colorectal cancer]. DER PATHOLOGE 2016; 36:137-44. [PMID: 25777075 DOI: 10.1007/s00292-015-0005-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
In recent years, several predictive and prognostic biomarkers have been established in colorectal cancer (CRC). The RAS-mutation status is widely applied in the daily routine diagnostic as predictive biomarker for treatment with EGFR-inhibitors. A BRAF- mutation has no predictive value in this context. The detection of high-grade microsatellite instability (MSI-H) is a predictive biomarker for response to 5-Fluoruracil-monotherapy. Prognostic biomarkers in CRC are the MSI-status and the mutational status of BRAF. According to the current WHO classification poorly and undifferentiated CRC and MSI-associated special morphological subtypes are molecular graded depending on their MSI-status. The detection of a BRAF-mutation in the context of microsatellite stability (MSS) is associated with a very poor prognosis and thus represents the most aggressive molecular subtype of CRC. In patients with positive Bethesda criteria a stepwise immunohistochemical and molecular diagnostic scheme is proposed.
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Affiliation(s)
- J H L Neumann
- Pathologisches Institut, Ludwig-Maximilians-Universität München, Thalkirchner Straße 36, 80337, München, Deutschland,
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21
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Wallace K, Brandt HM, Bearden JD, Blankenship BF, Caldwell R, Dunn J, Hegedus P, Hoffman BJ, Marsh CH, Marsh WH, Melvin CL, Seabrook ME, Sterba RE, Stinson ML, Thibault A, Berger FG, Alberg AJ. Race and Prevalence of Large Bowel Polyps Among the Low-Income and Uninsured in South Carolina. Dig Dis Sci 2016; 61:265-72. [PMID: 26386856 PMCID: PMC5125220 DOI: 10.1007/s10620-015-3862-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 08/28/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND Compared to whites, blacks have higher colorectal cancer incidence and mortality rates and are at greater risk for early-onset disease. The reasons for this racial disparity are poorly understood, but one contributing factor could be differences in access to high-quality screening and medical care. AIMS The present study was carried out to assess whether a racial difference in prevalence of large bowel polyps persists within a poor and uninsured population (n = 233, 124 blacks, 91 whites, 18 other) undergoing screening colonoscopy. METHODS Eligible patients were uninsured, asymptomatic, had no personal history of colorectal neoplasia, and were between the ages 45-64 years (blacks) or 50-64 years (whites, other). We examined the prevalence of any adenoma (conventional, serrated) and then difference in adenoma/polyp type by race and age categories. RESULTS Prevalence for ≥1 adenoma was 37 % (95 % CI 31-43 %) for all races combined and 36 % in blacks <50 years, 38 % in blacks ≥50 years, and 35 % in whites. When stratified by race, blacks had a higher prevalence of large conventional proximal neoplasia (8 %) compared to whites (2 %) (p value = 0.06) but a lower prevalence of any serrated-like (blacks 18 %, whites 32 %; p value = 0.02) and sessile serrated adenomas/polyps (blacks 2 %, whites 8 % Chi-square p value; p = 0.05). CONCLUSIONS Within this uninsured population, the overall prevalence of adenomas was high and nearly equal by race, but the racial differences observed between serrated and conventional polyp types emphasize the importance of taking polyp type into account in future research on this topic.
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Affiliation(s)
- Kristin Wallace
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
- Department of Public Health Sciences, Medical University of South Carolina, 68 President Street, Charleston, SC, 29425, USA.
| | - Heather M Brandt
- Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA
- Department of Health Promotion, Education, and Behavior, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
| | - James D Bearden
- Gibbs Cancer Center and Research Institute, Spartanburg Regional Healthcare System, Spartanburg, SC, USA
| | - Bridgette F Blankenship
- Department of Public Health Sciences, Medical University of South Carolina, 68 President Street, Charleston, SC, 29425, USA
| | - Renay Caldwell
- Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA
| | - James Dunn
- Gibbs Cancer Center and Research Institute, Spartanburg Regional Healthcare System, Spartanburg, SC, USA
| | - Patricia Hegedus
- Gibbs Cancer Center and Research Institute, Spartanburg Regional Healthcare System, Spartanburg, SC, USA
| | - Brenda J Hoffman
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
- Department of Gastroenterology, Center for Digestive Disease, MUSC, Charleston, SC, USA
| | - Courtney H Marsh
- Department of Public Health Sciences, Medical University of South Carolina, 68 President Street, Charleston, SC, 29425, USA
| | - William H Marsh
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Cathy L Melvin
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
- Department of Public Health Sciences, Medical University of South Carolina, 68 President Street, Charleston, SC, 29425, USA
| | - March E Seabrook
- Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA
| | - Ronald E Sterba
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Mary Lou Stinson
- Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA
| | - Annie Thibault
- Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA
| | - Franklin G Berger
- Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA
| | - Anthony J Alberg
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
- Department of Public Health Sciences, Medical University of South Carolina, 68 President Street, Charleston, SC, 29425, USA
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22
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Thomas ML, Hewett PJ, Ruszkiewicz AR, Moore JWE. Clinicopathological predictors of benefit from adjuvant chemotherapy for stage C colorectal cancer: Microsatellite unstable cases benefit. Asia Pac J Clin Oncol 2015; 11:343-51. [PMID: 26471980 DOI: 10.1111/ajco.12411] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/12/2015] [Indexed: 12/18/2022]
Abstract
AIM In colorectal cancer (CRC), adjuvant therapy is offered on the basis of stage and attempts to identify factors to better target treatment have not been successful. Recent work suggested that mismatch repair deficient CRCs may not benefit from 5FU adjuvant chemotherapy but studies remain conflicting. We aimed to determine if gender, tumor site, tumor pathological characteristics and microsatellite instability (MSI) predict survival benefit from adjuvant chemotherapy in stage C CRC. METHODS Data were collated on ACPS (Australian Clinico-pathological Staging System) stage C CRC cases that underwent curative resection over a 23-year period. Pathology was reevaluated, DNA was extracted from the formalin-fixed paraffin specimen, and MSI status was established by BAT26 instability. Multivariate analysis was performed using Cox proportional hazard model and effects modification interaction testing. RESULTS In total 814 unselected cases were included, of whom 37% received chemotherapy. Seventy-seven cases exhibited MSI. Overall, adjuvant chemotherapy produced a cancer-specific survival benefit (HR 0.52, 95% CI 0.39-0.70; P < 0.0001). On interaction testing, none of the examined parameters significantly influenced the magnitude of that survival benefit. Chemotherapy was beneficial in both the MSI (HR 0.08, 95% CI 0.02-0.27; P = < 0.0001) and the microsatellite stable cohort (HR 0.62, 95% CI 0.47-0.81; P = 0.001). CONCLUSION These results suggest that survival benefit from 5FU adjuvant chemotherapy for stage C CRC does not vary according to gender, site of tumor, pathological characteristics or MSI status. This study suggests that it would be unwise to exclude patients from being offered adjuvant chemotherapy on the basis of MSI.
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Affiliation(s)
- Michelle L Thomas
- Royal Adelaide Hospital, Department of Surgery, University of Adelaide, Adelaide, South Australia, Australia.,Department of Surgery, University of Adelaide, Adelaide, South Australia, Australia
| | - Peter J Hewett
- The Queen Elizabeth Hospital, Department of Surgery, University of Adelaide, Adelaide, South Australia, Australia.,Department of Surgery, University of Adelaide, Adelaide, South Australia, Australia
| | - Andrew R Ruszkiewicz
- Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia.,Anatomical Pathology, SA Pathology, Adelaide, South Australia, Australia
| | - James W E Moore
- Royal Adelaide Hospital, Department of Surgery, University of Adelaide, Adelaide, South Australia, Australia.,Department of Surgery, University of Adelaide, Adelaide, South Australia, Australia
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23
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Maby P, Tougeron D, Hamieh M, Mlecnik B, Kora H, Bindea G, Angell HK, Fredriksen T, Elie N, Fauquembergue E, Drouet A, Leprince J, Benichou J, Mauillon J, Le Pessot F, Sesboüé R, Tuech JJ, Sabourin JC, Michel P, Frébourg T, Galon J, Latouche JB. Correlation between Density of CD8+ T-cell Infiltrate in Microsatellite Unstable Colorectal Cancers and Frameshift Mutations: A Rationale for Personalized Immunotherapy. Cancer Res 2015; 75:3446-3455. [PMID: 26060019 DOI: 10.1158/0008-5472.can-14-3051] [Citation(s) in RCA: 203] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Accepted: 05/14/2015] [Indexed: 01/30/2023]
Abstract
Colorectal cancers with microsatellite instability (MSI) represent 15% of all colorectal cancers, including Lynch syndrome as the most frequent hereditary form of this disease. Notably, MSI colorectal cancers have a higher density of tumor-infiltrating lymphocytes (TIL) than other colorectal cancers. This feature is thought to reflect the accumulation of frameshift mutations in sequences that are repeated within gene coding regions, thereby leading to the synthesis of neoantigens recognized by CD8(+) T cells. However, there has yet to be a clear link established between CD8(+) TIL density and frameshift mutations in colorectal cancer. In this study, we examined this link in 103 MSI colorectal cancers from two independent cohorts where frameshift mutations in 19 genes were analyzed and CD3(+), CD8(+), and FOXP3(+) TIL densities were quantitated. We found that CD8(+) TIL density correlated positively with the total number of frameshift mutations. TIL densities increased when frameshift mutations were present within the ASTE1, HNF1A, or TCF7L2 genes, increasing even further when at least one of these frameshift mutations was present in all tumor cells. Through in vitro assays using engineered antigen-presenting cells, we were able to stimulate peripheral cytotoxic T cells obtained from colorectal cancer patients with peptides derived from frameshift mutations found in their tumors. Taken together, our results highlight the importance of a CD8(+) T cell immune response against MSI colorectal cancer-specific neoantigens, establishing a preclinical rationale to target them as a personalized cellular immunotherapy strategy, an especially appealing goal for patients with Lynch syndrome.
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Affiliation(s)
- Pauline Maby
- Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France
| | - David Tougeron
- Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Gastroenterology, Poitiers University Hospital, Poitiers, France. Laboratoire Inflammation Tissus Epithéliaux et Cytokines, Poitiers University, Poitiers, France
| | - Mohamad Hamieh
- Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France
| | - Bernhard Mlecnik
- Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris, France
| | - Hafid Kora
- Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France
| | - Gabriela Bindea
- Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris, France
| | - Helen K Angell
- Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris, France. AstraZeneca Pharmaceuticals, Alderley Park, Cheshire, United Kingdom
| | - Tessa Fredriksen
- Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris, France
| | - Nicolas Elie
- Imaging Core Facility, CMABIO, Caen University Hospital, Caen, France
| | - Emilie Fauquembergue
- Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France
| | - Aurélie Drouet
- Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France
| | - Jérôme Leprince
- Inserm U982, Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, France
| | - Jacques Benichou
- Biostatistics Unit, Inserm U657, Rouen University Hospital, Rouen University, Rouen, France
| | - Jacques Mauillon
- Department of Genetics, Rouen University Hospital, Rouen, France. Department of Gastroenterology, Le Havre Hospital, Le Havre, France
| | | | - Richard Sesboüé
- Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France
| | - Jean-Jacques Tuech
- Department of Digestive Surgery, Rouen University Hospital, Rouen, France
| | - Jean-Christophe Sabourin
- Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Pathology, Rouen University Hospital, Rouen, France
| | - Pierre Michel
- Department of Gastroenterology, Rouen University Hospital, Rouen, France
| | - Thierry Frébourg
- Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Genetics, Rouen University Hospital, Rouen, France
| | - Jérôme Galon
- Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris, France
| | - Jean-Baptiste Latouche
- Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Genetics, Rouen University Hospital, Rouen, France.
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Burge ME, Leggett BA, Whitehall VLJ. Deficient mismatch repair in colorectal cancer: current perspectives on patient management and future directions. COLORECTAL CANCER 2015. [DOI: 10.2217/crc.15.7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Abstract Molecular aberrations leading to colorectal cancer are diverse and heterogeneity exists both at a molecular level and in clinical behavior. Defective mismatch repair (dMMR) is a feature of 15% of colorectal cancers. These are hypermutated tumors, mostly right sided and histopathologically elicit a marked immune response. A proportion of these arise due to germline mutation of a mismatch repair gene giving rise to Lynch syndrome, while the majority arise sporadically due to somatic alteration of the MLH1 mismatch repair gene. Although dMMR is associated with an excellent patient prognosis, as tumor stage advances the frequency of dMMR declines and the association with improved prognosis dissipates. It is apparent that dMMR tumors do not represent a unique molecular subset. As the knowledge of the underlying biology evolves, the hope is for individualized therapy that goes well beyond the crude and oversimplified categorization of dMMR versus proficient MMR.
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Affiliation(s)
- Matthew E Burge
- Royal Brisbane & Women's Hospital, Department of Medical Oncology, Brisbane, QLD, Australia
| | - Barbara A Leggett
- Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- The University of Queensland, School of Medicine, Brisbane, QLD, Australia
- Royal Brisbane & Women's Hospital, Department of Gastroenterology & Hepatology, Brisbane, QLD, Australia
| | - Vicki LJ Whitehall
- Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- The University of Queensland, School of Medicine, Brisbane, QLD, Australia
- Pathology Queensland, Brisbane, QLD, Australia
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Yang L, Sun Y, Huang XE, Yu DS, Zhou JN, Zhou X, Li DZ, Guan X. Carcinoma microsatellite instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for stage II rectal cancer. Asian Pac J Cancer Prev 2015; 16:1545-1551. [PMID: 25743829 DOI: 10.7314/apjcp.2015.16.4.1545] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
PURPOSE Rectal cancers with high microsatellite-instable have clinical and pathological features that differentiate them from microsatellite-stable or low- frequency carcinomas, which was studied rarely in stage II rectal cancer, promoting the present investigation of the usefulness of microsatellite-instability status as a predictor of the benefit of adjuvant chemotherapy with fluorouracil in stage II rectal cancer. PATIENTS AND METHODS Data of 460 patients who underwent primary anterior resection with a double stapling technique for rectal carcinoma at a single institution from 2008 to 2012 were retrospectively collected. All patients experienced a total mesorectal excision (TME) operation. Survival analysis were analyzed using the Cox regression method. RESULTS Five-year rate of disease-free survival (DFS) was noted in 390 (84.8%) of 460 patients with stage II rectal cancer. Of 460 tissue specimens, 97 (21.1%) exhibited high-frequency microsatellite instability. Median age of the patients was 65 (50-71) and 185 (40.2%) were male. After univariate and multivariate analysis, microsatellite instability (p= 0.001), female sex (p< 0.05) and fluorouracil-based adjuvant chemotherapy (p< 0.001), the 3 factors were attributed to a favorable survival status independently. Among 201 patients who did not receive adjuvant chemotherapy, those cancers displaying high-frequency microsatellite instability had a better 5-year rate of DFS than tumors exhibiting microsatellite stability or low-frequency instability (HR, 13.61 [95% CI, 1.88 to 99.28]; p= 0.010), while in 259 patients who received adjuvant chemotherapy, there was no DFS difference between the two groups (p= 0.145). Furthermore, patients exhibiting microsatellite stability or low-frequency instability who received adjuvant chemotherapy had a better 5-year rate of DFS than patients did not (HR, 5.16 [95% CI, 2.90 to 9.18]; p< 0.001), while patients exhibiting high-frequency microsatellite instability were not connected with increased DFS (p= 0.696). It was implied that female patients had better survival than male. CONCLUSION Survival status after anterior resection of rectal carcinoma is related to the microsatellite instability status, adjuvant chemotherapy and gender. Fluorouracil-based adjuvant chemotherapy benefits patients of stage II rectal cancer with microsatellite-stable or low microsatellite-instable, but not those with high microsatellite- instable. Additionally, free of adjuvant chemotherapy, carcinomas with high microsatellite-instable have a better 5-year rate of DFS than those with microsatellite-stable or low microsatellite-instable, and female patients have a better survival as well.
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Affiliation(s)
- Liu Yang
- Colorectal Cancer Center, the Affiliated Jiangsu Cancer Hospital of Nanjing Medical University and Jiangsu Institute of Cancer Research, Nanjing, China E-mail :
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26
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Establishing a biological profile for interval colorectal cancers. Dig Dis Sci 2014; 59:2390-402. [PMID: 24839919 DOI: 10.1007/s10620-014-3210-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Accepted: 05/07/2014] [Indexed: 12/16/2022]
Abstract
Colorectal cancer (CRC) remains the second leading cause of cancer-related deaths in North America. Screening for CRC and its precursor lesions is highly effective in reducing the incidence and deaths due to the disease. However, there remain a substantial number of individuals who are diagnosed with CRC soon after a negative/clearing colonoscopy with no documented evidence of CRC. The occurrence of these interval CRCs (I-CRCs) reduces the effectiveness of CRC screening and detection tests and has only recently attracted wide spread attention. I-CRCs can be subdivided into those that occur most likely due to the failure of the colonoscopy examination (missed CRC and CRC that developed from missed or incompletely resected precursor lesions) and those that develop rapidly after the colonoscopy (de novo I-CRCs). In this review, we discuss the current literature and present both the clinical and biological factors that have been identified to account for I-CRCs, with a particular focus on the aberrant molecular features that are candidate causative agents for I-CRCs. We conclude additional studies are required to fully understand the molecular features that lead to the development of I-CRCs, which in turn is essential to develop measures to prevent the occurrence of this group of CRCs and thereby improve CRC screening and detection strategies.
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IGFBP3 methylation is a novel diagnostic and predictive biomarker in colorectal cancer. PLoS One 2014; 9:e104285. [PMID: 25127039 PMCID: PMC4134211 DOI: 10.1371/journal.pone.0104285] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Accepted: 07/07/2014] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND AIM Aberrant hypermethylation of cancer-related genes has emerged as a promising strategy for the development of diagnostic, prognostic and predictive biomarkers in human cancer, including colorectal cancer (CRC). The aim of this study was to perform a systematic and comprehensive analysis of a panel of CRC-specific genes as potential diagnostic, prognostic and predictive biomarkers in a large, population-based CRC cohort. PATIENTS AND METHODS Methylation status of the SEPT9, TWIST1, IGFBP3, GAS7, ALX4 and miR137 genes was studied by quantitative bisulfite pyrosequencing in a population-based cohort of 425 CRC patients. RESULTS Methylation levels of all genes analyzed were significantly higher in tumor tissues compared to normal mucosa (p<0.0001); however, cancer-associated hypermethylation was most frequently observed for miR137 (86.7%) and IGFBP3 (83%) in CRC patients. Methylation analysis using the combination of these two genes demonstrated greatest accuracy for the identification of colonic tumors (sensitivity 95.5%; specificity 90.5%). Low levels of IGFBP3 promoter methylation emerged as an independent risk factor for predicting poor disease free survival in stage II and III CRC patients (HR = 0.49, 95% CI: 0.28-0.85, p = 0.01). Our results also suggest that stage II & III CRC patients with high levels of IGFBP3 methylation do not benefit from adjuvant 5FU-based chemotherapy. CONCLUSION By analyzing a large, population-based CRC cohort, we demonstrate the potential clinical significance of miR137 and IGFBP3 hypermethylation as promising diagnostic biomarkers in CRC. Our data also revealed that IGFBP3 hypermethylation may serve as an independent prognostic and predictive biomarker in stage II and III CRC patients.
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28
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Neumann JHL, Kirchner T. [Colorectal carcinoma in consideration of the new German S3 guideline 2013]. DER PATHOLOGE 2014; 35:615-21; quiz 622-3. [PMID: 25106124 DOI: 10.1007/s00292-014-1945-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
In the current German S3 guidelines for colorectal carcinoma (CRC), morphologically based tumor grading is extended by molecular grading for poorly differentiated and undifferentiated carcinomas, as well as for special morphological subtypes. These CRC are classified as low-grade when microsatellite instability (MSI) is found. In routine diagnostics, immunohistochemistry for hMLH1 and hMSH2, capturing MSI-CRC with high sensitivity and specificity, can be used as an inexpensive substitute for molecular MSI-testing. In patients with positive Bethesda criteria, a stepwise immunohistochemical and molecular diagnostic scheme is proposed. The detection of a BRAF mutation in tumors with hMLH1 loss allows distinguishing between sporadic and HNPCC-associated MSI-CRC. For rectal cancer the residual tumor classification (R-status) is completed by the circumferential resection margin classification (CRM).
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Affiliation(s)
- J H L Neumann
- Pathologisches Institut, Ludwig-Maximilians-Universität München, Thalkirchner Str. 36, 80337, München, Deutschland,
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29
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Eveno C, Lefevre JH, Svrcek M, Bennis M, Chafai N, Tiret E, Parc Y. Oncologic results after multivisceral resection of clinical T4 tumors. Surgery 2014; 156:669-75. [PMID: 24953279 DOI: 10.1016/j.surg.2014.03.040] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2013] [Accepted: 03/26/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND Standard operative management of colorectal cancer (CRC) with adherent adjacent organs is en bloc resection to obtain clear resection margins. We analyzed early and long-term outcomes after multivisceral resection for clinically suspected T4 CRC and identified factors predicting survival. METHODS All patients operated on for clinically suspected T4 CRC between 2000 and 2010 were identified retrospectively. Data concerning demographics, surgery, pathologic examination and oncologic outcome were analyzed. RESULTS One hundred fifty-two patients underwent partial or total en bloc resection of ≥1 adherent organ. An R0 resection was achieved in 136 patients (89.5%). Malignant invasion of the adherent organ was histologically confirmed in 98 patients (64.5%). Five-year overall survival and disease-free survival rates were 77.4% and 58.1%, respectively. On univariate analysis, margin positivity, pT4 stage, and lymph node invasion were predictors of a worse disease-free survival. The presence of liver metastases and concomitant hepatectomy were both factors of poor overall and disease-free survival. On multivariate analysis, resection of ≥2 adjacent organs was a predictor of better overall survival. This finding may be explained by the significantly higher rate of tumors with microsatellite instability (MSI) in the group with resection of multiple organs. CONCLUSION The oncologic outcome of multivisceral resection for clinically suspected colorectal T4 tumors was good, especially in MSI patients and patients without liver metastases. The number of organs requiring resection should not contraindicated radical surgery as in this study it was associated with a good prognosis.
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Affiliation(s)
- Clarisse Eveno
- Department of Digestive Surgery (AP-HP), Hôpital Saint-Antoine, Université Pierre & Marie Curie, Paris, France
| | - Jeremie H Lefevre
- Department of Digestive Surgery (AP-HP), Hôpital Saint-Antoine, Université Pierre & Marie Curie, Paris, France.
| | - Magali Svrcek
- Department of Pathology (AP-HP), Hôpital Saint-Antoine, Université Pierre & Marie Curie, Paris, France
| | - Malika Bennis
- Department of Pathology (AP-HP), Hôpital Saint-Antoine, Université Pierre & Marie Curie, Paris, France
| | - Najim Chafai
- Department of Digestive Surgery (AP-HP), Hôpital Saint-Antoine, Université Pierre & Marie Curie, Paris, France
| | - Emmanuel Tiret
- Department of Digestive Surgery (AP-HP), Hôpital Saint-Antoine, Université Pierre & Marie Curie, Paris, France
| | - Yann Parc
- Department of Digestive Surgery (AP-HP), Hôpital Saint-Antoine, Université Pierre & Marie Curie, Paris, France
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Saridaki Z, Souglakos J, Georgoulias V. Prognostic and predictive significance of MSI in stages II/III colon cancer. World J Gastroenterol 2014; 20:6809-6814. [PMID: 24944470 PMCID: PMC4051919 DOI: 10.3748/wjg.v20.i22.6809] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2013] [Revised: 12/29/2013] [Accepted: 03/05/2014] [Indexed: 02/07/2023] Open
Abstract
In colon cancer, classic disease staging remains the key prognosis and treatment determinant. Although adjuvant chemotherapy has an established role in stage III colon cancer patients, in stage II it is still a subject of controversy due to its restriction to a small subgroup of patients with high-risk histopathologic features. Patients with stage II tumors form a highly heterogeneous group, with five-year relative overall survival rates ranging from 87.5% (IIA) to 58.4% (IIC). Identifying those for whom adjuvant chemotherapy would be appropriate and necessary has been challenging, and prognostic markers which could serve in the selection of patients more likely to recur or benefit from adjuvant chemotherapy are eagerly needed. The stronger candidate in this category seems to be microsatellite instability (MSI). The recently reported European Society for Medical Oncology guidelines suggest that MSI should be evaluated in stage II colorectal cancer patients in order to contribute in treatment decision-making regarding chemotherapy administration. The hypothetical predictive role of MSI regarding its response to 5-fluorouracil-based adjuvant chemotherapy has proven a much more difficult issue to address. Almost every possible relation between MSI and chemotherapy outcome has been described in the adjuvant colon cancer setting in the international literature, and the matter is far from being settled. In this current report we critically evaluate the prognostic and predictive impact of MSI status in patients with stage II and stage III colon cancer patients.
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Kanth VVR, Bhalsing S, Sasikala M, Rao GV, Pradeep R, Avanthi US, Reddy DN. Microsatellite instability and promoter hypermethylation in colorectal cancer in India. Tumour Biol 2014; 35:4347-4355. [PMID: 24408015 DOI: 10.1007/s13277-013-1570-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 12/17/2013] [Indexed: 12/01/2022] Open
Abstract
Microsatellite instability (MSI) is an important factor in tumor development and is a hypermutable phenotype caused by the loss of DNA mismatch repair activity. It is important to identify tumors with microsatellite instability as the patients have a better prognosis and differ with response to chemotherapy. Limited data are available on the incidence of MSI in Indian colorectal cancers (CRCs). The objectives of this study were to identify the extent of MSI in Indian CRC patients below 50 years and to determine promoter methylation status of hMLH1 and hMSH2 in relation to MSI. A total of 450 patients were diagnosed with CRC, out of which 91 individuals were recruited as per Bethesda guidelines and were tested for instability by the NCI-recommended Bethesda panel (BAT25, BAT26, D2S123, D5S346, and D17S2720) using labeled primers. The fragments were separated and analyzed on a Beckman GeXP sequencer. Promoter methylation status was determined by restriction enzyme digestion and PCR. MSI (high and low) was seen in 48.4% (44/91) of CRC patients, out of which microsatellite instability-high (MSI-H) was detected in 13.2% (12/91) and microsatellite instability-low (MSI-L) in 35.2% (32/91) and the rest were microsatellite stable (MSS), 51.6% (47/91). Majority of the MSI-H tumors were adenocarcinomas (10/12), in the rectum (8/12), and moderately or poorly differentiated (12/12). Promoter hypermethylation was seen in 75% of the MSI-H, 56.24% of MSI-L, and only 23.4% of MSS individuals. MSI (high and low) was associated with 48.4% of CRC patients, and a significantly higher proportion of promoter hypermethylation of hMLH1 and hMSH2 genes was associated with instable tumors.
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32
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Ziadi S, Ksiaa F, Gacem RB, Labaied N, Mokni M, Trimeche M. Clinicopathologic characteristics of colorectal cancer with microsatellite instability. Pathol Res Pract 2014; 210:98-104. [DOI: 10.1016/j.prp.2013.10.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Revised: 07/29/2013] [Accepted: 10/22/2013] [Indexed: 11/28/2022]
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Atreya I, Neurath MF. Immune cells in colorectal cancer: prognostic relevance and therapeutic strategies. Expert Rev Anticancer Ther 2014; 8:561-72. [DOI: 10.1586/14737140.8.4.561] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Kohonen-Corish MRJ, Tseung J, Chan C, Currey N, Dent OF, Clarke S, Bokey L, Chapuis PH. KRAS mutations and CDKN2A promoter methylation show an interactive adverse effect on survival and predict recurrence of rectal cancer. Int J Cancer 2013; 134:2820-8. [PMID: 24259266 DOI: 10.1002/ijc.28619] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Revised: 10/08/2013] [Accepted: 11/07/2013] [Indexed: 12/26/2022]
Abstract
Colonic and rectal cancers differ in their clinicopathologic features and treatment strategies. Molecular markers such as gene methylation, microsatellite instability and KRAS mutations, are becoming increasingly important in guiding treatment decisions in colorectal cancer. However, their association with clinicopathologic variables and utility in the management of rectal cancer is still poorly understood. We analyzed CDKN2A gene methylation, CpG island methylator phenotype (CIMP), microsatellite instability and KRAS/BRAF mutations in a cohort of 381 rectal cancers with extensive clinical follow-up data. BRAF mutations (2%), CIMP-high (4%) and microsatellite instability-high (2%) were rare, whereas KRAS mutations (39%), CDKN2A methylation (20%) and CIMP-low (25%) were more common. Only CDKN2A methylation and KRAS mutations showed an association with poor overall survival but these did not remain significant when analyzed with other clinicopathologic factors. In contrast, this prognostic effect was strengthened by the joint presence of CDKN2A methylation and KRAS mutations, which independently predicted recurrence of cancer and was associated with poor overall and cancer-specific survival. This study has identified a subgroup of more aggressive rectal cancers that may arise through the KRAS-p16 pathway. It has been previously shown that an interaction of p16 deficiency and oncogenic KRAS promotes carcinogenesis in the mouse and is characterized by loss of oncogene-induced senescence. These findings may provide avenues for the discovery of new treatments in rectal cancer.
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Affiliation(s)
- Maija R J Kohonen-Corish
- Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia; St Vincent's Clinical School UNSW Medicine, University of NSW, Sydney, NSW, Australia; School of Medicine, University of Western Sydney, Liverpool, NSW, Australia
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Jamal-Hanjani M, Thanopoulou E, Peggs KS, Quezada SA, Swanton C. Tumour heterogeneity and immune-modulation. Curr Opin Pharmacol 2013; 13:497-503. [PMID: 23664091 PMCID: PMC3988963 DOI: 10.1016/j.coph.2013.04.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2013] [Revised: 04/09/2013] [Accepted: 04/11/2013] [Indexed: 12/21/2022]
Abstract
Intratumour heterogeneity (ITH) has been demonstrated in various tumour types. Distinct clonal subpopulations can exist within different regions of a tumour. ITH has evident implications for cancer diagnosis and treatment. There is increasing evidence for the association between ITH and drug resistance. ITH may allow the effective use of immunotherapeutics against tumour neo-antigens. Recent advances in sequencing technologies have revealed extensive intratumour heterogeneity (ITH) both within individual tumours and between primary and metastatic tumours for different cancer types. Such genetic diversity may have clinical implications for both cancer diagnosis and treatment with increasing evidence linking ITH and therapeutic resistance. Nonetheless, whilst limiting the activity of targeted agents, tumour genetic heterogeneity may provide a new therapeutic opportunity through generation of neo-antigens that could be recognised and targeted by the patient's own immune system in response to immune-modulatory therapies. Longitudinal genomic studies assessing tumour clonal architecture and its correlation with the underlying immune response to cancer in each particular patient are needed to follow tumour evolutionary dynamics over time and through therapy, in order to further understand the mechanisms behind drug resistance and to inform the development of new combinatorial therapeutic strategies.
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Affiliation(s)
- Mariam Jamal-Hanjani
- Translational Cancer Therapeutics Laboratory, Cancer Research UK, London Research Institute, London WC2A 3LY, UK
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36
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Gaiser T, Meinhardt S, Hirsch D, Killian JK, Gaedcke J, Jo P, Ponsa I, Miró R, Rüschoff J, Seitz G, Hu Y, Camps J, Ried T. Molecular patterns in the evolution of serrated lesion of the colorectum. Int J Cancer 2012; 132:1800-10. [PMID: 23011871 DOI: 10.1002/ijc.27869] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Accepted: 09/03/2012] [Indexed: 12/22/2022]
Abstract
Colorectal cancer (CRC) mostly develops from a variety of polyps following mainly three different molecular pathways: chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylation (CIMP). Polyps are classified histologically as conventional adenomas, hyperplastic polyps, sessile serrated adenomas/polyps (SSA/P) and traditional serrated adenomas (TSA). However, the association of these polyps with the different types of CRCs and the underlying genetic and epigenetic aberrations has yet to be resolved. In order to address this question we analyzed 140 tumors and 20 matched mucosae by array comparative genomic hybridization, by sequence analysis of the oncogenes BRAF, KRAS, PI3K3CA and by methylation arrays. MSI was tested indirectly by immunohistochemistry (IHC) and a loss of MLH1, MSH2, MSH6 or PMS2 was assigned as high microsatellite instability (MSI-H), while low microsatellite instability (MSI-L) was defined as MGMT IHC negativity only. CIN was detected in 78% of all MSI-H CRCs, most commonly as a gain of chromosome 8. Methylation data analyses allowed classification of samples into four groups and detected similar methylation profiles in SSA/P and MSI-H CRC. TSA also revealed aberrant methylation pattern, but clustered more heterogeneously and closer to microsatellite stable (MSS) CRCs. SSA/P, TSA and MSI-H CRCs had the highest degree of promotor methylation (CIMP pathway). Chromosomal instability, in contrast to the established doctrine, is a common phenomenon in MSI CRCs, yet to a lower extent and at later stages than in MSS CRCs. Methylation analyses suggest that SSA/P are precursors for MSI-H CRCs and follow the CIMP pathway.
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Affiliation(s)
- Timo Gaiser
- Section of Cancer Genomics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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Funkhouser WK, Lubin IM, Monzon FA, Zehnbauer BA, Evans JP, Ogino S, Nowak JA. Relevance, pathogenesis, and testing algorithm for mismatch repair-defective colorectal carcinomas: a report of the association for molecular pathology. J Mol Diagn 2012; 14:91-103. [PMID: 22260991 DOI: 10.1016/j.jmoldx.2011.11.001] [Citation(s) in RCA: 143] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2011] [Revised: 10/04/2011] [Accepted: 11/09/2011] [Indexed: 02/06/2023] Open
Abstract
Loss-of-function defects in DNA mismatch repair (MMR), which manifest as high levels of microsatellite instability (MSI), occur in approximately 15% of all colorectal carcinomas (CRCs). This molecular subset of CRC characterizes patients with better stage-specific prognoses who experience no benefit from 5-fluorouracil chemotherapy. Most MMR-deficient (dMMR) CRCs are sporadic, but 15% to 20% are due to inherited predisposition (Lynch syndrome). High penetrance of CRCs in germline MMR gene mutation carriers emphasizes the importance of accurate diagnosis of Lynch syndrome carriers. Family-based (Amsterdam), patient/family-based (Bethesda), morphology-based, microsatellite-based, and IHC-based screening criteria do not individually detect all germline mutation carriers. These limitations support the use of multiple concurrent tests and the screening of all patients with newly diagnosed CRC. This approach is resource intensive but would increase detection of inherited and de novo germline mutations to guide family screening. Although CRC prognosis and prediction of 5-fluorouracil response are similar in both the Lynch and sporadic dMMR subgroups, these subgroups differ significantly with regard to the implications for family members. We recommend that new CRCs should be classified into sporadic MMR-proficient, sporadic dMMR, or Lynch dMMR subgroups. The concurrent use of MSI testing, MMR protein IHC, and BRAF c.1799T>A mutation analysis would detect almost all dMMR CRCs, would classify 94% of all new CRCs into these MMR subgroups, and would guide secondary molecular testing of the remainder.
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Affiliation(s)
- William K Funkhouser
- Mismatch Repair-Defective CRC Working Group of the Association for Molecular Pathology Clinical Practice Committee, University of North Carolina, Chapel Hill, North Carolina, USA.
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Bond CE, Umapathy A, Ramsnes I, Greco SA, Zhen Zhao Z, Mallitt KA, Buttenshaw RL, Montgomery GW, Leggett BA, Whitehall VLJ. p53 mutation is common in microsatellite stable, BRAF mutant colorectal cancers. Int J Cancer 2011; 130:1567-76. [PMID: 21557216 DOI: 10.1002/ijc.26175] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2010] [Accepted: 04/12/2011] [Indexed: 12/16/2022]
Abstract
The majority of "serrated pathway" colorectal cancers have mutation of the BRAF oncogene and display the CpG island methylator phenotype (CIMP). Half these cancers have microsatellite instability (MSI) and an excellent prognosis. In the absence of MSI (microsatellite stable, MSS), BRAF mutation has been associated with a particularly poor prognosis. "Traditional pathway" cancers are BRAF wild type. Mutation of p53 is common and this correlates with advanced stage. We therefore hypothesized that p53 mutation would be common in MSS/BRAF mutant colorectal cancer. One thousand and eighty-one colorectal cancers were screened for BRAF mutation to identify two BRAF mutant study groups (MSI: n = 77; MSS: n = 69) and a BRAF wild type control group (n = 101). These were screened for p53 mutation by high resolution melt analysis and classified for CIMP and MGMT methylation by quantitative methylation specific PCR. Molecular data were compared to patient age, gender, tumor location and stage. p53 was mutated significantly more frequently in MSS/BRAF mutant (28/69, 40.6%) compared to MSI/BRAF mutant cancers (13/77, 16.9%), but this mutation rate did not differ from MSS/BRAF wild type cancers (47/101, 46.5%)(p < 0.0001). CIMP was less common in MSS/BRAF mutant (26/47, 55.3%) compared to MSI/BRAF mutant cancers (41/54, 75.9%), but was more common than in MSS/BRAF wild type cancers (3/85, 3.5%) (p < 0.0001). MSS/BRAF mutant cancers were more commonly proximal (38/54, 70.3%), but were similar to MSS/BRAF wild type cancers in terms of patient age, gender distribution and stage at presentation. MSS/BRAF mutant cancers share molecular and clinical features of both the serrated and traditional pathways of colorectal tumorigenesis.
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Affiliation(s)
- Catherine E Bond
- Conjoint Gastroenterology Laboratory, Royal Brisbane and Women's Hospital Research Foundation, Clinical Research Centre and the Queensland Institute of Medical Research, Brisbane, Australia.
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Quality assessment and correlation of microsatellite instability and immunohistochemical markers among population- and clinic-based colorectal tumors results from the Colon Cancer Family Registry. J Mol Diagn 2011; 13:271-81. [PMID: 21497289 DOI: 10.1016/j.jmoldx.2010.12.004] [Citation(s) in RCA: 119] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2010] [Revised: 12/13/2010] [Accepted: 12/22/2010] [Indexed: 01/16/2023] Open
Abstract
The detection of defective mismatch repair (MMR), as assessed by the presence of tumor microsatellite instability (MSI) and/or loss of MMR protein expression by IHC, has been useful for risk assessment, prognosis, and prediction of treatment in patients with colorectal cancer. We analyzed tumors for the presence of defective MMR from 5927 Colorectal Cancer Family Registry patients recruited at six international consortium sites. We evaluated the appropriate percentage instability cutoff used to distinguish the three MSI phenotypes [ie, stable (MSS), low instability (MSI-L), and high instability (MSI-H)]; the sensitivity, specificity, and performance characteristics of individual markers; and the concordance between MSI and IHC phenotypes. Guided by the results of the IHC testing, our findings indicate that the distinction between an MSI-H phenotype from a low-instability or MSS phenotype can best be accomplished by using a cutoff of 30% or greater of the markers showing instability. The sensitivity and specificity of the mononucleotide markers were higher than those of the dinucleotide markers. Specifically, BAT26 and BAT25 had the highest sensitivity (94%) and specificity (98%), and the use of mononucleotide markers alone identified 97% of the MSI-H cases correctly. As expected, the presence of MSI-H correlated with an older age of diagnosis, the presence of tumor in the proximal colon, and female sex.
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Zaanan A, Meunier K, Sangar F, Fléjou JF, Praz F. Microsatellite instability in colorectal cancer: from molecular oncogenic mechanisms to clinical implications. Cell Oncol (Dordr) 2011; 34:155-76. [PMID: 21484480 DOI: 10.1007/s13402-011-0024-x] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/13/2011] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Microsatellite instability (MSI) constitutes an important oncogenic molecular pathway in colorectal cancer (CRC), representing approximately 15% of all colorectal malignant tumours. In roughly one third of the cases, the underlying DNA mismatch repair (MMR) defect is inherited through the transmission of a mutation in one of the genes involved in MMR, predominantly MSH2 and MLH1, or less frequently, MSH6 or PMS2. In the overwhelming number of sporadic cases, MSI results from epigenetic MLH1 silencing through hypermethylation of its promoter. MMR deficiency promotes colorectal oncogenesis through the accumulation of numerous mutations in crucial target genes harbouring mononucleotide repeats, notably in those involved in the control of cell proliferation and differentiation, as well as DNA damage signalling and repair. DESIGN In this review, we describe the molecular aspects of the MMR system and the biological consequences of its defect on the oncogenic process, and we discuss the various experimental systems used to evaluate the efficacy of cytotoxic drugs on MSI colorectal cells lines. There is increasing evidence showing that MSI CRCs differ from all CRCs in terms of prognosis and response to the treatment. We report the clinical studies that have evaluated the prognostic and predictive value of MSI status on clinical outcome in patients treated with various chemotherapy regimens used in the adjuvant setting or for advanced CRCs. CONCLUSION In view of this, the opportunity of a systematic MSI phenotyping in the clinical management of patients with CRC is further discussed.
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Affiliation(s)
- Aziz Zaanan
- INSERM, UMR_S, Centre de Recherche Saint-Antoine, Paris, France
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Sporadic colorectal carcinomas with low-level microsatellite instability: a distinct subgroup with specific clinicopathological and molecular features. Int J Colorectal Dis 2011; 26:445-53. [PMID: 21336644 DOI: 10.1007/s00384-011-1133-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/07/2011] [Indexed: 02/04/2023]
Abstract
PURPOSE The biologic significance of low-level microsatellite instability (MSI) in sporadic colorectal cancers (CRCs) is not clearly defined. In particular, the relationship of MSI-low to MSI-high and microsatellite stable (MSS) tumours is currently under debate and the prognostic impact of these genetic changes remains unclear. The objective of this study was to investigate whether sporadic MSI-low CRCs have different clinicopathological and molecular features from MSS and MSI-high tumours. METHODS A series of 184 primary sporadic CRCs were divided, according to the level of MSI, into three groups (94 MSS, 22 MSI-low and 68 MSI-high) and were analyzed for baseline clinicopathological features and outcome, allelic losses at 18q, 8p and 4p chromosomes and immunohistochemical expression of MGMT, hMlh1, hMsh2, Fhit, Cox-2, p21 and p27 proteins. RESULTS MSI-low tumours were more frequently distal (59.1%) whereas MSS tumours had a strong predilection for distal (72.3%) and MSI-high tumours for proximal location (54.4%; p = 0.003). When compared with MSI-high tumors, MSI-low CRCs were adenocarcinoma, not otherwise specified (p = 0.0138) and well to/moderately differentiated (p = 0.027). MSI-low CRCs also showed specific molecular features including intermediate 18q allelic losses, altered MGMT and Cox-2 expression. Finally, the 5-year overall survival rates were 79% for MSI-low, 40.3% for MSS and 71% for MSI-high CRCs (p = 0.0160 MSS vs. MSI-low groups). CONCLUSIONS Sporadic MSI-low CRCs display characteristic clinicopathological and genetic features that distinguish them from MSS CRCs.
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Furlan D, Carnevali IW, Bernasconi B, Sahnane N, Milani K, Cerutti R, Bertolini V, Chiaravalli AM, Bertoni F, Kwee I, Pastorino R, Carlo C. Hierarchical clustering analysis of pathologic and molecular data identifies prognostically and biologically distinct groups of colorectal carcinomas. Mod Pathol 2011; 24:126-37. [PMID: 20852594 DOI: 10.1038/modpathol.2010.179] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
This work has evaluated the potential superiority of a morphomolecular classification based on the combination of clinicopathologic and molecular features of colorectal cancers. A cohort of 126 colorectal carcinomas was investigated by unsupervised hierarchical clustering analysis to combine 13 routinely assessed clinicopathologic features and all five molecular markers recently suggested by Jass' classification to distinguish four molecular subtypes of sporadic colorectal carcinomas. Survival analysis was assessed by a Cox proportional hazards model. A clear separation into three prognostically significant groups was identified: cluster A and cluster C were associated with good prognosis and cluster B with poor prognosis (P=0.006). Clinicopathologic and molecular features of cluster A and cluster B tumors were strongly concordant with colorectal cancer profiles characterized by microsatellite instability or by chromosomal instability, respectively. The clinicopathologic features of cluster C tumors were suggestive of a less aggressive disease than cluster B tumors. Genetically, they appeared intermediate between cluster A and cluster B tumors, as they were mainly microsatellite stable tumors showing high levels of both MGMT methylation and loss of heterozygosity. Chromosomal instability was significantly lower in cluster C than in cluster B tumors. A more accurate tumor classification should combine the prognostic power of clinicopathologic parameters with molecular biomarkers that provide information regarding the natural history of the cancer. Hierarchical clustering seems to be a useful, promising and powerful tool for further translational studies and should lead us to define a diagnostic and prognostic signature for different carcinomas.
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Affiliation(s)
- Daniela Furlan
- Department of Human Morphology, Section of Anatomic Pathology, Centro Insubre di Biotecnologie per la Salute Umana, University of Insubria and Ospedale di Circolo, Varese, Italy.
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Wang W, Wang GQ, Sun XW, Chen G, Li YF, Zhang LY, Qiu HB, Huang CY, Zhan YQ, Zhou ZW. Prognostic values of chromosome 18q microsatellite alterations in stage II colonic carcinoma. World J Gastroenterol 2010; 16:6026-34. [PMID: 21157981 PMCID: PMC3007106 DOI: 10.3748/wjg.v16.i47.6026] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the prognostic value of chromosome 18q microsatellite alterations (MA) in stage II colon cancer.
METHODS: One hundred and six patients with sporadic stage II colon cancer were enrolled in this study. DNA was extracted from formalin-fixed, paraffin-embedded tumor and adjacent normal mucosal tissue samples. MA, including loss of heterozygosity (LOH) and microsatellite instability (MSI), was analyzed by polymerase chain reaction, polyacrylamide gel-electrophoresis and DNA sequencing at 5 microsatellite loci on chromosome 18q (D18S474, D18S55, D18S58, D18S61 and D18S64).
RESULTS: Among the 102 patients eligible for MA information, the overall frequencies of LOH, high and low frequency MSI/microsatellite stable were 49.0%, 17.6% and 82.4%, respectively. The high frequency of 18q-LOH was significantly associated with the poor 5-year overall survival (OS) (P = 0.008) and disease free survival (P = 0.006). High levels of MSI were significantly associated with a longer 5-year OS (P = 0.045) while the higher frequency of 18q-LOH at the loci of D18S474 and D18S61 was significantly associated with a poorer 5-year OS (P = 0.010 and 0.005, respectively). But multivariate analysis showed that only the frequency of 18q-LOH was significantly associated with the prognosis of the disease.
CONCLUSION: High frequency of 18q-LOH is an independent prognostic factor indicating poor prognosis of the patients with stage II colon cancer.
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Fenoglio L, Castagna E, Comino A, Luchino C, Senore C, Migliore E, Capucci F, Panzone S, Silvestri A, Ghezzo L, Ferrigno D. A shift from distal to proximal neoplasia in the colon: a decade of polyps and CRC in Italy. BMC Gastroenterol 2010; 10:139. [PMID: 21108823 PMCID: PMC3001711 DOI: 10.1186/1471-230x-10-139] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2009] [Accepted: 11/25/2010] [Indexed: 12/24/2022] Open
Abstract
Background In the last years a trend towards proximalization of colorectal carcinomas (CRC) has been reported. This study aims to evaluate the distribution of CRC and adenomatous polyps (ADP) to establish the presence of proximalization and to assess the potential predictors. Methods We retrieved histology reports of colonic specimens excised during colonoscopy, considering the exams performed between 1997 and 2006 at Cuneo Hospital, Italy. We compared the proportion of proximal lesions in the period 1997-2001 and in the period 2002-2006. Results Neoplastic lesions were detected in 3087 people. Proximal CRC moved from 25.9% (1997-2001) to 30.0% (2002-2006). Adjusting for sex and age, the difference was not significant (OR 1.23; 95% CI: 0,95-1,58). The proximal ADP proportion increased from 19.2% (1997-2001) to 26.0% (2002-2006) (OR: 1.43; 95% CI: 1.17-1.89). The corresponding figures for advanced proximal ADP were 6.6% and 9.5% (OR: 1.48; 95% CI: 1.02-2.17). Adjusting for gender, age, diagnostic period, symptoms and number of polyps the prevalence of proximal advanced ADP was increased among people ≥ 70 years compared to those aged 55-69 years (OR 1.49; 95% CI: 1.032.16). The main predictor of proximal advanced neoplasia was the number of polyps detected per exam (> 1 polyp versus 1 polyp: considering all ADP: OR 2.16; 95% CI: 1.59-2.93; considering advanced ADP OR 1.63; 95% CI: 1.08-2.46). Adjusting for these factors, the difference between the two periods was no longer significant. Conclusions CRC do not proximalize while a trend towards a proximal shift in adenomas was observed among people ≥ 70 years.
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Affiliation(s)
- Luigi Fenoglio
- Medicina Interna, Azienda Ospedaliera S, Croce e Carle, Cuneo, Italy.
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Association between hMLH1 hypermethylation and JC virus (JCV) infection in human colorectal cancer (CRC). Clin Epigenetics 2010; 2:1-5. [PMID: 22704265 PMCID: PMC3365371 DOI: 10.1007/s13148-010-0013-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2010] [Accepted: 11/11/2010] [Indexed: 12/31/2022] Open
Abstract
Incorporation of viral DNA may interfere with the normal sequence of human DNA bases on the genetic level or cause secondary epigenetic changes such as gene promoter methylation or histone acetylation. Colorectal cancer (CRC) is the second leading cause of cancer mortality in the USA. Chromosomal instability (CIN) was established as the key mechanism in cancer development. Later, it was found that CRC results not only from the progressive accumulation of genetic alterations but also from epigenetic changes. JC virus (JCV) is a candidate etiologic factor in sporadic CRC. It may act by stabilizing β-catenin, facilitating its entrance to the cell nucleus, initialing proliferation and cancer development. Diploid CRC cell lines transfected with JCV-containing plasmids developed CIN. This result provides direct experimental evidence for the ability of JCV T-Ag to induce CIN in the genome of colonic epithelial cells. The association of CRC hMLH1 methylation and tumor positivity for JCV was recently documented. JC virus T-Ag DNA sequences were found in 77% of CRCs and are associated with promoter methylation of multiple genes. hMLH1 was methylated in 25 out of 80 CRC patients positive for T-Ag (31%) in comparison with only one out of 11 T-Ag negative cases (9%). Thus, JCV can mediate both CIN and aberrant methylation in CRC. Like other viruses, chronic infection with JCV may induce CRC by different mechanisms which should be further investigated. Thus, gene promoter methylation induced by JCV may be an important process in CRC and the polyp-carcinoma sequence.
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hMLH1 promoter methylation and JC virus T antigen presence in the tumor tissue of colorectal cancer Israeli patients of different ethnic groups. Eur J Gastroenterol Hepatol 2010; 22:938-41. [PMID: 20531010 DOI: 10.1097/meg.0b013e32832e9d2c] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Hypermethylation of tumor suppressor genes' promoter and JC virus infection may be etiologic factors in the development of colorectal cancer (CRC). OBJECTIVES To look at both JC virus T antigen and hMLH1 promoter methylation in CRC tissue in Israeli ethnic groups with different incidence of CRC. METHODS Twenty-four consecutive patients with sporadic CRC were included in the study. Genomic DNA was isolated from paraffin-embedded microdomains removed from five slides of 7 mum by deparaffinizing in multiple xylene washes. Isolated DNA was used as a template for PCR to amplify DNA sequences coding the amino terminus of JC virus T antigen. Methylation-specific PCR was performed on bisulfite-modified DNA templates from CRC tissue materials to study methylation status of hMLH1 promoter, using two sets of primers specific for amplification of methylated and unmethylated alleles. RESULTS hMLH1 promoter methylation was observed in five patients (20.8%) who were also positive for JC virus T antigen, with even distribution among the ethnic groups. JC virus T antigen DNA was found in cancer tissues of 20 of the 24 patients; 50, 90.9, and 100% of Asia-Africa-born Jews, Europe-America-born Jews, and Israeli Arabs, respectively (P = 0.036 between the first group to the other). CONCLUSION Evidence for higher JC virus infection was shown among Europe-America-born Jews and Israeli Arabs. hMLH1 promoter methylation was evenly distributed between different ethnic groups in Israel.
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Park JW, Chang HJ, Park S, Kim BC, Kim DY, Baek JY, Kim SY, Oh JH, Choi HS, Park SC, Jeong SY. Absence of hMLH1 or hMSH2 expression as a stage-dependent prognostic factor in sporadic colorectal cancers. Ann Surg Oncol 2010; 17:2839-46. [PMID: 20549564 DOI: 10.1245/s10434-010-1135-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2009] [Indexed: 12/18/2022]
Abstract
BACKGROUND The predictive role of mismatch repair (MMR) status for survival after sporadic colorectal cancer remains a point of controversy. This study was designed to test the prognostic value of MMR status in sporadic colorectal cancers. METHODS The study included 318 patients with sporadic colorectal cancer who underwent primary tumor resection. MMR status was determined by the immunohistochemical analysis of hMLH1 and hMSH2 expression. RESULTS Thirty-six carcinomas (11.3%) showed abnormal MMR protein expression (22 hMLH1 negative and 14 hMSH2 negative) and were classified as MMR-defective tumors. An MMR defect was strongly associated with a reduced likelihood of lymph node (odds ratio, 0.32; 95% confidence interval [95% CI], 0.13-0.75) or distant organ metastases at diagnosis (odds ratio, 0.07; 95% CI, 0.01-0.62), independent of the clinicopathological features. Overall survival was significantly better in patients with MMR-defective tumors than in those with MMR-intact tumors (P = 0.013). In the subgroup analysis by stage, adjusted for other potential confounding variables, MMR status was not a statistically significant prognostic factor in stage I and II patients, while the MMR defect predicted a significantly better overall survival in stage III and IV patients (adjusted hazard ratio, 0.23; 95% CI, 0.06-0.97; P = 0.045). CONCLUSIONS At initial diagnosis, metastases were found at lower rates in MMR-defective tumors. MMR status may be a stage-dependent prognostic factor in patients with sporadic colorectal cancer.
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Affiliation(s)
- Ji Won Park
- National Cancer Center, Goyang, Republic of Korea
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Guastadisegni C, Colafranceschi M, Ottini L, Dogliotti E. Microsatellite instability as a marker of prognosis and response to therapy: a meta-analysis of colorectal cancer survival data. Eur J Cancer 2010; 46:2788-98. [PMID: 20627535 DOI: 10.1016/j.ejca.2010.05.009] [Citation(s) in RCA: 304] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2010] [Accepted: 05/04/2010] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND METHODS We have reviewed and pooled data from published studies to evaluate the relationship between microsatellite instability (MSI) and colorectal cancer (CRC) prognosis. Thirty-one eligible studies reporting survival in 12782 patients characterised for MSI were pooled using a fixed- or random-effects model. RESULTS The summary odds ratio (OR) estimate for overall survival (OS) associated with MSI was 0.6 (95%CI 0.53-0.69, p<0.0001), with no evidence of heterogeneity. The effect was similar for disease-free survival (DFS) (OR=0.58, 95%CI 0.47-0.72, p<0.0001). In a subset of patients treated with 5-fluorouracil (5-FU)-based chemotherapy a significant improved prognosis was found for microsatellite stable (MSS) tumours (OR=0.52, 95%CI 0.4-0.6, p<0.0001) with no heterogeneity (p=0.53; I(2)=0%). By contrast a large heterogeneity characterised the data relative to 396 patients with MSI tumours (OR=0.69, 95%CI 0.3-1.5, p=0.1; heterogeneity: p=0.03; I(2)=58%). CONCLUSIONS This study confirmed the association between MSI and favourable prognosis as determined by both OS and DFS of CRC patients. A significant beneficial effect of 5-FU therapy was found for MSS tumours whilst no clear conclusion was reached for MSI tumours due to the high inter-study heterogeneity. We propose that this inconclusive result is due to the use of a single marker, such as MSI, that cannot account alone for the complexity of the mechanisms underlying 5-FU cytotoxicity. Future studies to predict response to 5-FU chemotherapy should include additional genome stability markers.
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Affiliation(s)
- Cecilia Guastadisegni
- Department of Environment and Primary Prevention, Molecular Epidemiology Unit, Istituto Superiore di Sanità, Rome, Italy
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Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology 2010; 138:2088-100. [PMID: 20420948 DOI: 10.1053/j.gastro.2009.12.066] [Citation(s) in RCA: 722] [Impact Index Per Article: 48.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2009] [Revised: 12/16/2009] [Accepted: 12/29/2009] [Indexed: 02/06/2023]
Abstract
The "serrated neoplastic pathway" describes the progression of serrated polyps, including sessile serrated adenomas and traditional serrated adenomas, to colorectal cancer. The recognition of this pathway during the last 15 years has led to a paradigm shift in our understanding of the molecular basis of colorectal cancer and significant changes in clinical practice. These findings are particularly relevant to prevention of interval cancers through colonoscopy surveillance programs-an important issue for colonoscopists. In the past, all serrated polyps were classified simply as hyperplastic polyps and were considered to have no malignant potential. Reappraisal of this view was largely driven by increasing recognition of the malignant potential of hyperplastic polyposis.
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[Pathological diagnosis for individualized therapy of colorectal cancer]. DER PATHOLOGE 2010; 31:16-21. [PMID: 19957085 DOI: 10.1007/s00292-009-1240-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Pathological diagnosis is essential today for the individualized therapy of colorectal cancer. In the routine analysis of colorectal carcinomas the molecular-pathological detection of a KRAS mutation predicts unresponsiveness to EGFR-targeted antibody therapies. Moreover, the detection of mismatch-repair deficiency or high-degree microsatellite instability indicates unresponsiveness to 5-FU monotherapy. Colorectal carcinomas with high-grade microsatellite instability and their associated morphologic subtypes, such as the medullary carcinoma, exhibit a low risk of distant metastasis and might be considered as carcinomas with low need for adjuvant chemotherapy.
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