Tumor and Patient Characteristics of Individuals with Mismatch Repair Deficient Colorectal Cancer

Aims: To investigate tumor and patient characteristics of individuals with mismatch repair (MMR)-deficient colorectal carcinomas. Methods: We immunhistochemically investigated tissue samples of 307 consecutive patients with colorectal cancer for defects in DNA MMR proteins (hMLH1, hMSH2, hMSH6, hPMS2) and those with mutations further for microsatellite instability (MSI) and BRAF V600E mutations. Results: 32/308 (10.4%) tumors showed MMR deficiency. Seventy five percent (n = 24) had loss of hMLH1 and hPMS2 expression, 3% (n = 1) of hPMS2 alone, 18.8% (n = 6) of hMSH6 and hMSH2, 3% (n = 1) of hMSH2 alone. All MMR-deficient tumors showed high MSI. These tumors occurred preferably in the right-sided colon, in women and showed specific histological features. We obtained the family history of 18/32 patients; 2 (11.1%) met Amsterdam Criteria, 5 (27.8%) Bethesda Guidelines and 6 (33.3%) revised Bethesda Guidelines. BRAF V600E mutations were found in 16 (67%) of hMLH1 and none of the hMSH2 deficient tumors. Conclusion: We suggest using immunhistochemical testing of tumor tissues with subsequent MSI analysis, which may be justified as a screening method for MMR deficiency in colorectal cancer, since it identifies patients with possibly hereditary defects and unalike response to chemotherapy.

[1]  P. Laurent-Puig,et al.  Hypermethylator phenotype in sporadic colon cancer: study on a population-based series of 582 cases. , 2008, Cancer research.

[2]  King-Jen Chang,et al.  High‐frequency microsatellite instability predicts better chemosensitivity to high‐dose 5‐fluorouracil plus leucovorin chemotherapy for stage IV sporadic colorectal cancer after palliative bowel resection , 2002, International journal of cancer.

[3]  Shuji Ogino,et al.  CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer , 2008, Gut.

[4]  V. Torri,et al.  Reduced Likelihood of Metastases in Patients with Microsatellite-Unstable Colorectal Cancer , 2007, Clinical Cancer Research.

[5]  E. Jacobs,et al.  Association between body mass index and colorectal neoplasia at follow-up colonoscopy: a pooling study. , 2009, American journal of epidemiology.

[6]  P. Peltomäki.  Role of DNA mismatch repair defects in the pathogenesis of human cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  J. Herman,et al.  Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[8]  H. Lynch,et al.  Hereditary colorectal cancer syndromes: molecular genetics, genetic counseling, diagnosis and management , 2007, Familial Cancer.

[9]  D. Neklason,et al.  Genetic testing for inherited colon cancer. , 2005, Gastroenterology.

[10]  J. Mecklin,et al.  The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC) , 1991, Diseases of the colon and rectum.

[11]  M. O'brien,et al.  Comparison of Microsatellite Instability, CpG Island Methylation Phenotype, BRAF and KRAS Status in Serrated Polyps and Traditional Adenomas Indicates Separate Pathways to Distinct Colorectal Carcinoma End Points , 2006, The American journal of surgical pathology.

[12]  C. Boland,et al.  A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. , 1997, Journal of the National Cancer Institute.

[13]  Y. Nakamura,et al.  Genetic alterations during colorectal-tumor development. , 1988, The New England journal of medicine.

[14]  S Srivastava,et al.  A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. , 1998, Cancer research.

[15]  Jeremy R. Jass,et al.  HNPCC and Sporadic MSI-H Colorectal Cancer: A Review of the Morphological Similarities and Differences , 2004, Familial Cancer.

[16]  Li Lin,et al.  Evidence for the role of aberrant DNA methylation in the pathogenesis of Lynch syndrome adenomas , 2007, International journal of cancer.

[17]  Sudhir Srivastava,et al.  Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. , 2004, Journal of the National Cancer Institute.

[18]  A. Rustgi,et al.  The genetics of hereditary colon cancer. , 2007, Genes & development.

[19]  Daniel J Sargent,et al.  Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. , 2003, The New England journal of medicine.

[20]  T. Seufferlein,et al.  S3-Leitlinie „Kolorektales Karzinom” – Aktualisierung 2008 , 2008, Zeitschrift fur Gastroenterologie.

[21]  O. Sieber,et al.  Genomic instability — the engine of tumorigenesis? , 2003, Nature Reviews Cancer.

[22]  S N Thibodeau,et al.  Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. , 1998, Cancer research.

[23]  A. Ristimäki,et al.  BRAF mutation in sporadic colorectal cancer and Lynch syndrome , 2013, Virchows Archiv.

[24]  John L Hopper,et al.  Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  B. Vogelstein,et al.  Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. , 1994, The American journal of pathology.

[26]  W. Frankel,et al.  Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). , 2005, The New England journal of medicine.

[27]  J. Bond,et al.  Microsatellite instability in interval colon cancers. , 2006, Gastroenterology.

[28]  R. Sandler,et al.  Epidemiology of colorectal adenomas. , 1994, Epidemiologic reviews.

[29]  Walter Willett,et al.  Risk factors for advanced colonic neoplasia and hyperplastic polyps in asymptomatic individuals. , 2003, JAMA.

[30]  Á. Carracedo,et al.  Risk of cancer in cases of suspected lynch syndrome without germline mutation. , 2013, Gastroenterology.

[31]  H. Brenner,et al.  Interval cancers after negative colonoscopy: population-based case-control study , 2011, Gut.

[32]  K. Kinzler,et al.  Lessons from Hereditary Colorectal Cancer , 1996, Cell.

[33]  W. Grady,et al.  Genomic and epigenetic instability in colorectal cancer pathogenesis. , 2008, Gastroenterology.

[34]  H. Lynch,et al.  Overview of natural history, pathology, molecular genetics and management of HNPCC (Lynch syndrome) , 1996, International journal of cancer.

[35]  C. Boland,et al.  Prevalence of somatic mutl homolog 1 promoter hypermethylation in Lynch syndrome colorectal cancer , 2015, Cancer.

[36]  R. Ward,et al.  Routine testing for mismatch repair deficiency in sporadic colorectal cancer is justified , 2005, The Journal of pathology.

[37]  D. Evans,et al.  Tumour MLH1 promoter region methylation testing is an effective prescreen for Lynch Syndrome (HNPCC) , 2014, Journal of Medical Genetics.

[38]  M. Loda,et al.  Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. , 1997, Cancer research.

[39]  J. Jass.  Classification of colorectal cancer based on correlation of clinical, morphological and molecular features , 2007, Histopathology.

[40]  W. Klaisuban,et al.  Deficient DNA mismatch repair is associated with favorable prognosis in Thai patients with sporadic colorectal cancer. , 2015, World journal of gastroenterology.

[41]  J. Baron,et al.  The Association of Lifestyle and Dietary Factors with the Risk for Serrated Polyps of the Colorectum , 2009, Cancer Epidemiology, Biomarkers & Prevention.

[42]  M. Andreu,et al.  Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. , 2005, JAMA.

[43]  A. Lindblom.  Different mechanisms in the tumorigenesis of proximal and distal colon cancers , 2001, Current opinion in oncology.

[44]  D. Snover.  Update on the serrated pathway to colorectal carcinoma. , 2011, Human pathology.

[45]  M. Kloor,et al.  Clinical significance of microsatellite instability in colorectal cancer , 2013, Langenbeck's Archives of Surgery.

[46]  I. Nagtegaal,et al.  Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. , 2014, Gastroenterology.

[47]  P. Møller,et al.  Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts , 2013, Gut.

[48]  G. Tortora,et al.  EGFR antagonists in cancer treatment. , 2008, The New England journal of medicine.

[49]  Á. Carracedo,et al.  Comparison between universal molecular screening for Lynch syndrome and revised Bethesda guidelines in a large population-based cohort of patients with colorectal cancer , 2011, Gut.

[50]  Megan Hitchins,et al.  MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer. , 2005, Gastroenterology.