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• W31576990 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. 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. Primary colorectal carcinoma (CRC) is a solid tumor that occurs commonly in US adults. In 2011, the American Cancer Society expects approximately 142,000 new cases of CRC. Independent prognostic variables include stage (extent of disease),1Griffin M.R. Bergstralh E.J. Coffey R.J. Beart Jr., R.W. Melton 3rd, L.J. Predictors of survival after curative resection of carcinoma of the colon and rectum.Cancer. 1987; 60: 2318-2324Crossref PubMed Google Scholar, 2Gryfe R. Kim H. Hsieh E.T. Aronson M.D. Holowaty E.J. Bull S.B. Redston M. Gallinger S. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer.N Engl J Med. 2000; 342: 69-77Crossref PubMed Scopus (763) Google Scholar grade (degree of differentiation),1Griffin M.R. Bergstralh E.J. Coffey R.J. Beart Jr., R.W. Melton 3rd, L.J. Predictors of survival after curative resection of carcinoma of the colon and rectum.Cancer. 1987; 60: 2318-2324Crossref PubMed Google Scholar, 2Gryfe R. Kim H. Hsieh E.T. Aronson M.D. Holowaty E.J. Bull S.B. Redston M. Gallinger S. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer.N Engl J Med. 2000; 342: 69-77Crossref PubMed Scopus (763) Google Scholar angiolymphatic invasion,3Compton C. Fenoglio-Preiser C.M. Pettigrew N. Fielding L.P. American Joint Committee on Cancer Prognostic Factors Consensus Conference: Colorectal Working Group.Cancer. 2000; 88: 1739-1757Crossref PubMed Scopus (303) Google Scholar carcinoembryonic antigen level,3Compton C. Fenoglio-Preiser C.M. Pettigrew N. Fielding L.P. American Joint Committee on Cancer Prognostic Factors Consensus Conference: Colorectal Working Group.Cancer. 2000; 88: 1739-1757Crossref PubMed Scopus (303) Google Scholar and DNA mismatch repair (MMR) status.2Gryfe R. Kim H. Hsieh E.T. Aronson M.D. Holowaty E.J. Bull S.B. Redston M. Gallinger S. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer.N Engl J Med. 2000; 342: 69-77Crossref PubMed Scopus (763) Google Scholar, 4Aarnio M. Mustonen H. Mecklin J.P. Jarvinen H.J. Prognosis of colorectal cancer varies in different high-risk conditions.Ann Med. 1998; 30: 75-80Crossref PubMed Google Scholar, 5Sankila R. Aaltonen L.A. Jarvinen H.J. Mecklin J.P. Better survival rates in patients with MLH1-associated hereditary colorectal cancer.Gastroenterology. 1996; 110: 682-687Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar, 6Halling K.C. French A.J. McDonnell S.K. Burgart L.J. Schaid D.J. Peterson B.J. Moon-Tasson L. Mahoney M.R. Sargent D.J. O'Connell M.J. Witzig T.E. Farr Jr., G.H. Goldberg R.M. Thibodeau S.N. Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers.J Natl Cancer Inst. 1999; 91: 1295-1303Crossref PubMed Google Scholar This article focuses on the relevance, molecular subgroups, and testing strategies for DNA MMR status. Protein heterodimers of MutS homologues (MSH2, MSH6) and of MutL homologues (MLH1, PMS2) are sine qua non components of the human multimeric DNA MMR protein complexes that correct strand alignment and base matching errors during DNA replication.7Karran P. Microsatellite instability and DNA mismatch repair in human cancer.Cancer Biol. 1996; 7: 15-24Crossref PubMed Scopus (63) Google Scholar, 8Arnheim N. Shibata D. DNA mismatch repair in mammals: role in disease and meiosis.Curr Opin Genet Dev. 1997; 7: 364-370Crossref PubMed Scopus (36) Google Scholar When any one of these MMR proteins is absent or nonfunctional, the MMR process malfunctions, as reflected by length alterations in microsatellites, ie, microsatellite instability (MSI).9Aaltonen L.A. Peltomaki P. Leach F.S. Sistonen P. Pylkkanen L. Mecklin J.P. Jarvinen H. Powell S.M. Jen J. Hamilton S.R. Petersen G.M. Kinzler K.W. Vogelstein B. de la Chapelle A. Clues to the pathogenesis of familial colorectal cancer [see comments].Science. 1993; 260: 812-816Crossref PubMed Google Scholar, 10Thibodeau S.N. Bren G. Schaid D. Microsatellite instability in cancer of the proximal colon.Science. 1993; 260: 816-819Crossref PubMed Google Scholar, 11Dietmaier W. Wallinger S. Bocker T. Kullmann F. Fishel R. Ruschoff J. Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression.Cancer Res. 1997; 57: 4749-4756PubMed Google Scholar Therefore, loss-of-function defects in MMR result in error-prone DNA replication and MSI. The in vitro effect of this loss is marked—CRC cell lines with defective MLH1 or MSH2 show a three-log increase in the rate of dinucleotide repeat length changes per locus per generation when compared with a MMR-proficient (pMMR) cell line.12Hanford M.G. Rushton B.C. Gowen L.C. Farber R.A. Microsatellite mutation rates in cancer cell lines deficient or proficient in mismatch repair.Oncogene. 1998; 16: 2389-2393Crossref PubMed Google Scholar With the use of panels of microsatellites to screen CRCs a bimodal distribution of MSI can be observed, with most cases showing <20% or >60% of microsatellites to be unstable.13Thibodeau S.N. French A.J. Cunningham J.M. Tester D. Burgart L.J. Roche P.C. McDonnell S.K. Schaid D.J. Vockley C.W. Michels V.V. Farr Jr., G.H. O'Connell M.J. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1.Cancer Res. 1998; 58: 1713-1718PubMed Google Scholar An empirical cutoff at 30% unstable microsatellites has been adopted, resulting in three test results: MSI-high (MSI-H; ≥30% MSI), MSI-low (MSI-L; 0<MSI <30%), and microsatellite stability (MSS; MSI = 0%).10Thibodeau S.N. Bren G. Schaid D. Microsatellite instability in cancer of the proximal colon.Science. 1993; 260: 816-819Crossref PubMed Google Scholar With few exceptions (eg, CRCs due to MSH6 gene mutations), MSI-L cases arise and behave like MSS cases and are considered to be pMMR.13Thibodeau S.N. French A.J. Cunningham J.M. Tester D. Burgart L.J. Roche P.C. McDonnell S.K. Schaid D.J. Vockley C.W. Michels V.V. Farr Jr., G.H. O'Connell M.J. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1.Cancer Res. 1998; 58: 1713-1718PubMed Google Scholar, 14Baudhuin L.M. Burgart L.J. Leontovich O. Thibodeau S.N. Use of microsatellite instability and immunohistochemistry testing for the identification of individuals at risk for Lynch syndrome.Fam Cancer. 2005; 4: 255-265Crossref PubMed Scopus (67) Google Scholar MSI-H cases correlate with differences in stage at presentation and improved stage-specific prognosis15Myrhoj T. Bisgaard M.L. Bernstein I. Svendsen L.B. Sondergaard J.O. Bulow S. Hereditary non-polyposis colorectal cancer: clinical features and survival Results from the Danish HNPCC register.Scand J Gastroenterol. 1997; 32: 572-576Crossref PubMed Google Scholar, 16Samowitz W.S. Curtin K. Ma K.N. Schaffer D. Coleman L.W. Leppert M. Slattery M.L. Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level.Cancer Epidemiol Biomarkers Prev. 2001; 10: 917-923PubMed Google Scholar and are considered MMR deficient dMMR.13Thibodeau S.N. French A.J. Cunningham J.M. Tester D. Burgart L.J. Roche P.C. McDonnell S.K. Schaid D.J. Vockley C.W. Michels V.V. Farr Jr., G.H. O'Connell M.J. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1.Cancer Res. 1998; 58: 1713-1718PubMed Google Scholar Approximately 15% of CRCs are dMMR, as estimated by MSI-H testing.17Jass J.R. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features.Histopathology. 2007; 50: 113-130Crossref PubMed Scopus (425) Google Scholar, 18Nosho K. Irahara N. Shima K. Kure S. Kirkner G.J. Schernhammer E.S. Hazra A. Hunter D.J. Quackenbush J. Spiegelman D. Giovannucci E.L. Fuchs C.S. Ogino S. Comprehensive biostatistical analysis of CpG island methylator phenotype in colorectal cancer using a large population-based sample.PLoS One. 2008; 3: e3698Crossref PubMed Scopus (120) Google Scholar Most of these (12% to 13%) are somatically acquired/sporadic,16Samowitz W.S. Curtin K. Ma K.N. Schaffer D. Coleman L.W. Leppert M. Slattery M.L. Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level.Cancer Epidemiol Biomarkers Prev. 2001; 10: 917-923PubMed Google Scholar, 19Kim H. Jen J. Vogelstein B. Hamilton S.R. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences.Am J Pathol. 1994; 145: 148-156PubMed Google Scholar and the remaining 2% to 3% are due to inherited/germline mutation of one allele of an MMR gene.20de la Chapelle A. Genetic predisposition to colorectal cancer.Nat Rev Cancer. 2004; 4: 769-780Crossref PubMed Scopus (338) Google Scholar This latter subgroup characterizes CRCs diagnosed in the inherited Lynch (also known as hereditary nonpolyposis colorectal cancer)21Vasen H.F. Mecklin J.P. Khan P.M. Lynch H.T. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC).Dis Colon Rectum. 1991; 34: 424-425Crossref PubMed Google Scholar, 22Lynch H.T. Smyrk T.C. Watson P. Lanspa S. Lynch J.F. Lynch P.M. Cavalieri R.J. Boland C.R. Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an update review.Gastroenterology. 1993; 104: 1535-1549Abstract PubMed Google Scholar, 23Rossi S.C. Srivastava S. National Cancer Institute workshop on genetic screening for colorectal cancer.J Natl Cancer Inst. 1996; 88: 331-339Crossref PubMed Google Scholar, 24Aaltonen L.A. Salovaara R. Kristo P. Canzian F. Hemminki A. Peltomaki P. 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Molecular pathologic analysis enhances the diagnosis and management of Muir-Torre syndrome and gives insight into its underlying molecular pathogenesis.Am J Surg Pathol. 2001; 25: 936-941Crossref PubMed Scopus (30) Google Scholar syndromes. Both Lynch and sporadic dMMR subgroups differ in origin but share a final common pathogenesis in terms of loss of MMR protein function/expression and MSI-H.11Dietmaier W. Wallinger S. Bocker T. Kullmann F. Fishel R. Ruschoff J. Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression.Cancer Res. 1997; 57: 4749-4756PubMed Google Scholar, 25Cunningham J.M. Kim C.Y. Christensen E.R. Tester D.J. Parc Y. Burgart L.J. Halling K.C. McDonnell S.K. Schaid D.J. Walsh Vockley C. Kubly V. Nelson H. Michels V.V. Thibodeau S.N. The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas.Am J Hum Genet. 2001; 69: 780-790Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar Both subgroups have improved stage-specific prognoses,2Gryfe R. Kim H. Hsieh E.T. Aronson M.D. Holowaty E.J. Bull S.B. Redston M. Gallinger S. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer.N Engl J Med. 2000; 342: 69-77Crossref PubMed Scopus (763) Google Scholar, 6Halling K.C. French A.J. McDonnell S.K. Burgart L.J. Schaid D.J. Peterson B.J. Moon-Tasson L. Mahoney M.R. Sargent D.J. O'Connell M.J. Witzig T.E. Farr Jr., G.H. Goldberg R.M. Thibodeau S.N. Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers.J Natl Cancer Inst. 1999; 91: 1295-1303Crossref PubMed Google Scholar, 15Myrhoj T. Bisgaard M.L. Bernstein I. Svendsen L.B. Sondergaard J.O. Bulow S. Hereditary non-polyposis colorectal cancer: clinical features and survival Results from the Danish HNPCC register.Scand J Gastroenterol. 1997; 32: 572-576Crossref PubMed Google Scholar, 16Samowitz W.S. Curtin K. Ma K.N. Schaffer D. Coleman L.W. Leppert M. Slattery M.L. Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level.Cancer Epidemiol Biomarkers Prev. 2001; 10: 917-923PubMed Google Scholar, 27Watson P. Lin K.M. Rodriguez-Bigas M.A. Smyrk T. Lemon S. Shashidharan M. Franklin B. Karr B. Thorson A. Lynch H.T. Colorectal carcinoma survival among hereditary nonpolyposis colorectal carcinoma family members.Cancer. 1998; 83: 259-266Crossref PubMed Scopus (164) Google Scholar, 28Popat S. Hubner R. Houlston R.S. Systematic review of microsatellite instability and colorectal cancer prognosis.J Clin Oncol. 2005; 23: 609-618Crossref PubMed Scopus (602) Google Scholar, 29Benatti P. Gafa R. Barana D. Marino M. Scarselli A. 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DNA mismatch repair and adjuvant chemotherapy in sporadic colon cancer.Nat Rev Clin Oncol. 2010; 7: 174-177Crossref PubMed Scopus (14) Google Scholar Roughly 40% of new CRC patients have nodal metastasis without distant metastasis at presentation (AJCC stage III), and roughly 15% of new CRC patients have distant metastasis at presentation (AJCC stage IV).38Siegel R. Ward E. Brawley O. Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths.CA Cancer J Clin. 2011; 61: 212-236Crossref PubMed Scopus (1774) Google Scholar Although 5-FU is included in common combination chemotherapy regimens for patients with node-positive (stage III) and distant metastatic (stage IV) CRC, dMMR does not currently preclude use of these regimens.37Sinicrope F.A. 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Recent emphasis on the detection of all Lynch probands and subclinical carriers has advocated universal testing for MMR defects in all patients with newly diagnosed CRC,39Berg: Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives.Genet Med. 2009; 11: 35-41Crossref PubMed Scopus (147) Google Scholar with a goal of improved clinical decision-making and treatment outcomes. Such an approach requires a realistic and effective laboratory practice algorithm for diagnostic testing that will detect all dMMR cases and then distinguish Lynch and sporadic dMMR subgroups. Sporadic dMMR CRC comprises 12% to 13% of all new cases of CRC16Samowitz W.S. Curtin K. Ma K.N. Schaffer D. Coleman L.W. Leppert M. Slattery M.L. 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Classification of colorectal cancer based on correlation of clinical, morphological and molecular features.Histopathology. 2007; 50: 113-130Crossref PubMed Scopus (425) Google Scholar, 45Snover D.C. Update on the serrated pathway to colorectal carcinoma.Hum Pathol. 2011; 42: 1-10Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar SSA/Ps with dysplasia are considered the precursor for sporadic dMMR CRC and show unique molecular features, including BRAF c.1799T>A mutation, generalized increase in CpG island methylation (the CpG island methylator phenotype [CIMP]), MLH1 promoter hypermethylation (PHM), and MSI-H.17Jass J.R. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features.Histopathology. 2007; 50: 113-130Crossref PubMed Scopus (425) Google Scholar, 45Snover D.C. 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