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MLH1 promotor hypermethylation does not rule out a diagnosis of Lynch syndrome: a case report

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There are approximately 136,830 new colorectal cancer (CRC) cases diagnosed annually in the United States. In an effort to identify those at highest risk for Lynch Syndrome, an inherited CRC predisposition syndrome, several professional guidelines advocate for routine screening of all colorectal adenocarcinomas for features of DNA mismatch repair, microsatellite instability (MSI) and/or absent immunohistochemistry staining. Approximately 12–17 % of CRCs demonstrate MSI with germline mutations in genes involved in DNA mismatch repair, MLH1, MSH2, MSH6, PMS2 and TACSTD1/EPCAM and somatic MLH1 promotor hypermethylation being alternative pathways for the development of microsatellite unstable CRC. It is important to distinguish between these two events as the underlying cause of cancer development as management and implications for the patient and family members vary significantly. We describe a patient with multiple primary cancers, a deleterious germline MSH6 mutation and somatic MLH1 promotor hypermethylation highlighting the importance of incorporating the clinical history with the genetic evaluation.

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  1. Hampel H, Frankel WL, Martin E et al (2005) Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 352:1851–1860

    Article  CAS  PubMed  Google Scholar 

  2. Moreira L, Balaguer F, Lindor N et al (2012) Identification of Lynch syndrome among patients with colorectal cancer. JAMA 308:1555–1565

    Article  CAS  PubMed  Google Scholar 

  3. Recommendations from the EGAPP Working Group (2009) genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med 11:35–41

    Article  Google Scholar 

  4. Stoffel E, Mukherjee B, Raymond VM et al (2009) Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology 137:1621–1627

    Article  PubMed Central  PubMed  Google Scholar 

  5. Bonadona V, Bonaiti B, Olschwang S et al (2011) Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 305:2304–2310

    Article  CAS  PubMed  Google Scholar 

  6. Win AK, Young JP, Lindor NM et al (2012) Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol 30:958–964

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Ward R, Meagher A, Tomlinson I et al (2001) Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut 48:821–829

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Popat S, Hubner R, Houlston RS (2005) Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 23:609–618

    Article  CAS  PubMed  Google Scholar 

  9. Bessa X, Balleste B, Andreu M et al (2008) A prospective, multicenter, population-based study of BRAF mutational analysis for Lynch syndrome screening. Clin Gastroenterol Hepatol 6:206–214

    Article  CAS  PubMed  Google Scholar 

  10. McGivern A, Wynter CV, Whitehall VL et al (2004) Promoter hypermethylation frequency and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer. Fam Cancer 3:101–107

    Article  CAS  PubMed  Google Scholar 

  11. Senter L, Clendenning M, Sotamaa K et al (2008) The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 135:419–428

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Domingo E, Espin E, Armengol M et al (2004) Activated BRAF targets proximal colon tumors with mismatch repair deficiency and MLH1 inactivation. Genes Chromosomes Cancer 39:138–142

    Article  CAS  PubMed  Google Scholar 

  13. Bettstetter M, Dechant S, Ruemmele P et al (2007) Distinction of hereditary nonpolyposis colorectal cancer and sporadic microsatellite-unstable colorectal cancer through quantification of MLH1 methylation by real-time PCR. Clin Cancer Res 13:3221–3228

    Article  CAS  PubMed  Google Scholar 

  14. Weissman SM, Burt R, Church J et al (2012) Identification of individuals at risk for lynch syndrome using targeted evaluations and genetic testing: national society of genetic counselors and the collaborative group of the Americas on inherited colorectal cancer joint practice guideline. J Genet Couns 21:484–493

    Article  PubMed  Google Scholar 

  15. Heald B, Plesec T, Liu X, et al. (2013) Implementation of universal microsatellite instability and immunohistochemistry screening for diagnosing lynch syndrome in a large academic medical center. J Clin Oncol 31(10):1336–1340

  16. Beamer LC, Grant ML, Espenschied CR et al (2012) Reflex immunohistochemistry and microsatellite instability testing of colorectal tumors for Lynch syndrome among US cancer programs and follow-up of abnormal results. J Clin Oncol 30:1058–1063

    Article  PubMed Central  PubMed  Google Scholar 

  17. Hall G, Clarkson A, Shi A et al (2010) Immunohistochemistry for PMS2 and MSH6 alone can replace a four antibody panel for mismatch repair deficiency screening in colorectal adenocarcinoma. Pathology 42:409–413

    Article  PubMed  Google Scholar 

  18. Domingo E, Laiho P, Ollikainen M et al (2004) BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J Med Genet 41:664–668

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Hagen CE, Lefferts J, Hornick JL, Srivastava A (2011) “Null pattern” of immunoreactivity in a Lynch syndrome-associated colon cancer due to germline MSH2 mutation and somatic MLH1 hypermethylation. Am J Surg Pathol 35:1902–1905

    Article  PubMed  Google Scholar 

  20. Rahner N, Friedrichs N, Steinke V et al (2008) Coexisting somatic promoter hypermethylation and pathogenic MLH1 germline mutation in Lynch syndrome. J Pathol 214:10–16

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Victoria M. Raymond.

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Raymond, V.M., Morris, A.M., Hafez, K.S. et al. MLH1 promotor hypermethylation does not rule out a diagnosis of Lynch syndrome: a case report. Familial Cancer 14, 77–80 (2015).

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