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A patient with four metachronous cancers and multiple adenomatous colon polyps harboring the American Founder Lynch syndrome mutation: a case report


Lynch syndrome (LS) is a genetic disorder that accounts for approximately 3% of all colorectal cancers (CRC) [1]. Clinical characteristics of LS include proximal CRC, multiple CRCs, occurrence at a young age, accelerated carcinogenesis, and an increase in risk of extracolonic cancers [1]. LS is an autosomal dominant disorder, caused by germline mutations in DNA mismatch repair (MMR) genes. Mutations in MSH2 account for 1-2% of all CRCs and up to 20% of these are large germline deletions [2]. The MSH2 deletion of exons 1-6 has been characterized as a North American Founder Mutation (AFM) [2, 3].

Case report

A 68-year-old Caucasian male presented to cancer genetics following a second primary diagnosis of infiltrating poorly differentiated adenocarcinoma of the colon. His history included; moderately differentiated invasive adenocarcinoma of the sigmoid colon at age 40; left ureteral carcinoma diagnosed at 54; and a bladder carcinoma diagnosed at age 59. Additionally, colonoscopy revealed multiple adenomatous polyps within a ten year period. Family history is significant for a son diagnosed with colon cancer at age 34, father with gastric cancer, two paternal aunts and paternal grandfather with colon cancer, and German ancestry. Peripheral blood was sent for analysis of the MLH1 and MSH2 genes [4]. Molecular analysis identified a deleterious mutation, del exons 1-6, in the MSH2 gene. This results in the premature truncation of the MSH2 protein and confirms the diagnosis of LS.


This case reveals a LS patient with a history of four metachronous cancers. Phenotypic variations exist amongst the different MMR genes causative for LS [57]. Individuals with MSH2 mutations are at a higher risk of developing extracolonic cancers than individuals with MLH1 mutations [5, 6]. There is a 7-fold higher risk for urinary tract cancers in individuals with MSH2 mutations and male carriers have up to a 28% lifetime risk of developing uroepithelial cancers [8]. It is controversial whether or not large deletions lead to a more severe phenotype with multiple cancers and earlier ages of onset [7, 9]. The severity of clinical presentation may correlate more with which MMR gene is altered than the specific mutation type [9]. A better understanding of genotype-phenotype correlations may allow for a personalized surveillance plan in the future.


  1. 1.

    Lynch HT, et al.: Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clinical Genetics 2009, 76: 1–18. 10.1111/j.1399-0004.2009.01230.x

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  2. 2.

    Clendenning M, et al.: Origins and Prevalence of the American Founder Mutation of MSH2. Cancer Research 2008,68(7):2145–2153. 10.1158/0008-5472.CAN-07-6599

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Wagner A, et al.: Molecular Analysis of Hereditary Nonpolyposis Colorectal Cancer in the United States: High Mutation Detection Rate among Clinically Selected Families and Characterization of an American Founder Genomic Deletion of the MSH2 Gene. American Journal of Human Genetics 2003, 72: 1088–1100. 10.1086/373963

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  4. 4.

    Colaris® Technical Specifications, Myriad Genetic Laboratories 2009. []

  5. 5.

    Vasen HFA, et al.: MSH2 Mutation Carriers Are at Higher Risk of Cancer Than MLH1 Mutation Carriers: A Study of Hereditary Nonpolyposis Colrectal Cancer Families. Journal of Clinical Oncology 2001,19(20):4074–4080.

    CAS  PubMed  Google Scholar 

  6. 6.

    Lin KM, et al.: Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Diseases of the Colon and Rectum 1998,41(4):428–433. 10.1007/BF02235755

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Kastrinos Fay, et al.: Phenotype Comparison of MLH1 and MSH2 Mutation Carriers in a Cohort of 1,914 Individuals Undergoing Clinical Genetic Testing in the United States. Cancer Epidemiol Biomarkers Prev 2008,17(8):2044–2051. 10.1158/1055-9965.EPI-08-0301

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Watson P, et al.: The Risk of Extra-colonic, Extra-endometrial Cancer in the Lynch Syndrome. International Journal of Cancer 2008,123(2):444–449. 10.1002/ijc.23508

    CAS  Article  Google Scholar 

  9. 9.

    Bandhuin LM, et al.: Characterization of hMLH1 and hMLH2 gene dosage alterations in Lynch Syndrome patients. Gastroenterology 2005, 129: 846–854. 10.1053/j.gastro.2005.06.026

    Article  Google Scholar 

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Correspondence to Lindsay Dohany.

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Dohany, L., Ducaine, W. & Zakalik, D. A patient with four metachronous cancers and multiple adenomatous colon polyps harboring the American Founder Lynch syndrome mutation: a case report. Hered Cancer Clin Pract 9, P8 (2011).

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  • Lynch Syndrome
  • MSH2 Mutation
  • MSH2 Gene
  • Metachronous Cancer
  • Lynch Syndrome Patient