MSH6 germline mutations are rare in colorectal cancer families

Paolo Peterlongo, Khedoudja Nafa, Gabriel S. Lerman, Emily Glogowski, Jinru Shia, Tian Z. Ye, Arnold J. Markowitz, José G. Guillem, Prema Kolachana, Jeffrey A. Boyd, Kenneth Offit, Nathan A. Ellis

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


Germline mutations in MSH6 can cause HNPCC, which is associated with a tumor phenotype featuring MSI. However, tumors arising in persons with disease-causing mutations of MSH6 may or may not exhibit MSI. We used D-HPLC to screen for germline mutations in the promoter region, the coding region and the 3′-UTR of MSH6. Eighty-four families, enrolled on the basis of Amsterdam I and II criteria (HNPCC families) and less stringent criteria (HNPCC-like families), were tested for MMR gene mutations; 27 families had a disease-causing mutation in MLHI or MSH2, and the remaining 57 families were tested for mutations in MSH6. Two protein-truncating mutations were identified in each of 2 families fulfilling the Amsterdam I criteria, being present in persons affected with early-onset colorectal cancers exhibiting MSI. Immunohistochemical analysis showed that expression of both MSH2 and MSH6 proteins was lost in the cancer cells of the 2 mutation carriers but only MSH6 protein expression was lost in 2 adenomatous polyps. A third possibly disease-causing mutation was found in a person affected with a tumor that did not exhibit MSI. In addition, we found 4 new polymorphisms and determined that neither of the 2 studied by association analysis conferred susceptibility to colorectal or endometrial cancer. Altogether, our results indicate that disease-causing germline mutations of MSH6 are rare in HNPCC and HNPCC-like families.

Original languageEnglish (US)
Pages (from-to)571-579
Number of pages9
JournalInternational Journal of Cancer
Issue number4
StatePublished - Nov 20 2003


  • Colorectal cancer
  • Hereditary nonpolyposis colorectal cancer
  • Microsatellite instability
  • Mismatch repair gene

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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