Penetrance and Expressivity of MSH6 Germline Mutations in Seven Kindreds Not Ascertained by Family History

Thomas Jefferson University, Filadelfia, Pennsylvania, United States
The American Journal of Human Genetics (Impact Factor: 10.93). 07/2004; 74(6):1262-9. DOI: 10.1086/421332
Source: PubMed


Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by inherited mutations in DNA mismatch-repair genes, most commonly MLH1 or MSH2. The role MSH6 plays in inherited cancer susceptibility is less well defined. The aim of this study was to investigate the penetrance and expressivity of MSH6 mutations in kindreds ascertained through endometrial cancer probands unselected for family history. Detailed pedigrees were constructed for six MSH6 mutation carriers. All reported cancers and precancers were confirmed, and tissues were obtained when available. Tumors were analyzed for microsatellite instability (MSI) and for expression of MSH2, MLH1, and MSH6. MSH6 mutation status was determined for 59 family members. Of these 59 individuals, 19 (32%) had confirmed cancers and precancers. There was an excess of mutation carriers among the 19 affected family members (11 [58%] of 19) compared with those among the 40 unaffecteds (8 [20%] of 40, P=.0065, odds ratio = 5.5, 95% CI = 1.66-18.19). In four of the seven tumors analyzed from mutation carriers other than the probands, MSI and/or MMR protein expression was consistent with the involvement of MSH6. Overall estimated penetrance of the MHS6 mutations was 57.7%. Of the tumors in mutation carriers, 78% were part of the extended HNPCC spectrum. This study demonstrates that MSH6 germline mutations are, indeed, associated with increased cancer risk and that the penetrance of mutations may be higher than appreciated elsewhere. A combination of MSI and immunohistochemistry analyses may be helpful in screening for MSH6 mutation carriers.

Download full-text


Available from: Thomas J Herzog
  • Source
    • "The acknowledged Lynch syndrome tumour spectrum is shown in Table 1. The cumulative risks and average ages of diagnosis shown in this table were retrieved from papers reporting these data in proven mutation carriers [8-17], rather than from papers that had included untested patients and/or first-degree relatives in their analyses. The reports on 'unusual' tumours in Lynch syndrome patients are presented in Table 2. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Lynch syndrome (HNPCC) is a dominantly inherited disorder characterized by germline defects in DNA mismatch repair (MMR) genes and the development of a variety of cancers, predominantly colorectal and endometrial. We present a 44-year-old woman who was shown to carry the truncating MSH2 gene mutation that had previously been identified in her family. Recently, she had been diagnosed with an undifferentiated carcinoma of the thyroid and an adenoma of her coecum. Although the thyroid carcinoma was not MSI-high (1 out of 5 microsatellites instable), it did show complete loss of immunohistochemical expression for the MSH2 protein, suggesting that this tumour was not coincidental. Although the risks for some tumour types, including breast cancer, soft tissue sarcoma and prostate cancer, are not significantly increased in Lynch syndrome, MMR deficiency in the presence of a corresponding germline defect has been demonstrated in incidental cases of a growing range of tumour types, which is reviewed in this paper. Interestingly, the MSH2-associated tumour spectrum appears to be wider than that of MLH1 and generally the risk for most extra-colonic cancers appears to be higher for MSH2 than for MLH1 mutation carriers. Together with a previously reported case, our findings show that anaplastic thyroid carcinoma can develop in the setting of Lynch syndrome. Uncommon Lynch syndrome-associated tumour types might be useful in the genetic analysis of a Lynch syndrome suspected family if samples from typical Lynch syndrome tumours are unavailable.
    Full-text · Article · Feb 2008 · Hereditary Cancer in Clinical Practice
  • [Show abstract] [Hide abstract]
    ABSTRACT: Techniques for constructing a single description of the unit under test (UUT) for use with multiple test methods are proposed. They conclude a consistent user interface, a set of library and model tools, and a coherent set of data structures. The board and library software provide: an interface for use in bulk loading of board data; interactive software tools to allow modification and correction of the board and device descriptions; mechanisms for test preparation tools to be used to select data from the library; and facilities to allow the user to create special versions of models for use in the preparation and running of test data for a single board
    No preview · Conference Paper · May 1989
  • [Show abstract] [Hide abstract]
    ABSTRACT: Colorectal cancer and its potential precursor, adenomatous polyps, tend to aggregate in families, but it is not clear why. Heritability is established for only rare colorectal cancers, some prominently involving polyposis. Preliminary studies suggest, however, that susceptibility to the common colorectal cancer precursors, "sporadic" adenomatous polyps, is also inherited.
    No preview · Article · Dec 1989 · Hospital practice (Office ed.)
Show more