Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers

Department of Pathology and Medical Genetics, St Olavs University Hospital, Trondheim, Norway.
Journal of Medical Genetics (Impact Factor: 5.64). 09/2010; 47(9):579-85. DOI: 10.1136/jmg.2010.077677
Source: PubMed

ABSTRACT Reported prevalence, penetrance and expression of deleterious mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2, may reflect differences in the clinical criteria used to select families for DNA testing. The authors have previously reported that clinical criteria are not sensitive enough to identify MMR mutation carriers among incident colorectal cancer cases.
To describe the sensitivity of the criteria when applied to families with a demonstrated MMR mutation.
Families with an aggregation of colorectal cancers were examined for deleterious MMR mutations according to the Mallorca guidelines. All families with a detected MMR mutation as of November 2009 were reclassified according to the Amsterdam and Bethesda criteria.
Sixty-nine different DNA variants were identified in a total of 129 families. The original Amsterdam clinical criteria were met by 38%, 12%, 78% and 25% of families with mutations in MSH2, MSH6, MLH1 and PMS2, respectively. Corresponding numbers for the revised Amsterdam criteria were 62%, 48%, 87% and 38%. Similarly, each of the four clinical Bethesda criteria had low sensitivity for identifying MSH6 or PMS2 mutations.
Amsterdam criteria and each of the Bethesda criteria were inadequate for identifying MSH6 mutation-carrying kindreds. MSH6 mutations may be more common than currently assumed, and the penetrance/expression of MSH6 mutations, as derived from families meeting current clinical criteria, may be misleading. To increase detection rate of MMR mutation carriers, all cancers in the Lynch syndrome tumour spectrum should be subjected to immunohistochemical analysis and/or analysis for microsatellite instability.

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    • "However, in contrast to prior reports suggesting only 10% of HNPCC families harbour MSH6 mutations (Wijnen et al, 1999; Berends et al, 2002), such mutations accounted for over half of the clearly pathogenic mutations in our study. The low percentage of MSH6 mutations may be due to inadequate clinical criteria to accurately identify these families (Sjursen et al, 2010), who typically present with later age of colorectal cancer, and higher risk but later age of endometrial cancer in females (Wijnen et al, 1999; Wagner et al, 2001; Devlin et al, 2008; Ramsoekh et al, 2009). Thus, although infrequent in classical HNPCC families, our results suggest MSH6 mutations may be better represented in families with ovarian cancer. "
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    ABSTRACT: Background: Mutations in genes for hereditary non-polyposis colorectal cancer (HNPCC) in ovarian cancer patients remains poorly defined. We sought to estimate the frequency and characteristics of HNPCC gene mutations in a population-based sample of women with epithelial ovarian cancer. Methods: The analysis included 1893 women with epithelial ovarian cancer ascertained from three population-based studies. Full-germline DNA sequencing of the coding regions was performed on three HNPCC genes, MLH1, MSH2 and MSH6. Collection of demographic, clinical and family history information was attempted in all women. Results: Nine clearly pathogenic mutations were identified, including five in MSH6, two each in MLH1 and MSH2. In addition, 28 unique predicted pathogenic missense variants were identified in 55 patients. Pathogenic mutation carriers had an earlier mean age at diagnosis of ovarian cancer, overrepresentation of cancers with non-serous histologies and a higher number of relatives with HNPCC-related cancers. Conclusions: Our findings suggest that fewer than 1% of women with ovarian cancer harbour a germline mutation in the HNPCC genes, with overrepresentation of MSH6 mutations. This represents a lower-range estimate due to the large number of predicted pathogenic variants in which pathogenicity could not definitively be determined. Identification of mismatch repair gene mutations has the potential to impact screening and treatment decisions in these women.
    British Journal of Cancer 10/2012; 107(10). DOI:10.1038/bjc.2012.452 · 4.82 Impact Factor
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    • "Suspected LS families are usually identified using the Amsterdam or Bethesda criteria that are biased towards high disease penetrance. Indeed, these criteria were recently shown to lack sensitivity to identify MSH6 mutation carriers [Sjursen et al., 2010]. "
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    ABSTRACT: Lynch syndrome (LS) is an autosomal dominant disorder that predisposes to colon, endometrial, and other cancers. LS is caused by a heterozygous germline mutation in one of the DNA mismatch repair (MMR) genes. A significant proportion of all mutations found in suspected LS patients comprises single amino acid alterations. The pathogenicity of these variants of uncertain significance (VUS) is difficult to assess, precluding diagnosis of carriers and their relatives. Here we present a rapid cell-free assay to investigate MMR activity of MSH2 or MSH6 VUS. We used this assay to analyze a series of MSH2 and MSH6 VUS, selected from the Leiden Open Variation Database. Whereas a significant fraction of the MSH2 VUS has lost MMR activity, suggesting pathogenicity, the large majority of the MSH6 VUS appears MMR proficient. We anticipate that this assay will be an important tool in the development of a comprehensive and widely applicable diagnostic procedure for LS-associated VUS.
    Human Mutation 03/2012; 33(3):488-94. DOI:10.1002/humu.22000 · 5.05 Impact Factor
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    ABSTRACT: Approximately 100,000 cases of cancer in the U.S. each year are due to inherited genetic conditions. Scores of hereditary cancer syndromes have been described, associated with nearly every cancer type, and prevention measures have proven to decrease cancer risk. With the advent of new technology, increasingly complex genetic testing options exist. Specially trained genetic counselors coordinate the identification, testing, education and care of patients with hereditary cancer risks. Thus, genetic counselors are at the forefront of the integration of new technology into medical care for hereditary cancer patients. New methods test many more genes, faster and more affordably but with the potential challenges of uninformative or undesired information. Additionally, algorithms using these tests will revolutionize the screening of large numbers of people for hereditary cancer syndromes. Genetic counselors are prepared to offer a broad range of testing schemas as well as provide education regarding the impact of the results for providers, patients and families.
    06/2013; 1(2). DOI:10.1007/s40142-013-0015-5
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