Article

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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    • "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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