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: 6.34). 09/2010; 47(9):579-85. DOI: 10.1136/jmg.2010.077677
Source: PubMed


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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Available from: Lars Fredrik Engebretsen
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    • "Thirty-six percent had mutations in MSH6 and 39% in MSH2. MSH6 mutation carriers are less likely to meet Amsterdam II criteria [33] and have a lower risk of colorectal cancer (10-22% cumulative risk by 70 years of age) and of other LS-related cancers [34,35]. As the Amsterdam II criteria have a reported sensitivity of 60-80% for colorectal cancer [36], but of only 20-30% in consecutive endometrial cancers [11,30], it is likely that our selection criteria have missed a number of LS families, especially those caused by MSH6 mutations. "
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    ABSTRACT: Uterine cancer (UC) represents 5.1% of all female malignancies in Sweden. Accumulation of UC in families occurs in around 5% of cases. We wanted to identify any familial association between UC and other selected cancers and to study the frequency of Lynch,Cowden and cancer syndromes among consecutive UC patients in Sweden. 481 UC patients were included. Information on the cancer diagnoses of their relatives (first- (FDRs) and second-degree (SDRs) relatives and first cousins) was obtained. The relative frequencies of different cancers among relatives were compared to those in the Swedish general cancer population in 1970 and 2010. Families that fulfilled the criteria for hereditary cancer syndromes were tested for mutations in the causative genes. Families with at least one case of UC in addition to the index patient were compared to families with no additional cases to investigate possible characteristics of putative hereditary cancer syndromes. There was an increased prevalence of UC in our study population compared to the Swedish general cancer population in 1970 and 2010 (6% vs. 4% and 3%, respectively). Seven families had Lynch Syndrome according to the Amsterdam II criteria. No families fulfilled the criteria for Cowden syndrome. In total 13% of index patients had at least one relative with UC and these families tended to have more cases of early onset cancer among family members. In addition, 16% of index patients were diagnosed with at least one other cancer. No families fulfilled the criteria for Cowden syndrome. We showed a familial clustering of UC among relatives of our index patients. Of the seven families with mutation-verified Lynch Syndrome, only one had been previously diagnosed, highlighting the need to increase gynecologists’ awareness of the importance of taking family history. Our data on multiple cancers and young age of onset in families with uterine cancer is compatible with the existence of additional hereditary uterine cancer syndromes.
    Full-text · Article · May 2014 · Hereditary Cancer in Clinical Practice
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    • "Previous reports have referred to the gene as giving an attenuated form of Lynch Syndrome, a lower risk of CRC and a later age of onset than what has been described for MLH1 and MSH2[1]. Several studies have also demonstrated that the majority of families do not fulfill the clinical criteria for LS [1,10,11,24,25]. We observed that penetrance at 70 years for CRC was 30% and 56% for MSI cancers. "
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    ABSTRACT: Using immunohistochemistry (IHC) to select cases for mismatch repair (MMR) genetic testing, we failed to identify a large kindred with the deleterious PMS2 mutation c.989-1G > T. The purpose of the study was to examine the sensitivity of IHC and microsatellite instability-analysis (MSI) to identify carriers of the mutation, and to estimate its penetrance and expressions. All carriers and obligate carriers of the mutation were identified. All cancer diagnoses were confirmed. IHC and MSI-analysis were performed on available tumours. Penetrances of cancers included in the Amsterdam and the Bethesda Criteria, for MSI-high tumours and MSI-high and low tumours were calculated by the Kaplan-Meier algorithm. Probability for co-segregation of the mutation and cancers by chance was 0.000004. Fifty-six carriers or obligate carriers were identified. There was normal staining for PMS2 in 15/18 (83.3%) of tumours included in the AMS1/AMS2/Bethesda criteria. MSI-analysis showed that 15/21 (71.4%) of tumours were MSI-high and 4/21 (19.0%) were MSI-low. Penetrance at 70 years was 30.6% for AMS1 cancers (colorectal cancers), 42.8% for AMS2 cancers, 47.2% for Bethesda cancers, 55.6% for MSI-high and MSI-low cancers and 52.2% for MSI-high cancers. The mutation met class 5 criteria for pathogenicity. IHC was insensitive in detecting tumours caused by the mutation. Penetrance of cancers that displayed MSI was 56% at 70 years. Besides colorectal cancers, the most frequent expressions were carcinoma of the endometrium and breast in females and stomach and prostate in males.
    Full-text · Article · Apr 2014 · Hereditary Cancer in Clinical Practice
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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.
    Full-text · Article · Oct 2012 · British Journal of Cancer
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