Inherited (germline) mutations in several genes involved in DNA mismatch repair are the major cause of hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome. The syndrome predominantly shows autosomal dominant inheritance (only one copy of a mutation is necessary for expression of disease) and incomplete penetrance (not all mutation carriers will get the disease). However, there have been reports of early onset cases with biallelic mutations in MSH6 and PMS2.
HNPCC comprises about 5-10% of all colon cancer and confers up to an 80% lifetime risk of developing colon cancer, a 35% risk for endometrial cancer, a 9% risk for ovarian cancer, and a small risk (<10%) for several other extracolonic cancers as well1. At least five human genes (MLH1 1, 2, MSH2 3, 4 , MSH6 5, 8-13, PMS16, PMS26 ) have been implicated in HNPCC.
Alterations of the MLH1 and MSH2 genes account for a majority of mutations in HNPCC. Alterations of the MSH6 are estimated to account for approximately 7-10% of mutations in HNPCC 5, 12, 14. It has been sugggested that germline MSH6 mutations predispose a special subset of HNPCC individuals to primarily late-onset, familial colorectal or endometrial carcinomas that often do not fulfill classic criteria for HNPCC 9, 12, 13. MSH6 mutations have also been detected in patients with tumors that show no or low microsatellite instability.10, 11 The prevalence of PMS2 mutations is not as well established, though one paper reported a 4% detection rate in 97 Lynch syndrome cases that were negative for mutations in MLH1, MSH2, and MSH6 19. The detection rate jumps to approximately 60% if the patient is found to have abnormal staining for PMS2 by immunohistochemistry20. Interestingly, a number of biallelic PMS2 cases have been reported. One recent report described an individual with childhood onset malignancy and café-au-lait spots who was found to be biallelic for PMS2 mutations20. Other studies have reported similar phenotypes in biallelic cases with MSH6 or PMS2 mutations 21,22. Common features include CNS tumors, leukemia, and café-au-lait spots.
Large deletions or genetic rearrangements account for 5-10% of mutations in MLH1 and 17-50% of mutations in MSH2 gene 24. Large deletions of the MSH6 gene are estimated to account for approximately 2-3% of mutations in this gene 18. Large deletions in the PMS2 gene account for about 21-37 % of the mutations in PMS2 in patients with tumors that have PMS2 absent on IHC 20,25.
Alterations to these genes are predominantly single base pair changes, or small insertions/deletions and can be detected by sequencing based analysis. However, larger single and multi-exon deletions have also been reported and require some sort of quantitative analysis.
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