Familial endometrial cancer in female carriers of MSH6 germline mutations (2024)

Hereditary non-polyposis colorectal cancer (HNPCC) is a common autosomal dominant condition characterized by early onset colorectal cancer as well as other tumour types at different anatomical sites¹. HNPCC tumours often display a high level of genomic instability, characterized by changes in repeat numbers of simple repetitive sequences (microsatellite instability, MSI), which reflects the malfunction of the DNA mismatch repair machinery^2,3. Accordingly, HNPCC was shown to be caused by germline mutations in the DNA mismatch repair genes (MMR) MSH2, MLH1, PMS1, PMS2 and MSH6 (refs 3, 4, 5, 6). So far, more than 220 predisposing mutations have been identified, most in MSH2 and MLH1 and in families complying with the clinical Amsterdam criteria^3,7,8 (AMS+). Many HNPCC families, however, do not fully comply with these criteria, and in most cases the causative mutations are unknown.

Previously, we determined the prevalence of pathogenic mutations at MSH2 and MLH1 among 287 kindreds, of which 133 were AMS+ and 154 showed familial clustering of cancers reminiscent of HNPCC. Approximately one-half of AMS+ families revealed a predisposing mutation, whereas only 7% of AMS– families had a mutation in either gene^8,9,10. Here we analyse MSH6 by denaturing gradient gel electrophoresis (DGGE) in the remaining 214 kindreds, 71 AMS+ and 143 AMS–, in which no MSH2 or MLH1 mutations were found. We identified 9 different MSH6 pathogenic germline mutations in 10 kindreds (Table 1). These mutations were scattered along the coding sequence of MSH6 and predict the truncation of its protein product. We found 7 of 10 MSH6 mutations in atypical HNPCC families not fulfilling the Amsterdam criteria (7/154, 4.5%). These kindreds display a very high frequency of atypical hyperplastic lesions and carcinomas of the endometrium: 73% in female MSH6 mutation carriers compared with 29% in MSH2 and 31% in MLH1. Moreover, delayed age of cancer onset and incomplete penetrance were characteristic clinical features of the MSH6 mutation carriers (see Table 3 and Fig. 1, http://genetics.nature.com/supplementary_info/).

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