Do MSH6 mutations contribute to double primary cancers of the colorectum and endometrium?

Mismatch repair (MMR) gene mutations cause hereditary nonpolyposis colorect al cancer (HNPCC), a common form of familial colorectal cancer. Among MMR g enes, germline MSH6 mutations are often observed in HNPCC-like families wit h an increased frequency of endometrial cancer. We have previously shown th at a proportion of women affected with double primary cancers of the colore ctum and endometrium carry germline MSH2 or MLH1 mutations and, thus, belon g to HNPCC families. In this study, we have investigated the specific contr ibution of MSH6 defects to such double primary patients. By sequence analys is of the entire coding region of MSH6, three putative missense mutations w ere identified in patients with atypical family histories that do not meet HNPCC criteria. Moreover, one of these mutations, a novel substitution Arg9 01His, was found in a patient previously shown to carry a truncating germli ne MLH1 mutation. Thus, MSH6 mutations are likely to contribute to the etio logy of double primary cancers of the colorectum and endometrium.