Mismatch repair gene defects contribute to the genetic basis of double primary cancers of the colorectum and endometrium

Hereditary non-polyposis colorectal cancer (HNPCC) is a dominantly inherite d cancer syndrome caused by germline defects of mismatch repair (MMR) genes . Endometrial cancer is the most common extracolonic neoplasm in HNPCC and is the primary clinical manifestation of the syndrome in some families, The cumulative incidence of endometrial cancer among HNPCC mutation carriers i s high, estimated to be from 22 to 43%, We hypothesized that women with dou ble primary cancers of the colorectum and endometrium are likely to be memb ers of HNPCC families. In order to determine how frequently HNPCC manifests in the context of double primary cancers, we examined alterations of two M MR genes, hMSH2 and hMLH1, in 40 unrelated women affected with double prima ry cancers, These cases were identified using hospital-based and population -based cancer registries in Ontario, Canada. MMR gene mutations were screen ed by single-strand conformation polymorphism analysis and confirmed by dir ect sequencing. Eighteen percent (seven of 40) were found to harbor mutatio ns of one of the two MMR genes. Analysis of colorectal and/or endometrial t umors of mutation-negative probands found microsatellite instability in sev en of 20 cases. Six of seven mutation-positive probands had strong family h istories suggestive of HNPCC, First degree relatives of mutation-positive p robands had a very high relative risk (RR) of colorectal cancer (RR = 8.1, CI 3.5-15.9) and endometrial cancer (RR = 23.8, CI 6.4-61.0), The relative risk of mutation-negative cases was 2.8 (CI 1.7-4.5) for colorectal cancer and 5.4 (CI 2.0-11.7) for endometrial cancer. We recommend that all double primary patients with cancers at these sites should have a genetic evaluati on, including molecular analysis for HNPCC where appropriate.