Germline mutations in the base excision repair gene, MutY human homolog (MYH), have recently been associated with a recessively inherited multiple adenoma polyposis syndrome and colorectal cancer. The spectrum of extracolonic lesions is still being characterized, although preliminary reports suggest that bi-allelic mutation carriers may share some of the clinical features of other hereditary colon cancer syndromes. Of 225 endometrial cancer patients, we identified one individual as a compound heterozygote, carrying mutations Y165C and G382D of MYH, and five individuals with heterozygous defects (three G382D and two Y165C). The patient with the bi-allelic Y165C/G382D mutation also had a sebaceous carcinoma, a feature of Muir-Torre syndrome. Although several intronic polymorphisms were detected in the heterozygous carriers, no other pathogenic variants were identified. While not conclusive, this novel and interesting finding provides evidence that bi-allelic germline mutations in MYH may increase susceptibility to endometrial cancer.

Summary We have investigated the occurrence of attenuated extracolonic manifestations (AEMs) of familial adenomatous polyposis (FAP) in patients with non-polyposis colorectal cancer. In a prospective case-control study, we observed that significantly more colorectal cancer patients exhibited AEM 1985a, b; Houlston et al., 1992; Dunlop, 1983; Hunt et al., 1994). These features, congenital hypertrophy of the retinal pigment epithelium (CHRPE) and mandibular osteomas, occur in 90% and 75% respectively of patients with classical FAP (Utsunomiya and Nakamura, 1975;Bulow et al., 1984; Traboulsi et al., 1987;Berk et al., 1988;Chapman et al., 1989;Giardiello et al., 1991; Hodgson et al., 1994;Wallis et al., 1994). The finding of such extracolonic features in patients with non-FAP colorectal cancer is of considerable interest because of the central, and probably initiating, role of the gene for FAP (APC) in colorectal tumorigenesis. Constitutional and heterozygous mutation of the APC gene is responsible for the FAP syndrome (Groden et al., 1991; Nishishio et al., 1991;Nagase and Nakamura, 1993), while a high proportion of non-FAP colorectal adenomas and cancers have somatic APC mutations (Powell et al., 1992; Ichii et al., 1993; Nagasse and Nakamura, 1993). Inactivating APC mutations have also been noted in dysplastic aberrant crypt foci Smith et al., 1984), which are believed to be the very earliest histological manifestation of colorectal neoplasia.The available data suggest that the extracolonic manifestations of FAP, which we term attenuated extracholonic manifestations (AEMs), occur particularly in colorectal cancer patients with a family history of the disease (Sondergaard et al., 1985b; Houlston et al., 1992; Hunt et al., 1994). Thus we wished to determine whether there was any link with hereditary non-polyposis colorectal cancer (HNPCC), which is responsible for 2-5% of all colorectal cancer cases. HNPCC gene carriers develop few colorectal adenomas but are at high risk of colorectal cancer, particularly of the right colon, as well as other cancers Jass et al., 1994). Causative germline mutations in the DNA mismatch repair (MMR) genes hMSH2, hMLHI, hPMSJ and hPMS2 (Liu et al., 1996) have been identified in HNPCC families. Such mutations result in defective MMR (Parsons et al., 1993;Umar et al., 1994), manifest as instability of repetitive DNA in tumours (Ionov et al., 1993;Aaltonen et al., 1993;Thibodeau et al., 1993;Lothe et al., 1993;Aaltonen et al., 1994;Bhattacharyya et al., 1994;Liu et al., 1995a) (Traboulsi et al., 1987; Chapman et al., 1988;Berk et al., 1988; Giardello et al., 1991; Hodgson et al., 1994;Wallis et al., 1994). Because of the variety of CHRPE lesions, we devised a scoring system derived from the relative importance ascribed to each feature in previous FAP studies. Pigmented haloed lesions and lesions > 1 disc diameter scored 5: small lesions scored 1 and the total score for bilateral lesions was doubted.Posteroanterior, occlusal and pantomographic radiographic views of the mand...