First evidence for digenic inheritance in hereditary colorectal cancer by mutations in the base excision repair genes

Biallelic mutations in the base excision repair gene Mut Y homologue (MUTYH) are responsible for variable recessively inherited phenotypes of polyposis. Beside MUTYH, the proteins 8-oxo-guanine DNA glycosylase (OGG1) and MTH1 (or NUDT1) are also involved in the repair of 7,8-dihydro-8-oxoguanine (8-oxo-G), previous studies, however, only found missense mutations of unclear pathogenicity in either MTH1 or OGG1. To investigate the role of a defective 8-oxo-G repair we performed a germline mutation screening in the genes OGG1, MTH1 and MUTYH, in 81 patients with a clinical phenotype ranging from attenuated or atypical adenomatous polyposis coli including hyperplastic polyps to hereditary non-polyposis colorectal cancer (HNPCC) type X syndrome without mono- or biallelic mutations in either APC, MUTYH or the DNA mismatch repair genes. We describe here the first pathogenic germline mutation in OGG1, a splice site mutation affecting exon 1, which was inherited from the father, in combination with a maternal MUTYH missense mutation p.Ile223Val in a female patient with advanced synchronous colon cancer and adenomas at the age of 36 years pointing towards digenic inheritance for colorectal cancer (CRC) predisposition. Monoallelic missense mutations in MTH1 (3x), OGG1 (2x), or MUTYH (3x) were identified in 10 patients (12%), three of them were novel. Our findings indicate that mutations in other genes of the 8-oxo-G repair beside MUTYH are involved in CRC predisposition. Oligogenic inheritance affecting genes of a certain repair pathway might therefore be the missing link between monogenic and polygenic traits.