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.

Morak M ，Massdorf T ，Sykora H ，Kerscher M ，Holinski-Feder E ... -  《-》

MUTYH-associated polyposis - variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations.

To further characterize 215 APC mutation-negative patients with colorectal neoplasias classified in classical, attenuated, or atypical familial adenomatous polyposis (FAP) coli we performed mutation screening in the Mut Y homologue (MUTYH) gene. The incidence was 15% for biallelic and 3.7% for monoallelic MUTYH mutations. We describe six novel MUTYH mutations in biallelic constellation and two novel monoallelic missense mutations. Of 33 MUTYH-associated polyposis coli (MAP) patients 57% were attenuated familial adenomatous polyposis (AFAP) patients, 10% display early-onset classical FAP and 18% had only few adenomas at higher age. Biallelic cases had a high incidence of extracolonic polyposis in 32% and colorectal cancer (CRC) in 33% of the cases. The clinical picture of MAP ranged from classical FAP or synchronous CRC at age 30 years to few adenomas at age 54 years without evidence of CRC, initially suspected for hereditary non-polyposis colorectal cancer (HNPCC). The mean age of onset was 43 years, with 11 (33%) patients being younger than 40 years of age, indicating that the clinical manifestation can be earlier than so far reported. Monoallelic MUTYH mutation carriers had a positive family history in seven of eight cases allowing the hypothesis of a disease-causing synergism of MUTYH mutations with other genes.

Morak M ，Laner A ，Bacher U ，Keiling C ，Holinski-Feder E ... -  《-》

Low frequency of AXIN2 mutations and high frequency of MUTYH mutations in patients with multiple polyposis.

Lejeune S ，Guillemot F ，Triboulet JP ，Cattan S ，Mouton C ，PAFNORD Group ，Porchet N ，Manouvrier S ，Buisine MP ... -  《-》

No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients.

Steinke V ，Rahner N ，Morak M ，Keller G ，Schackert HK ，Görgens H ，Schmiegel W ，Royer-Pokora B ，Dietmaier W ，Kloor M ，Engel C ，Propping P ，Aretz S ，German HNPCC Consortium ... -  《EUROPEAN JOURNAL OF HUMAN GENETICS》

Germline mutations in APC and MUTYH are responsible for the majority of families with attenuated familial adenomatous polyposis.

Nielsen M ，Hes FJ ，Nagengast FM ，Weiss MM ，Mathus-Vliegen EM ，Morreau H ，Breuning MH ，Wijnen JT ，Tops CM ，Vasen HF ... -  《CLINICAL GENETICS》