Identification of MUTYH gene variants in a cohort of German patients with familial colorectal cancer (fCRC)

Introduction: Although up to 20% of colorectal cancer (CRC) patients show some kind of familiarity, genetic factors underlying polygenic fCRC have yet to be identified. Recently mutations of the base excision repair gene MUTYH have been reported as underlying genetic defect in autosomal-recessive colorectal adenomatous polyposis, with Y165C and G382D representing the most common mutations. Our aim now was to test a group of patients with strong evidence for CRC familiarity (but exclusion of the monogenic CRC syndromes FAP and HNPCC) for association with these two MUTYH mutations Y165C and G382D in comparison to (i) patients with sporadic CRCs and (ii) healthy controls.

Methods: We recruited 93 patients with fCRC, as defined by two of the following criteria: (1) three affected relatives, one of them a first-degree relative of the others; (2) one member diagnosed with CRC before age 50; or (3) two affected generations. All tumours showed regular expression of MLH1 and MSH2, and microsatellite instability was excluded. For comparison, we studied 93 CRC patients without inherited CRC syndromes and a negative family history as well as 93 ‘hyper-normal’ controls who displayed no adenomatous polyps on colonoscopy. Allelic discrimination was performed using a fluorescent dye marked reporter assay with predesigned probes (Taqman assays).

Results: The Y165C risk allele was observed in 3% of the fCRC patients, but was absent in patients with sporadic CRCs and controls. For the risk allele of the G382D variant, allele frequencies were 0.02 (fCRC), 0.01 (CRC), and 0.01 (controls). Overall, 6.0% of fCRC, 2.2% of CRC patients and 1.0% of controls harboured a mutation in the MUTYH gene. Of note, we detected one Y165C/Y165C and one ‘compound heterozygous’ patient in the fCRC group. Applying Armitage's trend test revealed a significantly increased odds ratio for the risk allele of the Y165C mutation in fCRC patients compared to sporadic CRCs and controls (OR 2.38; p=0.03).

Conclusions: In our cohort the prevalence of pathogenic MUTYH mutations was consistently increased among fCRC patients compared to sporadic CRCs and controls. As we found a significant association of the Y165C variant with fCRC, the presence of MUTYH variants might be a susceptibility factor for fCRC.