Genotype-phenotype correlations in MUTYH associated polyposis

M. Nielsen*, M.C. Joerink - van de Beld*, N. Jones, S. Vogt, J.J. Houwing - Duistermaat, C.M.J. Tops, H.F.A. Vasen, J.R. Sampson, S. Aretz, F.J. Hes

*both authors contributed equally

Department of Clinical Genetics, Leiden University Medical Center (MN, MCJB, CMJT, FJH); Institute of Medical Genetics, Cardiff University (NJ, JRS); Institute of Human Genetics, University of Bonn (SV, SA); Department of Medical and Bioinformatics, Leiden University Medical Center (JJHD); Department of Gastroenterology & Medical Oncology, Leiden University Medical Center (HFAV)

Background and aim: Bi-allelic mutations in the MUTYH gene lead to MUTYH associated polyposis (MAP) and thereby to colorectal cancer (CRC). Functional studies have already shown differences between various MUTYH mutations, including for the two most frequent mutations: Y179C and G396D (previously annotated as Y165C and G382D). Our aim was to unravel correlations between genotypes and their phenotypical expression.

Methods: In this multicenter study we analyzed different genotypes (non-truncating versus truncating and G396D versus Y179C) in 278 MAP patients. In these patients we studied the following clinical features: age at presentation of MAP, polyp count, age at presentation of CRC, age-related risk of developing CRC and location of CRC.

Results: The three possible bi-allelic combinations of truncating and non-truncating mutations showed no significant different phenotypes. In contrast, both G396D homozygotes and G396D/Y179C compound heterozygotes had a significantly lower age-related risk of developing CRC (P<0,001) than Y165C homozygotes. The median age of developing CRC was more than 10 years later in these carriers (60 and 59 years) than in Y179C homozygotes (48 years).

Conclusions: Our study shows that G396D homozygotes and G396D/Y179C compound heterozygotes have a relatively mild phenotype. Our observations imply that screening in these genotypes may start at a later age, e.g. at 25-30 years instead of 18-20 years, which is currently advised for MAP patients. However, further delineation of MAP genotype-phenotype correlations in larger series are required before such recommendations can be administered in clinical practice.