Identification of novel CRC pathway genes in familial CRC

Abstract

Background: The Wnt, DNA repair and bone morphogenetic protein (BMP) pathways are implicated in development of familial colorectal cancer (CRC) through inherited mutations in genes such as APC, MLH1, MSH2, MSH6, PMS2, POLE, POLD1, MUTYH, SMAD4 and BMPR1A.We hypothesised that mutations in other genes within these pathways may predispose to unexplained familial colorectal cancer, and sought rare potentially deleterious variants in genes within these pathways in a cohort of familial and/or young-onset CRC cases. Methods:We performed whole exome sequencing on constitutional DNA from 51 individuals with unexplained familial or young-onset ( <0.1%) loss-of-function (LoF) variants ie. stop-gained, frameshift and essential splice site variants in genes within the Wnt, DNA repair and BMP pathways from Gene Ontology. Identified variants were validated by Sanger sequencing. Results:We identified a rare LoF variant in each of the following genes: WNT10 and LRRFIP2 from the Wnt pathway, APLF, DMC1, ERCC3, MUS81, USP28 and XRCC6BP1 from the DNA repair pathway, and GDF2 from the BMP pathway. Each LoF variant was seen once in our cohort. The LoF variants in WNT10 and USP28 were seen in the same individual, whereas the other variants occurred in distinct individuals. Conclusions: Whole exome sequencing identified rare LoF variants in genes within CRC pathways in familial and/or young onset CRC cases. Validation in a larger cohort of familial and/or young onset CRC cases is required to determine the association of these genes with CRC development. Targeted sequencing of these genes in a cohort of 300-400 cases of familial and/or young onset CRC is underway.