APC Mutations Are Not Confined to Hotspot Regions in Early-Onset Colorectal Cancer

SIMPLE SUMMARY: Mutation of the APC gene is a common early event in colorectal cancer, however lower rates have been reported in younger cohorts of colorectal cancer patients. In sporadic cancer, mutations are typically clustered around a mutation cluster region, a narrowly defined hotspot within the APC gene. In this study we used a sequencing strategy aimed at identifying mutations more widely throughout the APC gene in patients aged 50 years or under. We found high rates of APC mutation in our young cohort that were similar to rates seen in older patients but the mutations we found were spread throughout the gene in a pattern more similar to that seen in inherited rather than sporadic mutations. Our study has implications both for the sequencing of the APC gene in early-onset colorectal cancer and for the etiology of this disease. ABSTRACT: While overall colorectal cancer (CRC) cases have been declining worldwide there has been an increase in the incidence of the disease among patients under 50 years of age. Mutation of the APC gene is a common early event in CRC but is reported at lower rates in early-onset colorectal cancer (EOCRC) than in older patients. Here we investigate the APC mutation status of a cohort of EOCRC patients in New Zealand using a novel sequencing approach targeting regions of the gene encompassing the vast majority of known APC mutations. Using this strategy we find a higher rate (72%) of APC mutation than previously reported in EOCRC with mutations being spread throughout the gene rather than clustered in hotspots as seen with sporadic mutations in older patients. The rate of mutations falling within hotspots was similar to those previously seen in EOCRC and as such our study has implications for sequencing strategies for EOCRC patients. Overall there were low rates of both loss of heterozygosity and microsatellite instability whereas a relatively high rate (40%) of APC promoter methylation was found, possibly reflecting increasing exposure of young people to pro-oncogenic lifestyle factors.