The largest Chinese cohort study indicates homologous recombination pathway gene mutations as another major genetic risk factor for colorectal cancer with heterogeneous clinical phenotypes

Abstract

Abstract Background: Colorectal cancer (CRC) is one of the most common malignancies globally with estimated 1.87 million new cases annually. Genetic factors were associated with over 30% of CRC incidence. However, the mutations in CRC-susceptibility genes recommended by the National Comprehensive Cancer Network (NCCN) guidelines accounted for only 5-10% of CRC cases, suggesting a large proportion of CRC-susceptibility genes remain unknown. As previous works on hereditary CRC were largely designed to analyze germline mutations in patients with a single category of genetic high-risk factor, this study aims to explore the genetic mutations underlying five categories of genetic high-risk factors in clinic. Methods: From January 2015 to December 2018, 2181 patients from a cohort of 8270 consecutive CRC cases were retrospectively enrolled, covering five categories of genetic high-risk factors. Their germline mutations under each category were detected and analyzed in association with CRC susceptibility, clinical phenotypes, and prognoses. Results:In total 462 pathogenic/likely pathogenic genetic variants were detected in 19.3% CRC patients enrolled. Mutations in the mismatch repair (MMR) genes were identified in 9.1% patients, most prevalent across all high-risk groups. Mutations in homologous recombination (HR) pathway genes were detected in 6.5% patients, which were mostly penetrated in early onset, family cancer history and extra-colonic cancer risk groups. HR pathway gene mutations, including BARD1, RAD50 and ATM, were associated with an increased risk of CRC in the cohort with an odds ratio of 2.8, 3.1 and 3.1-fold, respectively. CRC patients carrying different genetic mutations manifested heterogeneous phenotypes in clinicopathology and long-term prognoses, for which Lynch Syndrome demonstrated better prognoses than other groups, including those with HR pathway mutations. Conclusions: This largest Chinese cohort study of high-risk hereditary CRC is the first to cover five categories of genetic high-risk factors, which greatly expanded the list of CRC-susceptibility mutations. In contrast to the MMR mutations of Lynch syndrome, the study reveals for the first time at population level that carriers of mutations in the HR pathway genes are significantly susceptible to CRC, implicating HR pathway gene mutations as another major contributor for increased risk of developing CRC. Trial registration: Retrospectively registered.