Germline variation in RASAL2 may predict survival in patients with RAS-activated colorectal cancer.

Abstract

Therapeutic agents that specifically target patients with RAS mutant colorectal cancer (CRC) are needed. We sought potential drug targets by relating genome-wide association study and survival data in patients with advanced CRC profiled for mitogen-activated protein kinase (MAPK) pathway mutations. In total, 694 patients from the clinical trials COIN and COIN-B had MAPK-activated CRCs (assigned as KRAS, NRAS, or BRAF mutant). Genome-wide single nucleotide polymorphism (SNP), gene, and gene-set analyses were performed to identify determinants of survival. For rs12028023 in RAS protein activator-like 2 (RASAL2), we studied its effect by MAPK pathway activation status (by comparing to 760 patients without MAPK-activated CRCs), MAPK gene mutation status, surface area of the primary tumor (as a marker of proliferation), and expression on RASAL2. In MAGMA genome-wide analyses, RASAL2 was the most significant gene associated with survival (p=2.0× 10-5 ). Patients carrying the minor (A) allele in the lead SNP, rs12028023 in intron 1 of RASAL2, had a median increase in survival of 167 days as compared with patients carrying the major allele. rs12028023 was predictive for survival by MAPK-activation status (pZ-test = 2.1× 10-3 ). Furthermore, rs12028023 improved survival in patients with RAS mutant (hazard ratio [HR]=0.62, 95% confidence intervals [CI]=0.5-0.8, p= 3.4× 10-5 ) but not BRAF mutant (p= 0.87) CRCs. The rs12028023 A-allele was associated with reduced surface area of the primary tumor (Beta=-0.037, standard error [SE]=0.017, p= 3.2× 10-2 ) and reduced RASAL2 expression in cultured fibroblasts (p= 1.6× 10-11 ). Our data demonstrate a prognostic role for RASAL2 in patients with MAPK-activated CRCs, with potential as a therapeutic target.