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

• Published in: Genes chromosomes & cancer Vol. 62; no. 6; pp. 332 - 341
• Main Authors: Wills, Christopher, Watts, Katie, Maughan, Timothy S., Fisher, David, Al‐Tassan, Nada A., Houlston, Richard S., Escott‐Price, Valentina, Cheadle, Jeremy P.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-06-2023; Wiley Subscription Services, Inc
• Subjects: Alleles; Clinical trials; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - pathology; Fibroblasts; Gene polymorphism; Genome-Wide Association Study; Genomes; Germ Cells - metabolism; GTPase-Activating Proteins - genetics; Humans; Kinases; MAP kinase; MAPK‐activation; Mitogen-Activated Protein Kinases - genetics; Mitogen-Activated Protein Kinases - metabolism; Mutants; Mutation; Point mutation; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins p21(ras) - genetics; RAS; Ras protein; RASAL2; Single-nucleotide polymorphism; Surface area; Survival; Therapeutic targets; Tumors; colorectal cancer; RASAL2; RAS; MAPK-activation; survival
• ISSN: 1045-2257; 1098-2264; 1098-2264
• DOI: 10.1002/gcc.23133

Background
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.
Methods
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.
Results
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).
Conclusion
Our data demonstrate a prognostic role for RASAL2 in patients with MAPK‐activated CRCs, with potential as a therapeutic target.