Germline variation in RASAL2 may predict survival in patients with RAS-activated colorectal cancer.
Date
2023-06-01ICR Author
Author
Wills, C
Watts, K
Maughan, TS
Fisher, D
Al-Tassan, NA
Houlston, RS
Escott-Price, V
Cheadle, JP
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
MAPK-activation
RAS
RASAL2
colorectal cancer
survival
Humans
Genome-Wide Association Study
Proto-Oncogene Proteins B-raf
Mutation
Mitogen-Activated Protein Kinases
Colorectal Neoplasms
Germ Cells
Proto-Oncogene Proteins p21(ras)
GTPase-Activating Proteins
Research team
Cancer Genomics
Language
eng
Date accepted
2023-02-13
License start date
2023-06-01
Citation
Genes Chromosomes and Cancer, 2023, 62 (6), pp. 332 - 341
Publisher
WILEY