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

Wills, Christopher, Watts, Katie, Maughan, Timothy S., Fisher, David, Al-Tassan, Nada A., Houlston, Richard S., Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483 and Cheadle, Jeremy ORCID: https://orcid.org/0000-0001-9453-8458 2023. Germline variation in RASAL2 may predict survival in patients with RAS-activated colorectal cancer. Genes Chromosomes and Cancer 62 (6) , pp. 332-341. 10.1002/gcc.23133

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	Wiley & Sons
ISSN:	1098-2264
Funders:	Cancer Research UK, MRC
Date of First Compliant Deposit:	14 February 2023
Date of Acceptance:	13 February 2023
Last Modified:	20 Jun 2023 17:16
URI:	https://orca.cardiff.ac.uk/id/eprint/156996

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