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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; (2023) Germline variation in RASAL2 may predict survival in patients with RAS-activated colorectal cancer. Genes, Chromosomes & Cancer , 62 (6) pp. 332-341. 10.1002/gcc.23133. Green open access

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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 kinase (MAPK) pathway mutations. METHODS: 694 patients from the clinical trials COIN and COIN-B had MAPK-activated CRCs (assigned as KRAS, NRAS or BRAF mutant). Genome-wide 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 tumour (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=2.0x10-5 ). 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 to those carrying the major allele. rs12028023 was predictive for survival by MAPK-activation status (PZ-test =2.1x10-3 ). Furthermore, rs12028023 improved survival in patients with RAS mutant (Hazard Ratio [HR]=0.62, 95% Confidence Intervals [CI]=0.5-0.8, P=3.4x10-5 ) but not BRAF mutant (P=0.87) CRCs. The rs12028023 A-allele was associated with reduced surface area of the primary tumour (Beta= -0.037, Standard Error [SE]= 0.017, P=3.2x10-2 ) and reduced RASAL2 expression in cultured fibroblasts (P=1.6x10-11 ). CONCLUSION: Our data demonstrates a prognostic role for RASAL2 in patients with MAPK-activated CRCs, with potential as a therapeutic target. This article is protected by copyright. All rights reserved.

Type: Article
Title: Germline variation in RASAL2 may predict survival in patients with RAS-activated colorectal cancer
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/gcc.23133
Publisher version: https://doi.org/10.1002/gcc.23133
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Colorectal cancer, MAPK-activation, RAS, RASAL2, survival
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10165487
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