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.
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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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