dc.contributor.author | Wills, C | |
dc.contributor.author | Watts, K | |
dc.contributor.author | Maughan, TS | |
dc.contributor.author | Fisher, D | |
dc.contributor.author | Al-Tassan, NA | |
dc.contributor.author | Houlston, RS | |
dc.contributor.author | Escott-Price, V | |
dc.contributor.author | Cheadle, JP | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2023-06-02T10:26:35Z | |
dc.date.available | 2023-06-02T10:26:35Z | |
dc.date.issued | 2023-06-01 | |
dc.identifier.citation | Genes Chromosomes and Cancer, 2023, 62 (6), pp. 332 - 341 | en_US |
dc.identifier.issn | 1045-2257 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5823 | |
dc.identifier.eissn | 1098-2264 | |
dc.identifier.eissn | 1098-2264 | |
dc.identifier.doi | 10.1002/gcc.23133 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 332 - 341 | |
dc.language | eng | |
dc.language.iso | eng | en_US |
dc.publisher | WILEY | en_US |
dc.relation.ispartof | Genes Chromosomes and Cancer | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | MAPK-activation | |
dc.subject | RAS | |
dc.subject | RASAL2 | |
dc.subject | colorectal cancer | |
dc.subject | survival | |
dc.subject | Humans | |
dc.subject | Genome-Wide Association Study | |
dc.subject | Proto-Oncogene Proteins B-raf | |
dc.subject | Mutation | |
dc.subject | Mitogen-Activated Protein Kinases | |
dc.subject | Colorectal Neoplasms | |
dc.subject | Germ Cells | |
dc.subject | Proto-Oncogene Proteins p21(ras) | |
dc.subject | GTPase-Activating Proteins | |
dc.title | Germline variation in RASAL2 may predict survival in patients with RAS-activated colorectal cancer. | en_US |
dc.type | Journal Article | |
dcterms.dateAccepted | 2023-02-13 | |
dc.date.updated | 2023-06-02T10:25:52Z | |
rioxxterms.version | VoR | en_US |
rioxxterms.versionofrecord | 10.1002/gcc.23133 | en_US |
rioxxterms.licenseref.startdate | 2023-06-01 | |
rioxxterms.type | Journal Article/Review | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/36790221 | |
pubs.issue | 6 | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Cancer Genomics | |
pubs.publication-status | Published | |
pubs.publisher-url | http://dx.doi.org/10.1002/gcc.23133 | |
pubs.volume | 62 | |
icr.researchteam | Cancer Genomics | en_US |
dc.contributor.icrauthor | Houlston, Richard | |
icr.provenance | Deposited by Mr Arek Surman on 2023-06-02. Deposit type is initial. No. of files: 1. Files: Genes Chromosomes Cancer - 2023 - Wills - Germline variation in RASAL2 may predict survival in patients with.pdf | |