BRAF and NRAS locus-specific variants have different outcomes on survival to colorectal cancer

Summers, Matthew ORCID: https://orcid.org/0000-0001-6387-124X, Smith, Chris, Maughan, Timothy, Kaplan, Rick, Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483 and Cheadle, Jeremy Peter ORCID: https://orcid.org/0000-0001-9453-8458 2017. BRAF and NRAS locus-specific variants have different outcomes on survival to colorectal cancer. Clinical Cancer Research 23 (11) , pp. 2742-2749. 10.1158/1078-0432.CCR-16-1541

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Abstract

Purpose: Somatic mutation status at KRAS, BRAF and NRAS is associated with prognosis in patients with advanced colorectal cancer (aCRC); however, it remains unclear whether there are intra-locus, variant-specific differences in survival and other clinicopathological parameters. Experimental design: We profiled 2,157 aCRCs for somatic mutations in KRAS, BRAF and NRAS and determined microsatellite instability status. We sought inter- and intra-locus correlations between mutations, and variant-specific associations with survival and clinicopathology. Results: KRAS mutations were rarely found together and those in codons 12 and 13 conferred poor prognosis (HR 1.44, 95% CI 1.28-1.61, p=6.4e-10 and HR 1.53, 95% CI 1.26-1.86, p=1.5e-05, respectively). For BRAF, more c.1781A>G (p.D594G) CRCs carried RAS mutations (14% [3/21]) compared to c.1799T>A (p.V600E) CRCs (1% [2/178], p=9.0e-03). c.1799T>A (p.V600E) was associated with poor prognosis (HR 2.60, 95% CI 2.06-3.28, p=1.0e-15), whereas c.1781A>G (p.D594G) was not (HR 1.30, 95% CI 0.73-2.31, p=0.37); this intra-locus difference was significant (p=0.04). More c.1799T>A (p.V600E) CRCs were found in the right colon (47% [47/100]), compared to c.1781A>G (p.D594G) CRCs (7% [1/15], p=3.7e-03). For NRAS, 5% (3/60) of codon 61 mutant CRCs had KRAS mutations compared to 44% (10/23) of codons 12 and 13 mutant CRCs (p=7.9e-05). Codon 61 mutations conferred poor prognosis (HR 1.47, 95% CI 1.09-1.99, p=0.01), whereas codons 12 and 13 mutations did not (HR 1.29, 95% CI 0.64-2.58, p=0.48). Conclusions: Our data show considerable intra-locus variation in the outcomes of mutations in BRAF and NRAS. These data need to be considered in patient management and personalised cancer therapy.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher:	American Association for Cancer Research
ISSN:	1078-0432
Funders:	Wales Gene Park, Cancer Research Wales, National Institute for Social Care and Health Research Cancer Genetics Biomedical Research Unit
Date of First Compliant Deposit:	3 November 2016
Date of Acceptance:	1 November 2016
Last Modified:	11 Nov 2024 23:30
URI:	https://orca.cardiff.ac.uk/id/eprint/95828

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