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

Summers, M; Smith, CG; Maughan, TS; Kaplan, R; Escott-Price, V; Cheadle, JP; (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. Green open access

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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.

Type: Article
Title: BRAF and NRAS locus specific variants have different outcomes on survival to colorectal cancer
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1158/1078-0432.CCR-16-1541
Publisher version: http://doi.org/10.1158/1078-0432.CCR-16-1541
Language: English
Additional information: Copyright © 2016, American Association for Cancer Research.
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/1528739
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