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.
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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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