BRAFandNRASLocus-Specific Variants Have Different Outcomes on Survival to Colorectal Cancer.
Purpose:Somatic mutation status atKRAS, BRAF, andNRASis associated with prognosis in patients with advanced colorectal cancer (aCRC); however, it remains unclear whether there are intralocus, variant-specific differences in survival and other clinicopathologic parameters.Experimental Design:We profiled 2,157 aCRCs for somatic mutations inKRAS, BRAF, andNRASand determined microsatellite instability status. We sought inter- and intralocus correlations between mutations and variant-specific associations with survival and clinicopathology.Results:KRASmutations were rarely found together and those in codons 12 and 13 conferred poor prognosis [hazard ratio (HR), 1.44; 95% confidence interval (CI), 1.28-1.61;P= 6.4 × 10-10and HR, 1.53; 95% CI, 1.26-1.86;P= 1.5 × 10-05, respectively]. ForBRAF,more c.1781A>G (p.D594G) CRCs carriedRASmutations [14% (3/21)] compared with c.1799T>A (p.V600E) CRCs [1% (2/178),P= 9.0 × 10-03]. c.1799T>A (p.V600E) was associated with poor prognosis (HR, 2.60; 95% CI, 2.06-3.28;P= 1.0 × 10-15), whereas c.1781A>G (p.D594G) was not (HR, 1.30; 95% CI, 0.73-2.31;P= 0.37); this intralocus difference was significant (P= 0.04). More c.1799T>A (p.V600E) colorectal cancers were found in the right colon [47% (47/100)], compared with c.1781A>G (p.D594G) colorectal cancers [7% (1/15),P= 3.7 × 10-03]. ForNRAS, 5% (3/60) of codon 61 mutant colorectal cancers hadKRASmutations compared with 44% (10/23) of codons 12 and 13 mutant colorectal cancers (P= 7.9 × 10-05). 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 intralocus variation in the outcomes of mutations inBRAFandNRASThese data need to be considered in patient management and personalized cancer therapy.Clin Cancer Res; 23(11); 2742-9. ©2016 AACR.
Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Matthew G
MG
Summers
Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Christopher G
CG
Smith
CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom.
Timothy S
TS
Maughan
MRC Clinical Trials Unit, London, United Kingdom.
Richard
R
Kaplan
Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Valentina
V
Escott-Price
Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom. cheadlejp@cardiff.ac.uk.
Jeremy P
JP
Cheadle
D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D057285:Precision Medicine; D011379:Prognosis; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
C117307:KRAS protein, human; D008565:Membrane Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)