BRAF mutations in colorectal cancer are associated with distinct clinical characteristics and worse prognosis.
BACKGROUND
Colorectal cancer is a heterogeneous disease with multiple underlying genetic mutations causing different clinical phenotypes. Mutation in the BRAF oncogene is a key step in malignant transformation within the methylator pathway to colorectal cancer. However, there is a paucity of information about BRAF mutant colorectal tumors.


OBJECTIVE
This study defines the clinical characteristics and oncologic outcome associated with colorectal cancer BRAF mutations.


METHODS
Colorectal adenocarcinomas from a single-institution frozen-tumor biobank were studied. Genomic DNA was isolated and analyzed for mutations in the BRAF oncogene by polymerase chain reaction amplification followed by direct sequencing. A sample was classified as mutant if any of the tested loci were mutated. Patient and tumor characteristics were recorded including patient age, sex, tumor location, tumor differentiation, and microsatellite instability.


METHODS
Statistical associations with BRAF mutant tumors were determined by the Fisher exact probability test, χ test, or Wilcoxon analysis. Kaplan-Meier estimates and multivariate Cox regression analysis were performed for overall survival.


RESULTS
Four hundred seventy-five colorectal adenocarcinomas were included in the study population; 56 samples harbored a BRAF mutation (12%). There were significant differences between BRAF wild-type and mutant tumors in age (66 vs 75 years, p = 0.004), female sex (44% vs 71%, p < 0.001), proximal tumor location (44% vs 95%, p < 0.001), and frequency of microsatellite instability (16% vs 76%, p < 0.001). There was no difference in cancer stage between BRAF mutant and wild-type populations. Survival data were analyzed for 322 patients with stage I to III disease, and patients with a BRAF mutation had decreased overall survival than those without a mutation (p = 0.018). With the use of Cox regression analysis, BRAF mutation conferred a worse overall survival (HR 1.79, CI 1.05-3.05, p = 0.03) independent of microsatellite instability status.


CONCLUSIONS
BRAF mutations in colorectal cancers are associated with distinct clinical characteristics and worse prognosis.
Department of Colorectal Surgery, Digestive Disease Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. kaladym@ccf.org
Matthew F
MF
Kalady
Kathryn L
KL
Dejulius
Julian A
JA
Sanchez
Awad
A
Jarrar
Xiuli
X
Liu
Elena
E
Manilich
Marek
M
Skacel
James M
JM
Church
D000230:Adenocarcinoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012189:Retrospective Studies; D012737:Sex Factors; D055815:Young Adult
C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf