BRAF Mutations in Colorectal Cancer Are Associated With... : Diseases of the Colon & Rectum (original) (raw)

Original Contributions

BRAF Mutations in Colorectal Cancer Are Associated With Distinct Clinical Characteristics and Worse Prognosis

Kalady, Matthew F. M.D.1,2; DeJulius, Kathryn L. B.A., M.S.1,2; Sanchez, Julian A. M.D.1; Jarrar, Awad M.D.; Liu, Xiuli M.D., Ph.D.3; Manilich, Elena Ph.D.1; Skacel, Marek M.D.4; Church, James M. M.B., Ch.B.1

1Department of Colorectal Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio

2Cancer Biology Department, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio

3Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio

4Dahl-Chase Pathology Associates, Bangor, Maine

Financial Disclosures: None reported.

Podium presentation at the meeting of The American Society of Colon & Rectal Surgeons, Vancouver, BC, Canada, May 14 to 18, 2011.

Correspondence: Matthew F. Kalady, M.D., 9500 Euclid Ave, A30, Cleveland, OH 44195. E-mail: [email protected]

Abstract

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.

DESIGN:

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.

MAIN OUTCOME MEASURES:

Statistical associations with _BRA_F mutant tumors were determined by the Fisher exact probability test, χ2 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.