title: Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication.
abstract: BRAF mutation in colorectal cancer is associated with microsatellite instability (MSI) through its relationship with high-level CpG island methylator phenotype (CIMP) and MLH1 promoter methylation. MSI and BRAF mutation analyses are routinely used for familial cancer risk assessment. To clarify clinical outcome associations of combined MSI/BRAF subgroups, we investigated survival in 1253 rectal and colon cancer patients within the Nurses' Health Study and Health Professionals Follow-up Study with available data on clinical and other molecular features, including CIMP, LINE-1 hypomethylation, and KRAS and PIK3CA mutations. Compared with the majority subtype of microsatellite stable (MSS)/BRAF-wild-type, MSS/BRAF-mutant, MSI-high/BRAF-mutant, and MSI-high/BRAF-wild-type subtypes showed multivariable colorectal cancer-specific mortality hazard ratios of 1.60 (95% confidence interval [CI] =1.12 to 2.28; P = .009), 0.48 (95% CI = 0.27 to 0.87; P = .02), and 0.25 (95% CI = 0.12 to 0.52; P < .001), respectively. No evidence existed for a differential prognostic role of BRAF mutation by MSI status (P(interaction) > .50). Combined BRAF/MSI status in colorectal cancer is a tumor molecular biomarker for prognosic risk stratification.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Lochhead
authors.forename: Aya
authors.initials: A
authors.lastname: Kuchiba
authors.forename: Yu
authors.initials: Y
authors.lastname: Imamura
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Liao
authors.forename: Mai
authors.initials: M
authors.lastname: Yamauchi
authors.forename: Reiko
authors.initials: R
authors.lastname: Nishihara
authors.forename: Zhi Rong
authors.initials: ZR
authors.lastname: Qian
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.forename: Jeanne
authors.initials: J
authors.lastname: Shen
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Meyerhardt
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
mesh_terms: D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D018899:CpG Islands; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf