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Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes.
Sinicrope, Frank A; Shi, Qian; Smyrk, Thomas C; Thibodeau, Stephen N; Dienstmann, Rodrigo; Guinney, Justin; Bot, Brian M; Tejpar, Sabine; Delorenzi, Mauro; Goldberg, Richard M; Mahoney, Michelle; Sargent, Daniel J; Alberts, Steven R.
Afiliação
  • Sinicrope FA; Department of Medicine, Mayo Clinic, Rochester, Minnesota; Department of Oncology, Mayo Clinic, Rochester, Minnesota. Electronic address: sinicrope.frank@mayo.edu.
  • Shi Q; Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota.
  • Smyrk TC; Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
  • Thibodeau SN; Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
  • Dienstmann R; Sage Bionetworks, Seattle, Washington.
  • Guinney J; Sage Bionetworks, Seattle, Washington.
  • Bot BM; Sage Bionetworks, Seattle, Washington.
  • Tejpar S; Molecular Digestive Oncology, KU Leuven, The Netherlands.
  • Delorenzi M; Swiss Institute of Bioinformatics, University Lausanne, Switzerland.
  • Goldberg RM; Division of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
  • Mahoney M; Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota.
  • Sargent DJ; Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota.
  • Alberts SR; Department of Oncology, Mayo Clinic, Rochester, Minnesota.
Gastroenterology ; 148(1): 88-99, 2015 Jan.
Article em En | MEDLINE | ID: mdl-25305506
BACKGROUND & AIMS: Categorization of colon cancers into distinct subtypes using a combination of pathway-based biomarkers could provide insight into stage-independent variability in outcomes. METHODS: We used a polymerase chain reaction-based assay to detect mutations in BRAF (V600E) and in KRAS in 2720 stage III cancer samples, collected prospectively from patients participating in an adjuvant chemotherapy trial (NCCTG N0147). Tumors deficient or proficient in DNA mismatch repair (MMR) were identified based on detection of MLH1, MSH2, and MSH6 proteins and methylation of the MLH1 promoter. Findings were validated using tumor samples from a separate set of patients with stage III cancer (n = 783). Association with 5-year disease-free survival was evaluated using Cox proportional hazards models. RESULTS: Tumors were categorized into 5 subtypes based on MMR status and detection of BRAF or KRAS mutations which were mutually exclusive. Three subtypes were MMR proficient: those with mutations in BRAF (6.9% of samples), mutations in KRAS (35%), or tumors lacking either BRAF or KRAS mutations (49%). Two subtypes were MMR deficient: the sporadic type (6.8%) with BRAF mutation and/or or hypermethylation of MLH1 and the familial type (2.6%), which lacked BRAF(V600E) or hypermethylation of MLH1. A higher percentage of MMR-proficient tumors with BRAF(V600E) were proximal (76%), high-grade (44%), N2 stage (59%), and detected in women (59%), compared with MMR-proficient tumors without BRAF(V600E) or KRAS mutations (33%, 19%, 41%, and 42%, respectively; all P < .0001). A significantly lower proportion of patients with MMR-proficient tumors with mutant BRAF (hazard ratio = 1.43; 95% confidence interval: 1.11-1.85; Padjusted = .0065) or mutant KRAS (hazard ratio = 1.48; 95% confidence interval: 1.27-1.74; Padjusted < .0001) survived disease-free for 5 years compared with patients whose MMR-proficient tumors lacked mutations in either gene. Disease-free survival rates of patients with MMR-deficient sporadic or familial subtypes was similar to those of patients with MMR-proficient tumors without BRAF or KRAS mutations. The observed differences in survival rates of patients with different tumor subtypes were validated in an independent cohort. CONCLUSIONS: We identified subtypes of stage III colon cancer, based on detection of mutations in BRAF (V600E) or KRAS, and MMR status that show differences in clinical and pathologic features and disease-free survival. Patients with MMR-proficient tumors and BRAF or KRAS mutations had statistically shorter survival times than patients whose tumors lacked these mutations. The tumor subtype found in nearly half of the study cohort (MMR-proficient without BRAF(V600E) or KRAS mutations) had similar outcomes to those of patients with MMR-deficient cancers.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Adenocarcinoma / Biomarcadores Tumorais / Proteínas Proto-Oncogênicas / Neoplasias do Colo / Proteínas ras / Proteínas Proto-Oncogênicas B-raf / Reparo de Erro de Pareamento de DNA / Mutação Tipo de estudo: Clinical_trials / Etiology_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Aged80 Idioma: En Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Adenocarcinoma / Biomarcadores Tumorais / Proteínas Proto-Oncogênicas / Neoplasias do Colo / Proteínas ras / Proteínas Proto-Oncogênicas B-raf / Reparo de Erro de Pareamento de DNA / Mutação Tipo de estudo: Clinical_trials / Etiology_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Aged80 Idioma: En Ano de publicação: 2015 Tipo de documento: Article