Braf mutations are associated with increased mortality in colorectal cancer

• Published in: Journal of the American College of Surgeons Vol. 199; no. 3; p. 92
• Main Authors: Gimbel, Mark I., Nash, Garrett, Ndubuisi, Mackevin, Wong, Douglas, Barany, Francis, Paty, Philip
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.09.2004
• ISSN: 1072-7515; 1879-1190
• DOI: 10.1016/j.jamcollsurg.2004.05.202

Introduction: The Braf and Kras gene products are signaling molecules in the MAP kinase pathway that are known to harbor activating point mutations in colorectal cancer (CRC). In this study, we evaluated mutations in the Braf gene to assess prevalence and prognostic importance in CRC and compared the results with Kras mutation data. Methods: We evaluated 364 colorectal primary tumors (Stages I-IV) with a median follow-up of 3.5 years. DNA was extracted from frozen primary cancers and matched normal mucosa. Point mutations in Braf (codon 599) and Kras (codons 12/13) were detected using PCR-LDR. Microsatellite instability (MSI) tumors verus microsatellite stable (MSS) tumors were identified by PCR of the BAT25, BAT26, and D2S123 loci. Results: Mutation rates were: Braf = 8%, Kras = 37%, MSI = 13%. Sixty-two percent of Braf mutations were in MSI tumors (p < 0.001), whereas 93% of Kras mutations were in MSS tumors (p < 0.01). Only 1 of 26 Braf mutations was found with a Kras mutation. Braf and Kras mutations each conferred a significantly worse 5 year survival in both MSS tumors (p = 0.001 and 0.006, respectively) and MSI tumors (p = 0.01 and 0.03, respectively). Braf mutations identified decreased survival in stage III (p < 0.001) and stage IV (p < 0.04) patients. Conclusions: Braf mutations, like Kras mutations, are frequent genetic events in CRC, have distinct distribution relative to MSI status, and are associated with poor survival. These data implicate the MAP kinase pathway in tumor progression and define Braf, with Kras and MSI, as important prognostic markers in CRC.