Clinical detection and categorization of uncommon and concomitant mutations involving BRAF

Gang Zheng, Li Hui Tseng, Guoli Chen, Lisa Haley, Peter B Illei, Christopher Gocke, James Eshleman, Ming-Tseh Lin

Research output: Contribution to journalArticle

Abstract

Background: Selective BRAF inhibitors, vemurafenib and dabrafenib, and the MEK inhibitor, trametinib, have been approved for treatment of metastatic melanomas with a BRAF p.V600E mutation. The clinical significance of non-codon 600 mutations remains unclear, in part, due to variation of kinase activity for different mutants. Methods: In this study, we categorized BRAF mutations according to the reported mutant kinase activity. A total of 1027 lung cancer, colorectal cancer or melanoma specimens were submitted for clinical mutation detection by next generation sequencing. Results: Non-codon 600 mutations were observed in 37 % of BRAF-mutated tumors. Of all BRAF mutants, 75 % were kinase-activated, 15 % kinase-impaired and 10 % kinase-unknown. The most common kinase-impaired mutant involves codon 594, specifically, p.D594G (c.1781A > G) and p.D594N (c.1780G > A). Lung cancers showed significantly higher incidences of kinase-impaired or kinase-unknown mutants. Kinase-impaired BRAF mutants showed a significant association with concomitant activating KRAS or NRAS mutations, but not PIK3CA mutations, supporting the reported interaction of these mutations. Conclusions:BRAF mutants with impaired or unknown kinase activity as well as concomitant kinase-impaired BRAF mutations and RAS mutations were detected in lung cancers, colorectal cancers and melanomas. Different therapeutic strategies based on the BRAF mutant kinase activity and the concomitant mutations may be worthwhile.

Original languageEnglish (US)
Article number779
JournalBMC Cancer
Volume15
Issue number1
DOIs
StatePublished - Oct 24 2015

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Phosphotransferases
Mutation
Proto-Oncogene Proteins B-raf
Melanoma
Lung Neoplasms
Colorectal Neoplasms
Mitogen-Activated Protein Kinase Kinases
Codon
Incidence
Neoplasms

Keywords

  • BRAF
  • Colorectal cancer
  • Concomitant mutation
  • Kinase activity
  • Lung cancer
  • Melanoma
  • Next generation sequencing

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

Cite this

Clinical detection and categorization of uncommon and concomitant mutations involving BRAF. / Zheng, Gang; Tseng, Li Hui; Chen, Guoli; Haley, Lisa; Illei, Peter B; Gocke, Christopher; Eshleman, James; Lin, Ming-Tseh.

In: BMC Cancer, Vol. 15, No. 1, 779, 24.10.2015.

Research output: Contribution to journalArticle

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