Clinical detection and categorization of uncommon and concomitant mutations involving BRAF

BMC Cancer

Research Article

Guoli Chen¹  Lisa Haley²  Ming-Tseh Lin²  Peter Illei²  Gang Zheng²  Li-Hui Tseng³  James R. Eshleman⁴  Christopher D. Gocke⁴ 

[1] Department of Pathology, Penn State Hershey Medical Center, Pennsylvania, USA;Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, USA;Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, USA;Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan;Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, USA;Departments of Oncology, Johns Hopkins University School of Medicine, Baltimore, USA;

关键词: BRAF;    Lung cancer;    Colorectal cancer;    Melanoma;    Next generation sequencing;    Kinase activity;    Concomitant mutation;   

DOI  :  10.1186/s12885-015-1811-y

 received in 2015-05-13, accepted in 2015-10-16,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundSelective 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.MethodsIn 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.ResultsNon-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.ConclusionsBRAF 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.

【 授权许可】

CC BY   
© Zheng et al. 2015