Clinical detection and categorization of uncommon and concomitant mutations involving BRAF.
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.
Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, USA. gzheng5@jhmi.edu.
Gang
G
Zheng
Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, USA. Lhtseng@ntu.edu.tw.|Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan. Lhtseng@ntu.edu.tw.
Li-Hui
LH
Tseng
Department of Pathology, Penn State Hershey Medical Center, Pennsylvania, USA. garrychen2000@yahoo.com.
Guoli
G
Chen
Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, USA. lhaley2@jhmi.edu.
Lisa
L
Haley
Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, USA. pillei1@jhmi.edu.
Peter
P
Illei
Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, USA. cgocke1@jhmi.edu.|Departments of Oncology, Johns Hopkins University School of Medicine, Baltimore, USA. cgocke1@jhmi.edu.
Christopher D
CD
Gocke
Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, USA. jeshlem@jhmi.edu.|Departments of Oncology, Johns Hopkins University School of Medicine, Baltimore, USA. jeshlem@jhmi.edu.
James R
JR
Eshleman
Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, USA. mlin36@jhmi.edu.
Ming-Tseh
MT
Lin
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008545:Melanoma / Q000201:enzymology / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010770:Phosphotransferases / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
D010770:Phosphotransferases; D048493:Proto-Oncogene Proteins B-raf