Prevalence of class I–III BRAF mutations among 114,662 cancer patients in a large genomic database

作者：Jeff Owsley, Matthew K. Stein, Jason Porter, Gino Kim In, Mohamed E. Salem, Steven J O'Day, Andrew Elliott, Kelsey Anne Poorman, Geoffrey Thomas Gibney, Ari M. Vanderwalde · 发表于：Experimental Biology and Medicine · 年份：2020 · DOI：10.1177/1535370220959657 · 被引用次数：133 · 研究领域：Melanoma and MAPK Pathways、Cancer-related Molecular Pathways、Cancer Mechanisms and Therapy

BRAF mutations are relatively common in many cancers, particularly melanoma, colorectal cancer, and thyroid cancer and to a lesser extent in lung cancer. These mutations can be targeted by BRAF and MEK inhibitors, which exhibit good clinical activity. There are conflicting reports of the various relative rates of BRAF Class I mutations (V600 locus), defined as those that exhibit extremely strong kinase activity by stimulating monomeric activation of BRAF, Class II, define as non-V600 mutations that activate BRAF to signal as a RAS-independent dimer, and Class III mutations, defined as “kinase-dead” with low kinase activity as compared to wild type BRAF. Prospective studies have largely focused on patients with tumors harboring Class I BRAF mutations (limited to the V600 locus) where response rates up to 70% with BRAF plus MEK inhibition have been demonstrated. We report on the relative prevalence of various types of BRAF mutations across human cancers in a cohort of 114,662 patients that received comprehensive genomic profiling using next-generation sequencing. Of these patients, 4517 (3.9%) a pathogenic or presumed pathogenic BRAF mutation (3.9%). Of these, 1271 were seen in melanoma, representing 39.7% of all melanomas sequenced, representing the highest rate in all tumors. Class I (V600) mutations were seen overall in 2841 patients (62.1% of BRAF mutations, 2.4% of total cancers). Class II mutations were seen in 746 tumors (16.5% of BRAF mutant, 0.7% of total), and Class I...