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The distribution of BRAF gene fusions in solid tumors and response to targeted therapy
Author(s) -
Ross Jeffrey S.,
Wang Kai,
Chmielecki Juliann,
Gay Laurie,
Johnson Adrienne,
Chudnovsky Jacob,
Yelensky Roman,
Lipson Doron,
Ali Siraj M,
Elvin Julia A.,
Vergilio JoAnne,
Roels Steven,
Miller Vincent A,
Nakamura Brooke N.,
Gray Adam,
Wong Michael K,
Stephens Philip J
Publication year - 2015
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29825
Subject(s) - medicine , melanoma , cancer research , papillary thyroid cancer , sorafenib , thyroid carcinoma , fusion gene , colorectal cancer , pancreatic cancer , vemurafenib , adenocarcinoma , thyroid , cancer , pathology , gene , metastatic melanoma , biology , hepatocellular carcinoma , biochemistry
Although the BRAF V600E base substitution is an approved target for the BRAF inhibitors in melanoma, BRAF gene fusions have not been investigated as anticancer drug targets. In our study, a wide variety of tumors underwent comprehensive genomic profiling for hundreds of known cancer genes using the FoundationOne™ or FoundationOne Heme™ comprehensive genomic profiling assays. BRA F fusions involving the intact in‐frame BRAF kinase domain were observed in 55 (0.3%) of 20,573 tumors, across 12 distinct tumor types, including 20 novel BRAF fusions. These comprised 29 unique 5′ fusion partners, of which 31% (9) were known and 69% (20) were novel. BRAF fusions included 3% (14/531) of melanomas; 2% (15/701) of gliomas; 1.0% (3/294) of thyroid cancers; 0.3% (3/1,062) pancreatic carcinomas; 0.2% (8/4,013) nonsmall‐cell lung cancers and 0.2% (4/2,154) of colorectal cancers, and were enriched in pilocytic (30%) vs . nonpilocytic gliomas (1%; p < 0.0001), Spitzoid (75%) vs . nonSpitzoid melanomas (1%; p = 0.0001), acinar (67%) vs . nonacinar pancreatic cancers (<1%; p < 0.0001) and papillary (3%) vs . nonpapillary thyroid cancers (0%; p < 0.03). Clinical responses to trametinib and sorafenib are presented. In conclusion, BRAF fusions are rare driver alterations in a wide variety of malignant neoplasms, but enriched in Spitzoid melanoma, pilocytic astrocytomas, pancreatic acinar and papillary thyroid cancers.