title: The distribution of BRAF gene fusions in solid tumors and response to targeted therapy.
abstract: 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. BRAF 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.
authors: Foundation Medicine, Inc., Cambridge, MA.|Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, NY.
authors: Jeffrey S
authors: JS
authors: Ross
authors: Foundation Medicine, Inc., Cambridge, MA.
authors: Kai
authors: K
authors: Wang
authors: Foundation Medicine, Inc., Cambridge, MA.
authors: Juliann
authors: J
authors: Chmielecki
authors: Foundation Medicine, Inc., Cambridge, MA.
authors: Laurie
authors: L
authors: Gay
authors: Foundation Medicine, Inc., Cambridge, MA.
authors: Adrienne
authors: A
authors: Johnson
authors: Foundation Medicine, Inc., Cambridge, MA.
authors: Jacob
authors: J
authors: Chudnovsky
authors: Foundation Medicine, Inc., Cambridge, MA.
authors: Roman
authors: R
authors: Yelensky
authors: Foundation Medicine, Inc., Cambridge, MA.
authors: Doron
authors: D
authors: Lipson
authors: Foundation Medicine, Inc., Cambridge, MA.
authors: Siraj M
authors: SM
authors: Ali
authors: Foundation Medicine, Inc., Cambridge, MA.
authors: Julia A
authors: JA
authors: Elvin
authors: Foundation Medicine, Inc., Cambridge, MA.
authors: Jo-Anne
authors: JA
authors: Vergilio
authors: Foundation Medicine, Inc., Cambridge, MA.
authors: Steven
authors: S
authors: Roels
authors: Foundation Medicine, Inc., Cambridge, MA.
authors: Vincent A
authors: VA
authors: Miller
authors: Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA.
authors: Brooke N
authors: BN
authors: Nakamura
authors: Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA.
authors: Adam
authors: A
authors: Gray
authors: Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA.
authors: Michael K
authors: MK
authors: Wong
authors: Foundation Medicine, Inc., Cambridge, MA.
authors: Philip J
authors: PJ
authors: Stephens
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010671:Phenylurea Compounds / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011728:Pyridones / Q000627:therapeutic use; D011744:Pyrimidinones / Q000627:therapeutic use; D000077157:Sorafenib; D059467:Transcriptome; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D015514:Oncogene Proteins, Fusion; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D009536:Niacinamide; C560077:trametinib; D000077157:Sorafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF fusions; NGS; Sptizoid melanoma; cancer; comprehensive genomic profiling; pancreatic acinar carcinoma; pilocytic astrocytoma; solid tumors; targeted therapy