The Distribution of BRAF Gene Fusions in Solid Tumors and Response to Targeted Therapy

Int J Cancer. 2016 Feb 15;138(4):881-90. doi: 10.1002/ijc.29825. Epub 2015 Sep 8.

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.

Keywords: BRAF fusions; NGS; Sptizoid melanoma; cancer; comprehensive genomic profiling; pancreatic acinar carcinoma; pilocytic astrocytoma; solid tumors; targeted therapy.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / therapeutic use
  • Child
  • Child, Preschool
  • Female
  • Gene Expression Profiling
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Molecular Targeted Therapy / methods*
  • Neoplasms / drug therapy
  • Neoplasms / genetics*
  • Niacinamide / analogs & derivatives
  • Niacinamide / therapeutic use
  • Oncogene Proteins, Fusion / genetics
  • Phenylurea Compounds / therapeutic use
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins B-raf / genetics*
  • Pyridones / therapeutic use
  • Pyrimidinones / therapeutic use
  • Sorafenib
  • Transcriptome
  • Treatment Outcome
  • Young Adult

Substances

  • Antineoplastic Agents
  • Oncogene Proteins, Fusion
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Pyridones
  • Pyrimidinones
  • Niacinamide
  • trametinib
  • Sorafenib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf