Driver Fusions and Their Implications in the Development and Treatment of Human Cancers

Cell Rep. 2018 Apr 3;23(1):227-238.e3. doi: 10.1016/j.celrep.2018.03.050.

Abstract

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy.

Keywords: RNA; cancer; fusion; gene fusions; translocation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Carcinogenesis / drug effects
  • Carcinogenesis / genetics*
  • Carcinogenesis / metabolism
  • Cell Line, Tumor
  • Humans
  • Molecular Targeted Therapy / methods
  • Neoplasms / drug therapy
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Oncogene Fusion*
  • Oncogene Proteins, Fusion / chemistry
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism

Substances

  • Antineoplastic Agents
  • Oncogene Proteins, Fusion