Scientific Reports (Apr 2017)

Integrated analysis of gene expression and copy number identified potential cancer driver genes with amplification-dependent overexpression in 1,454 solid tumors

  • Keiichi Ohshima,
  • Keiichi Hatakeyama,
  • Takeshi Nagashima,
  • Yuko Watanabe,
  • Kaori Kanto,
  • Yuki Doi,
  • Tomomi Ide,
  • Yuji Shimoda,
  • Tomoe Tanabe,
  • Sumiko Ohnami,
  • Shumpei Ohnami,
  • Masakuni Serizawa,
  • Koji Maruyama,
  • Yasuto Akiyama,
  • Kenichi Urakami,
  • Masatoshi Kusuhara,
  • Tohru Mochizuki,
  • Ken Yamaguchi

DOI
https://doi.org/10.1038/s41598-017-00219-3
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 13

Abstract

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Abstract Identification of driver genes contributes to the understanding of cancer etiology and is imperative for the development of individualized therapies. Gene amplification is a major event in oncogenesis. Driver genes with tumor-specific amplification-dependent overexpression can be therapeutic targets. In this study, we aimed to identify amplification-dependent driver genes in 1,454 solid tumors, across more than 15 cancer types, by integrative analysis of gene expression and copy number. Amplification-dependent overexpression of 64 known driver oncogenes were found in 587 tumors (40%); genes frequently observed were MYC (25%) and MET (18%) in colorectal cancer; SKP2 (21%) in lung squamous cell carcinoma; HIST1H3B (19%) and MYCN (13%) in liver cancer; KIT (57%) in gastrointestinal stromal tumors; and FOXL2 (12%) in squamous cell carcinoma across tissues. Genomic aberrations in 138 known cancer driver genes and 491 established fusion genes were found in 1,127 tumors (78%). Further analyses of 820 cancer-related genes revealed 16 as potential driver genes, with amplification-dependent overexpression restricted to the remaining 22% of samples (327 tumors) initially undetermined genetic drivers. Among them, AXL, which encodes a receptor tyrosine kinase, was recurrently overexpressed and amplified in sarcomas. Our studies of amplification-dependent overexpression identified potential drug targets in individual tumors.