Genome Medicine (Oct 2017)

Actionable gene-based classification toward precision medicine in gastric cancer

  • Hiroshi Ichikawa,
  • Masayuki Nagahashi,
  • Yoshifumi Shimada,
  • Takaaki Hanyu,
  • Takashi Ishikawa,
  • Hitoshi Kameyama,
  • Takashi Kobayashi,
  • Jun Sakata,
  • Hiroshi Yabusaki,
  • Satoru Nakagawa,
  • Nobuaki Sato,
  • Yuki Hirata,
  • Yuko Kitagawa,
  • Toshiyuki Tanahashi,
  • Kazuhiro Yoshida,
  • Ryota Nakanishi,
  • Eiji Oki,
  • Dana Vuzman,
  • Stephen Lyle,
  • Kazuaki Takabe,
  • Yiwei Ling,
  • Shujiro Okuda,
  • Kohei Akazawa,
  • Toshifumi Wakai

DOI
https://doi.org/10.1186/s13073-017-0484-3
Journal volume & issue
Vol. 9, no. 1
pp. 1 – 12

Abstract

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Abstract Background Intertumoral heterogeneity represents a significant hurdle to identifying optimized targeted therapies in gastric cancer (GC). To realize precision medicine for GC patients, an actionable gene alteration-based molecular classification that directly associates GCs with targeted therapies is needed. Methods A total of 207 Japanese patients with GC were included in this study. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues were obtained from surgical or biopsy specimens and were subjected to DNA extraction. We generated comprehensive genomic profiling data using a 435-gene panel including 69 actionable genes paired with US Food and Drug Administration-approved targeted therapies, and the evaluation of Epstein-Barr virus (EBV) infection and microsatellite instability (MSI) status. Results Comprehensive genomic sequencing detected at least one alteration of 435 cancer-related genes in 194 GCs (93.7%) and of 69 actionable genes in 141 GCs (68.1%). We classified the 207 GCs into four The Cancer Genome Atlas (TCGA) subtypes using the genomic profiling data; EBV (N = 9), MSI (N = 17), chromosomal instability (N = 119), and genomically stable subtype (N = 62). Actionable gene alterations were not specific and were widely observed throughout all TCGA subtypes. To discover a novel classification which more precisely selects candidates for targeted therapies, 207 GCs were classified using hypermutated phenotype and the mutation profile of 69 actionable genes. We identified a hypermutated group (N = 32), while the others (N = 175) were sub-divided into six clusters including five with actionable gene alterations: ERBB2 (N = 25), CDKN2A, and CDKN2B (N = 10), KRAS (N = 10), BRCA2 (N = 9), and ATM cluster (N = 12). The clinical utility of this classification was demonstrated by a case of unresectable GC with a remarkable response to anti-HER2 therapy in the ERBB2 cluster. Conclusions This actionable gene-based classification creates a framework for further studies for realizing precision medicine in GC.

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