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 TakabeYiwei Ling, Shujiro Okuda, Kohei Akazawa, Toshifumi Wakai

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Article number93
JournalGenome Medicine
Volume9
Issue number1
DOIs
Publication statusPublished - Oct 31 2017

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Precision Medicine
Stomach Neoplasms
Genes
Microsatellite Instability
Atlases
Genome
Therapeutics
Neoplasms
Chromosomal Instability
Epstein-Barr Virus Infections
Neoplasm Genes
United States Food and Drug Administration
Human Herpesvirus 4
Paraffin
Formaldehyde
Phenotype
Biopsy
Mutation
DNA

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Ichikawa, H., Nagahashi, M., Shimada, Y., Hanyu, T., Ishikawa, T., Kameyama, H., ... Wakai, T. (2017). Actionable gene-based classification toward precision medicine in gastric cancer. Genome Medicine, 9(1), [93]. https://doi.org/10.1186/s13073-017-0484-3

Actionable gene-based classification toward precision medicine in gastric cancer. / Ichikawa, Hiroshi; Nagahashi, Masayuki; Shimada, Yoshifumi; Hanyu, Takaaki; Ishikawa, Takashi; Kameyama, Hitoshi; Kobayashi, Takashi; Sakata, Jun; Yabusaki, Hiroshi; Nakagawa, Satoru; Sato, Nobuaki; Hirata, Yuki; Kitagawa, Yuko; Tanahashi, Toshiyuki; Yoshida, Kazuhiro; Nakanishi, Ryota; Oki, Eiji; Vuzman, Dana; Lyle, Stephen; Takabe, Kazuaki; Ling, Yiwei; Okuda, Shujiro; Akazawa, Kohei; Wakai, Toshifumi.

In: Genome Medicine, Vol. 9, No. 1, 93, 31.10.2017.

Research output: Contribution to journalArticle

Ichikawa, H, Nagahashi, M, Shimada, Y, Hanyu, T, Ishikawa, T, Kameyama, H, Kobayashi, T, Sakata, J, Yabusaki, H, Nakagawa, S, Sato, N, Hirata, Y, Kitagawa, Y, Tanahashi, T, Yoshida, K, Nakanishi, R, Oki, E, Vuzman, D, Lyle, S, Takabe, K, Ling, Y, Okuda, S, Akazawa, K & Wakai, T 2017, 'Actionable gene-based classification toward precision medicine in gastric cancer', Genome Medicine, vol. 9, no. 1, 93. https://doi.org/10.1186/s13073-017-0484-3
Ichikawa H, Nagahashi M, Shimada Y, Hanyu T, Ishikawa T, Kameyama H et al. Actionable gene-based classification toward precision medicine in gastric cancer. Genome Medicine. 2017 Oct 31;9(1). 93. https://doi.org/10.1186/s13073-017-0484-3
Ichikawa, Hiroshi ; Nagahashi, Masayuki ; Shimada, Yoshifumi ; Hanyu, Takaaki ; Ishikawa, Takashi ; Kameyama, Hitoshi ; Kobayashi, Takashi ; Sakata, Jun ; Yabusaki, Hiroshi ; Nakagawa, Satoru ; Sato, Nobuaki ; Hirata, Yuki ; Kitagawa, Yuko ; Tanahashi, Toshiyuki ; Yoshida, Kazuhiro ; Nakanishi, Ryota ; Oki, Eiji ; Vuzman, Dana ; Lyle, Stephen ; Takabe, Kazuaki ; Ling, Yiwei ; Okuda, Shujiro ; Akazawa, Kohei ; Wakai, Toshifumi. / Actionable gene-based classification toward precision medicine in gastric cancer. In: Genome Medicine. 2017 ; Vol. 9, No. 1.
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AU - Nagahashi, Masayuki

AU - Shimada, Yoshifumi

AU - Hanyu, Takaaki

AU - Ishikawa, Takashi

AU - Kameyama, Hitoshi

AU - Kobayashi, Takashi

AU - Sakata, Jun

AU - Yabusaki, Hiroshi

AU - Nakagawa, Satoru

AU - Sato, Nobuaki

AU - Hirata, Yuki

AU - Kitagawa, Yuko

AU - Tanahashi, Toshiyuki

AU - Yoshida, Kazuhiro

AU - Nakanishi, Ryota

AU - Oki, Eiji

AU - Vuzman, Dana

AU - Lyle, Stephen

AU - Takabe, Kazuaki

AU - Ling, Yiwei

AU - Okuda, Shujiro

AU - Akazawa, Kohei

AU - Wakai, Toshifumi

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N2 - 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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