TY - JOUR
T1 - Actionable gene-based classification toward precision medicine in gastric cancer
AU - Ichikawa, Hiroshi
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
N1 - Funding Information:
This project was supported by funding from Denka Co., Ltd. H. Ichikawa is supported, in part, by the Japan Society for the Promotion of Science (JSPS) KAKENHI grant number JP16K10491. M. Nagahashi is supported by the JSPS KAKENHI grant numbers JP15H05676 and JP15K15471, the Uehara Memorial Foundation, Nakayama Cancer Research Institute, Takeda Science Foundation, and Tsukada Medical Foundation. T. Wakai is supported by the JSPS KAKENHI grant numbers JP15H04927 and JP16K15610. K. Yoshida is supported by the JSPS KAKENHI grant number JP17H04280. S. Okuda is supported by the JSPS KAKENHI grant number JP26700029. K. Takabe is supported by NIH/NCI grant R01CA160688 and Susan G. Komen Investigator Initiated Research Grant IIR12222224. S. Lyle is supported by a grant from the Massachusetts Life Sciences Center.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/10/31
Y1 - 2017/10/31
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.
AB - 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.
KW - Actionable gene
KW - Gastric cancer
KW - Gene panel
KW - Next-generation sequencing
KW - Precision medicine
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U2 - 10.1186/s13073-017-0484-3
DO - 10.1186/s13073-017-0484-3
M3 - Article
C2 - 29089060
AN - SCOPUS:85033404988
SN - 1756-994X
VL - 9
JO - Genome Medicine
JF - Genome Medicine
IS - 1
M1 - 93
ER -
