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Actionable gene-based classification toward precision medicine in gastric cancer
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664811/ https://www.ncbi.nlm.nih.gov/pubmed/29089060 http://dx.doi.org/10.1186/s13073-017-0484-3 |
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author | 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 |
author_facet | 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 |
author_sort | Ichikawa, Hiroshi |
collection | PubMed |
description | 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13073-017-0484-3) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5664811 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-56648112017-11-08 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 Genome Med Research 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13073-017-0484-3) contains supplementary material, which is available to authorized users. BioMed Central 2017-10-31 /pmc/articles/PMC5664811/ /pubmed/29089060 http://dx.doi.org/10.1186/s13073-017-0484-3 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research 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 |
title | Actionable gene-based classification toward precision medicine in gastric cancer |
title_full | Actionable gene-based classification toward precision medicine in gastric cancer |
title_fullStr | Actionable gene-based classification toward precision medicine in gastric cancer |
title_full_unstemmed | Actionable gene-based classification toward precision medicine in gastric cancer |
title_short | Actionable gene-based classification toward precision medicine in gastric cancer |
title_sort | actionable gene-based classification toward precision medicine in gastric cancer |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664811/ https://www.ncbi.nlm.nih.gov/pubmed/29089060 http://dx.doi.org/10.1186/s13073-017-0484-3 |
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