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Genome Med. 2017 Oct 31;9(1):93. doi: 10.1186/s13073-017-0484-3.

Actionable gene-based classification toward precision medicine in gastric cancer.

Author information

1
Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan. hichikawa-nii@med.niigata-u.ac.jp.
2
Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan.
3
Department of Gastroenterological Surgery, Niigata Cancer Center Hospital, 2-15-3 Kawagishi-cho, Chuo-ku, Niigata City, Niigata, 951-8566, Japan.
4
Department of Breast Oncology, Niigata Cancer Center Hospital, 2-15-3 Kawagishi-cho, Chuo-ku, Niigata City, Niigata, 951-8566, Japan.
5
Department of Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjyuku-ku, Tokyo, 160-8582, Japan.
6
Department of Surgical Oncology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.
7
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
8
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, 02115, USA.
9
Broad Institute of Harvard and MIT, Cambridge, Massachusetts, 02142, USA.
10
Molecular, Cell & Cancer Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts, 01655, USA. Stephen.lyle@umassmed.edu.
11
Breast Surgery, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, New York, 14263, USA.
12
Department of Surgery, University at Buffalo the State University of New York, 100 High Street, Buffalo, New York, 14203, USA.
13
Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan.
14
Department of Medical Informatics, Niigata University Medical and Dental Hospital, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan.
15
Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan. wakait@med.niigata-u.ac.jp.

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.

KEYWORDS:

Actionable gene; Gastric cancer; Gene panel; Next-generation sequencing; Precision medicine

PMID:
29089060
PMCID:
PMC5664811
DOI:
10.1186/s13073-017-0484-3
[Indexed for MEDLINE]
Free PMC Article

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