title: Genomic landscape of colorectal cancer in Japan: clinical implications of comprehensive genomic sequencing for precision medicine.
abstract: Comprehensive genomic sequencing (CGS) has the potential to revolutionize precision medicine for cancer patients across the globe. However, to date large-scale genomic sequencing of cancer patients has been limited to Western populations. In order to understand possible ethnic and geographic differences and to explore the broader application of CGS to other populations, we sequenced a panel of 415 important cancer genes to characterize clinically actionable genomic driver events in 201 Japanese patients with colorectal cancer (CRC).
  
  
  
  Using next-generation sequencing methods, we examined all exons of 415 known cancer genes in Japanese CRC patients (n = 201) and evaluated for concordance among independent data obtained from US patients with CRC (n = 108) and from The Cancer Genome Atlas-CRC whole exome sequencing (WES) database (n = 224). Mutation data from non-hypermutated Japanese CRC patients were extracted and clustered by gene mutation patterns. Two different sets of genes from the 415-gene panel were used for clustering: 61 genes with frequent alteration in CRC and 26 genes that are clinically actionable in CRC.
  
  
  
  The 415-gene panel is able to identify all of the critical mutations in tumor samples as well as WES, including identifying hypermutated tumors. Although the overall mutation spectrum of the Japanese patients is similar to that of the Western population, we found significant differences in the frequencies of mutations in ERBB2 and BRAF. We show that the 415-gene panel identifies a number of clinically actionable mutations in KRAS, NRAS, and BRAF that are not detected by hot-spot testing. We also discovered that 26% of cases have mutations in genes involved in DNA double-strand break repair pathway. Unsupervised clustering revealed that a panel of 26 genes can be used to classify the patients into eight different categories, each of which can optimally be treated with a particular combination therapy.
  
  
  
  Use of a panel of 415 genes can reliably identify all of the critical mutations in CRC patients and this information of CGS can be used to determine the most optimal treatment for patients of all ethnicities.
authors.affiliation: 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.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nagahashi
authors.affiliation: 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.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Wakai
authors.affiliation: 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.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Shimada
authors.affiliation: 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.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ichikawa
authors.affiliation: 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.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kameyama
authors.affiliation: 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.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Sakata
authors.affiliation: 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.
authors.forename: Ryoma
authors.initials: R
authors.lastname: Yagi
authors.affiliation: Niigata Cancer Center Hospital, 15-3 Kawagishi-cho 2-Chome, Chuo-ku, Niigata City, Niigata, 951-8566, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Sato
authors.affiliation: Department of Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjyuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kitagawa
authors.affiliation: Department of Chemotherapy and Oncosurgery, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Uetake
authors.affiliation: Department of Surgical Oncology, Gifu University School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Oki
authors.affiliation: Digestive Disease Center, Showa University Northern Yokohama Hospital, 35-1 Chigasaki-chuo, Tsuzuki-ku, Yokohama, 224-8503, Japan.
authors.forename: Shin-Ei
authors.initials: SE
authors.lastname: Kudo
authors.affiliation: Diagnostics Research Department, Life innovation Research Institute, Denka innovation center, Denka Co., Ltd., 3-5-1 Asahi-Machi, Machida-City, Tokyo, 194-8560, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Izutsu
authors.affiliation: Diagnostics Research Department, Life innovation Research Institute, Denka innovation center, Denka Co., Ltd., 3-5-1 Asahi-Machi, Machida-City, Tokyo, 194-8560, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kodama
authors.affiliation: Diagnostics Research Department, Life innovation Research Institute, Denka innovation center, Denka Co., Ltd., 3-5-1 Asahi-Machi, Machida-City, Tokyo, 194-8560, Japan.
authors.forename: Mitsutaka
authors.initials: M
authors.lastname: Nakada
authors.affiliation: KEW, Inc, 840 Memorial Drive, 4th floor, Cambridge, MA, 02139, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Tse
authors.affiliation: KEW, Inc, 840 Memorial Drive, 4th floor, Cambridge, MA, 02139, USA.
authors.forename: Meaghan
authors.initials: M
authors.lastname: Russell
authors.affiliation: KEW, Inc, 840 Memorial Drive, 4th floor, Cambridge, MA, 02139, USA.
authors.forename: Joerg
authors.initials: J
authors.lastname: Heyer
authors.affiliation: KEW, Inc, 840 Memorial Drive, 4th floor, Cambridge, MA, 02139, USA.
authors.forename: Winslow
authors.initials: W
authors.lastname: Powers
authors.affiliation: KEW, Inc, 840 Memorial Drive, 4th floor, Cambridge, MA, 02139, USA.
authors.forename: Ruobai
authors.initials: R
authors.lastname: Sun
authors.affiliation: KEW, Inc, 840 Memorial Drive, 4th floor, Cambridge, MA, 02139, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Ring
authors.affiliation: Breast Surgery, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY, 14263, USA.|Department of Surgery, University at Buffalo, The State University of New York, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Takabe
authors.affiliation: KEW, Inc, 840 Memorial Drive, 4th floor, Cambridge, MA, 02139, USA.
authors.forename: Alexei
authors.initials: A
authors.lastname: Protopopov
authors.affiliation: Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Ling
authors.affiliation: Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan. okd@med.niigata-u.ac.jp.
authors.forename: Shujiro
authors.initials: S
authors.lastname: Okuda
authors.affiliation: KEW, Inc, 840 Memorial Drive, 4th floor, Cambridge, MA, 02139, USA. slyle@kewinc.com.|University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA. slyle@kewinc.com.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lyle
mesh_terms: D000483:Alleles; D044466:Asian People; D015179:Colorectal Neoplasms / Q000235:genetics*; D030541:Databases, Genetic; D059472:Exome; D005260:Female; D052138:Genes, Neoplasm; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007564:Japan; D008297:Male; D057285:Precision Medicine
keywords: Actionable driver mutation; Colorectal cancer; Comprehensive genomic sequencing; Ethnicity; Hypermutation; Japanese; Precision medicine