Genomic landscape of colorectal cancer in Japan

Clinical implications of comprehensive genomic sequencing for precision medicine

Masayuki Nagahashi, Toshifumi Wakai, Yoshifumi Shimada, Hiroshi Ichikawa, Hitoshi Kameyama, Takashi Kobayashi, Jun Sakata, Ryoma Yagi, Nobuaki Sato, Yuukou Kitagawa, Hiroyuki Uetake, Kazuhiro Yoshida, Eiji Oki, Shin ei Kudo, Hiroshi Izutsu, Keisuke Kodama, Mitsutaka Nakada, Julie Tse, Meaghan Russell, Joerg Heyer & 8 others Winslow Powers, Ruobai Sun, Jennifer E. Ring, Kazuaki Takabe, Alexei Protopopov, Yiwei Ling, Shujiro Okuda, Stephen Lyle

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Background: 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). Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Article number136
JournalGenome Medicine
Volume8
Issue number1
DOIs
Publication statusPublished - 2016 Dec 22

Fingerprint

Precision Medicine
Colorectal Neoplasms
Japan
Mutation
Genes
Neoplasm Genes
Exome
Neoplasms
Cluster Analysis
Population
Double-Stranded DNA Breaks
Atlases
Mutation Rate
Exons
Genome
Databases

Keywords

  • Actionable driver mutation
  • Colorectal cancer
  • Comprehensive genomic sequencing
  • Ethnicity
  • Hypermutation
  • Japanese
  • Precision medicine

ASJC Scopus subject areas

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

Cite this

Genomic landscape of colorectal cancer in Japan : Clinical implications of comprehensive genomic sequencing for precision medicine. / Nagahashi, Masayuki; Wakai, Toshifumi; Shimada, Yoshifumi; Ichikawa, Hiroshi; Kameyama, Hitoshi; Kobayashi, Takashi; Sakata, Jun; Yagi, Ryoma; Sato, Nobuaki; Kitagawa, Yuukou; Uetake, Hiroyuki; Yoshida, Kazuhiro; Oki, Eiji; Kudo, Shin ei; Izutsu, Hiroshi; Kodama, Keisuke; Nakada, Mitsutaka; Tse, Julie; Russell, Meaghan; Heyer, Joerg; Powers, Winslow; Sun, Ruobai; Ring, Jennifer E.; Takabe, Kazuaki; Protopopov, Alexei; Ling, Yiwei; Okuda, Shujiro; Lyle, Stephen.

In: Genome Medicine, Vol. 8, No. 1, 136, 22.12.2016.

Research output: Contribution to journalArticle

Nagahashi, M, Wakai, T, Shimada, Y, Ichikawa, H, Kameyama, H, Kobayashi, T, Sakata, J, Yagi, R, Sato, N, Kitagawa, Y, Uetake, H, Yoshida, K, Oki, E, Kudo, SE, Izutsu, H, Kodama, K, Nakada, M, Tse, J, Russell, M, Heyer, J, Powers, W, Sun, R, Ring, JE, Takabe, K, Protopopov, A, Ling, Y, Okuda, S & Lyle, S 2016, 'Genomic landscape of colorectal cancer in Japan: Clinical implications of comprehensive genomic sequencing for precision medicine', Genome Medicine, vol. 8, no. 1, 136. https://doi.org/10.1186/s13073-016-0387-8
Nagahashi, Masayuki ; Wakai, Toshifumi ; Shimada, Yoshifumi ; Ichikawa, Hiroshi ; Kameyama, Hitoshi ; Kobayashi, Takashi ; Sakata, Jun ; Yagi, Ryoma ; Sato, Nobuaki ; Kitagawa, Yuukou ; Uetake, Hiroyuki ; Yoshida, Kazuhiro ; Oki, Eiji ; Kudo, Shin ei ; Izutsu, Hiroshi ; Kodama, Keisuke ; Nakada, Mitsutaka ; Tse, Julie ; Russell, Meaghan ; Heyer, Joerg ; Powers, Winslow ; Sun, Ruobai ; Ring, Jennifer E. ; Takabe, Kazuaki ; Protopopov, Alexei ; Ling, Yiwei ; Okuda, Shujiro ; Lyle, Stephen. / Genomic landscape of colorectal cancer in Japan : Clinical implications of comprehensive genomic sequencing for precision medicine. In: Genome Medicine. 2016 ; Vol. 8, No. 1.
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abstract = "Background: 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). Methods: 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. Results: 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. Conclusions: 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.",
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T1 - Genomic landscape of colorectal cancer in Japan

T2 - Clinical implications of comprehensive genomic sequencing for precision medicine

AU - Nagahashi, Masayuki

AU - Wakai, Toshifumi

AU - Shimada, Yoshifumi

AU - Ichikawa, Hiroshi

AU - Kameyama, Hitoshi

AU - Kobayashi, Takashi

AU - Sakata, Jun

AU - Yagi, Ryoma

AU - Sato, Nobuaki

AU - Kitagawa, Yuukou

AU - Uetake, Hiroyuki

AU - Yoshida, Kazuhiro

AU - Oki, Eiji

AU - Kudo, Shin ei

AU - Izutsu, Hiroshi

AU - Kodama, Keisuke

AU - Nakada, Mitsutaka

AU - Tse, Julie

AU - Russell, Meaghan

AU - Heyer, Joerg

AU - Powers, Winslow

AU - Sun, Ruobai

AU - Ring, Jennifer E.

AU - Takabe, Kazuaki

AU - Protopopov, Alexei

AU - Ling, Yiwei

AU - Okuda, Shujiro

AU - Lyle, Stephen

PY - 2016/12/22

Y1 - 2016/12/22

N2 - Background: 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). Methods: 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. Results: 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. Conclusions: 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.

AB - Background: 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). Methods: 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. Results: 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. Conclusions: 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.

KW - Actionable driver mutation

KW - Colorectal cancer

KW - Comprehensive genomic sequencing

KW - Ethnicity

KW - Hypermutation

KW - Japanese

KW - Precision medicine

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