Whole-genome sequencing revealed novel prognostic biomarkers and promising targets for therapy of ovarian clear cell carcinoma

Hiroaki Itamochi, Tetsuro Oishi, Nao Oumi, Satoshi Takeuchi, Kosuke Yoshihara, Mikio Mikami, Nobuo Yaegashi, Yasuhisa Terao, Kazuhiro Takehara, Kimio Ushijima, Hidemichi Watari, Daisuke Aoki, Tadashi Kimura, Toshiaki Nakamura, Yoshihito Yokoyama, Junzo Kigawa, Toru Sugiyama

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Abstract

Background:Ovarian clear cell carcinoma (OCCC) is mostly resistant to standard chemotherapy that results in poor patient survival. To understand the genetic background of these tumours, we performed whole-genome sequencing of OCCC tumours.Methods:Tumour tissue samples and matched blood samples were obtained from 55 Japanese women diagnosed with OCCC. Whole-genome sequencing was performed using the Illumina HiSeq platform according to standard protocols.Results:Alterations to the switch/sucrose non-fermentable (SWI/SNF) subunit, the phosphatidylinositol-3-kinase (PI3K)/Akt signalling pathway, and the receptor tyrosine kinase (RTK)/Ras signalling pathway were found in 51%, 42%, and 29% of OCCC tumours, respectively. The 3-year overall survival (OS) rate for patients with an activated PI3K/Akt signalling pathway was significantly higher than that for those with inactive pathway (91 vs 40%, hazard ratio 0.24 (95% confidence interval (CI) 0.10-0.56), P=0.0010). Similarly, the OS was significantly higher in patients with the activated RTK/Ras signalling pathway than in those with the inactive pathway (91 vs 53%, hazard ratio 0.35 (95% CI 0.13-0.94), P=0.0373). Multivariable analysis revealed that activation of the PI3K/Akt and RTK/Ras signalling pathways was an independent prognostic factor for patients with OCCC.Conclusions:The PI3K/Akt and RTK/Ras signalling pathways may be potential prognostic biomarkers for OCCC patients. Furthermore, our whole-genome sequencing data highlight important pathways for molecular and biological characterisations and potential therapeutic targeting in OCCC.

Original languageEnglish
Pages (from-to)717-724
Number of pages8
JournalBritish Journal of Cancer
Volume117
Issue number5
DOIs
Publication statusPublished - 2017 Aug 22

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Phosphatidylinositol 3-Kinase
Biomarkers
Genome
Carcinoma
Receptor Protein-Tyrosine Kinases
Therapeutics
Neoplasms
Confidence Intervals
Activation Analysis
Survival
Sucrose
Survival Rate
Drug Therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Whole-genome sequencing revealed novel prognostic biomarkers and promising targets for therapy of ovarian clear cell carcinoma. / Itamochi, Hiroaki; Oishi, Tetsuro; Oumi, Nao; Takeuchi, Satoshi; Yoshihara, Kosuke; Mikami, Mikio; Yaegashi, Nobuo; Terao, Yasuhisa; Takehara, Kazuhiro; Ushijima, Kimio; Watari, Hidemichi; Aoki, Daisuke; Kimura, Tadashi; Nakamura, Toshiaki; Yokoyama, Yoshihito; Kigawa, Junzo; Sugiyama, Toru.

In: British Journal of Cancer, Vol. 117, No. 5, 22.08.2017, p. 717-724.

Research output: Contribution to journalArticle

Itamochi, H, Oishi, T, Oumi, N, Takeuchi, S, Yoshihara, K, Mikami, M, Yaegashi, N, Terao, Y, Takehara, K, Ushijima, K, Watari, H, Aoki, D, Kimura, T, Nakamura, T, Yokoyama, Y, Kigawa, J & Sugiyama, T 2017, 'Whole-genome sequencing revealed novel prognostic biomarkers and promising targets for therapy of ovarian clear cell carcinoma', British Journal of Cancer, vol. 117, no. 5, pp. 717-724. https://doi.org/10.1038/bjc.2017.228
Itamochi, Hiroaki ; Oishi, Tetsuro ; Oumi, Nao ; Takeuchi, Satoshi ; Yoshihara, Kosuke ; Mikami, Mikio ; Yaegashi, Nobuo ; Terao, Yasuhisa ; Takehara, Kazuhiro ; Ushijima, Kimio ; Watari, Hidemichi ; Aoki, Daisuke ; Kimura, Tadashi ; Nakamura, Toshiaki ; Yokoyama, Yoshihito ; Kigawa, Junzo ; Sugiyama, Toru. / Whole-genome sequencing revealed novel prognostic biomarkers and promising targets for therapy of ovarian clear cell carcinoma. In: British Journal of Cancer. 2017 ; Vol. 117, No. 5. pp. 717-724.
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abstract = "Background:Ovarian clear cell carcinoma (OCCC) is mostly resistant to standard chemotherapy that results in poor patient survival. To understand the genetic background of these tumours, we performed whole-genome sequencing of OCCC tumours.Methods:Tumour tissue samples and matched blood samples were obtained from 55 Japanese women diagnosed with OCCC. Whole-genome sequencing was performed using the Illumina HiSeq platform according to standard protocols.Results:Alterations to the switch/sucrose non-fermentable (SWI/SNF) subunit, the phosphatidylinositol-3-kinase (PI3K)/Akt signalling pathway, and the receptor tyrosine kinase (RTK)/Ras signalling pathway were found in 51{\%}, 42{\%}, and 29{\%} of OCCC tumours, respectively. The 3-year overall survival (OS) rate for patients with an activated PI3K/Akt signalling pathway was significantly higher than that for those with inactive pathway (91 vs 40{\%}, hazard ratio 0.24 (95{\%} confidence interval (CI) 0.10-0.56), P=0.0010). Similarly, the OS was significantly higher in patients with the activated RTK/Ras signalling pathway than in those with the inactive pathway (91 vs 53{\%}, hazard ratio 0.35 (95{\%} CI 0.13-0.94), P=0.0373). Multivariable analysis revealed that activation of the PI3K/Akt and RTK/Ras signalling pathways was an independent prognostic factor for patients with OCCC.Conclusions:The PI3K/Akt and RTK/Ras signalling pathways may be potential prognostic biomarkers for OCCC patients. Furthermore, our whole-genome sequencing data highlight important pathways for molecular and biological characterisations and potential therapeutic targeting in OCCC.",
author = "Hiroaki Itamochi and Tetsuro Oishi and Nao Oumi and Satoshi Takeuchi and Kosuke Yoshihara and Mikio Mikami and Nobuo Yaegashi and Yasuhisa Terao and Kazuhiro Takehara and Kimio Ushijima and Hidemichi Watari and Daisuke Aoki and Tadashi Kimura and Toshiaki Nakamura and Yoshihito Yokoyama and Junzo Kigawa and Toru Sugiyama",
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T1 - Whole-genome sequencing revealed novel prognostic biomarkers and promising targets for therapy of ovarian clear cell carcinoma

AU - Itamochi, Hiroaki

AU - Oishi, Tetsuro

AU - Oumi, Nao

AU - Takeuchi, Satoshi

AU - Yoshihara, Kosuke

AU - Mikami, Mikio

AU - Yaegashi, Nobuo

AU - Terao, Yasuhisa

AU - Takehara, Kazuhiro

AU - Ushijima, Kimio

AU - Watari, Hidemichi

AU - Aoki, Daisuke

AU - Kimura, Tadashi

AU - Nakamura, Toshiaki

AU - Yokoyama, Yoshihito

AU - Kigawa, Junzo

AU - Sugiyama, Toru

PY - 2017/8/22

Y1 - 2017/8/22

N2 - Background:Ovarian clear cell carcinoma (OCCC) is mostly resistant to standard chemotherapy that results in poor patient survival. To understand the genetic background of these tumours, we performed whole-genome sequencing of OCCC tumours.Methods:Tumour tissue samples and matched blood samples were obtained from 55 Japanese women diagnosed with OCCC. Whole-genome sequencing was performed using the Illumina HiSeq platform according to standard protocols.Results:Alterations to the switch/sucrose non-fermentable (SWI/SNF) subunit, the phosphatidylinositol-3-kinase (PI3K)/Akt signalling pathway, and the receptor tyrosine kinase (RTK)/Ras signalling pathway were found in 51%, 42%, and 29% of OCCC tumours, respectively. The 3-year overall survival (OS) rate for patients with an activated PI3K/Akt signalling pathway was significantly higher than that for those with inactive pathway (91 vs 40%, hazard ratio 0.24 (95% confidence interval (CI) 0.10-0.56), P=0.0010). Similarly, the OS was significantly higher in patients with the activated RTK/Ras signalling pathway than in those with the inactive pathway (91 vs 53%, hazard ratio 0.35 (95% CI 0.13-0.94), P=0.0373). Multivariable analysis revealed that activation of the PI3K/Akt and RTK/Ras signalling pathways was an independent prognostic factor for patients with OCCC.Conclusions:The PI3K/Akt and RTK/Ras signalling pathways may be potential prognostic biomarkers for OCCC patients. Furthermore, our whole-genome sequencing data highlight important pathways for molecular and biological characterisations and potential therapeutic targeting in OCCC.

AB - Background:Ovarian clear cell carcinoma (OCCC) is mostly resistant to standard chemotherapy that results in poor patient survival. To understand the genetic background of these tumours, we performed whole-genome sequencing of OCCC tumours.Methods:Tumour tissue samples and matched blood samples were obtained from 55 Japanese women diagnosed with OCCC. Whole-genome sequencing was performed using the Illumina HiSeq platform according to standard protocols.Results:Alterations to the switch/sucrose non-fermentable (SWI/SNF) subunit, the phosphatidylinositol-3-kinase (PI3K)/Akt signalling pathway, and the receptor tyrosine kinase (RTK)/Ras signalling pathway were found in 51%, 42%, and 29% of OCCC tumours, respectively. The 3-year overall survival (OS) rate for patients with an activated PI3K/Akt signalling pathway was significantly higher than that for those with inactive pathway (91 vs 40%, hazard ratio 0.24 (95% confidence interval (CI) 0.10-0.56), P=0.0010). Similarly, the OS was significantly higher in patients with the activated RTK/Ras signalling pathway than in those with the inactive pathway (91 vs 53%, hazard ratio 0.35 (95% CI 0.13-0.94), P=0.0373). Multivariable analysis revealed that activation of the PI3K/Akt and RTK/Ras signalling pathways was an independent prognostic factor for patients with OCCC.Conclusions:The PI3K/Akt and RTK/Ras signalling pathways may be potential prognostic biomarkers for OCCC patients. Furthermore, our whole-genome sequencing data highlight important pathways for molecular and biological characterisations and potential therapeutic targeting in OCCC.

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