Mechanism of ovarian cancer carcinogenesis from fallopian tube epithelial cells

• Project/Area Number: 16K11155
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Keio University
• Principal Investigator: Akahane Tomoko 慶應義塾大学, 医学部(信濃町), 助教 (40398699)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 卵巣癌 / 卵管 / 卵管上皮 / TP53遺伝子

Outline of Final Research Achievements

Ovarian cancer has a poor prognosis. However, in cases where cancer does not progress outside the pelvis, the 5-year survival rate exceeds 90%. Thus, early detection is important for improving prognosis. Recent studies have suggested that ovarian cancer can also be caused by canceration from cells other than those of the ovaries. Therefore, it was thought that the early detection of ovarian cancer was in the early treatment of cells considered to be carcinogenic, leading to this study and achieving the following results.
1. TP53 mutation, the same as in ovarian cancer, was detected from a liquid cell sample collected. 2. In the process of establishing ovarian cancer cell lines, we succeeded in establishing cell lines from ascites collected from malignant peritoneal mesothelioma cases. The cell lines were found to be derived from a malignant peritoneal mesothelioma through the detailed analysis of protein expression, drug sensitivity testing, and next generation sequencing.

Academic Significance and Societal Importance of the Research Achievements

卵巣は腹腔内に存在し検診対象臓器ではないたことから癌の早期発見や対処が難しい。卵巣癌由来の細胞に起こった遺伝子レベルの変化を卵巣以外の部位から採取された液状細胞検体等の比較的簡便に採取可能な検体から検出できたことによる本研究内で得られた成果は、癌早期発見や再発予測を可能とする手技として有用であると考える。また、悪性腹膜中皮腫は腫瘍発症メカニズムや化学療法薬剤等の解明がいまだ課題である。しかしながら過去のアスベスト暴露歴との関連から、今後本邦では悪性中皮腫罹患例が増加傾向にあるとされ病態解明は急務である。樹立細胞は病態解明のための基礎的研究を実施するうえで貴重な生物資源となりうる可能性がある。

Research Products

• [Journal Article] GSTP1 rs1695 is associated with both hematological toxicity and prognosis of ovarian cancer treated with paclitaxel plus carboplatin combination chemotherapy: a comprehensive analysis using targeted resequencing of 100 pharmacogenes (2018)
  • Author(s): Yoshihama T, Fukunaga K, Hirasawa A, Nomura H, Akahane T, Kataoka F, Yamagami W, Aoki D, Mushiroda T
  • Journal Title: Oncotarget Volume: 9 Issue: 51 Pages: 29789-29800
  • DOI: 10.18632/oncotarget.25712
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prevalence of pathogenic germline variants detected by multigene sequencing in unselected Japanese patients with ovarian cancer (2017)
  • Author(s): Hirasawa Akira、Imoto Issei、Naruto Takuya、Akahane Tomoko、Yamagami Wataru、Nomura Hiroyuki、Masuda Kiyoshi、Susumu Nobuyuki、Tsuda Hitoshi、Aoki Daisuke
  • Journal Title: Oncotarget Volume: 8 Issue: 68 Pages: 112258-112267
  • DOI: 10.18632/oncotarget.22733
  • Peer Reviewed / Open Access
• [Journal Article] Clinical utility of a self-administered questionnaire for assessment of hereditary gynecologic cancer. (2017)
  • Author(s): Masuda K, Hirasawa A, Irie-Kunitomi H, Akahane T, Ueki A, Kobayashi Y, Yamagami W, Nomura H, Kataoka F, Tominaga E, Banno K, Susumu N, Aoki D.
  • Journal Title: Jpn J Clin Oncol. Volume: Mar 13:1. Issue: 5 Pages: 401-406
  • DOI: 10.1093/jjco/hyx037
  • Peer Reviewed / Open Access
• [Journal Article] UGT1A1 polymorphism as a prognostic indicator of stage I ovarian clear cell carcinoma patients treated with irinotecan. (2017)
  • Author(s): Yoshihama T, Hirasawa A, Nomura N, Akahane T, Nanki Y, Yamagami W, Kataoka F, Tominaga T, Susumu N, Mushiroda T, Aoki D.
  • Journal Title: Jpn J Clin Oncol Volume: 47(2) Issue: 2 Pages: 170-174
  • DOI: 10.1093/jjco/hyw163
  • Peer Reviewed / Open Access
• [Presentation] 乳癌既往歴があり耳下腺癌を発症したBRCA1 germline pathogenic variant保持者の１例 (2018)
  • Author(s): 赤羽智子、平沢 晃、片岡史夫、野村弘行、山下年成、羽田恵梨、亀山香織、小崎健次郎、青木大輔
  • Organizer: 第68回日本人類遺伝学会
• [Presentation] がん遺伝子パネル検査にてPMS2遺伝子に生殖細胞系列バリアントが検出された1例 (2018)
  • Author(s): 赤羽智子、平沢 晃、西原広史、植木有紗、谷嶋成樹、千代田達幸、岸郁子、青木大輔
  • Organizer: 第4回日本婦人科遺伝子診療学会
• [Presentation] 個別化医療を目指した腹水および組織由来 卵巣癌細胞の初代3次元(3D)細胞培養法の確立 (2018)
  • Author(s): 南木佳子、平沢晃、野村弘行、赤羽智子、早乙女啓子、同前愛、千代田達幸、 片岡史夫、冨永英一郎、青木大輔
  • Organizer: 第59回日本臨床細胞学会総会（春期大会）
• [Presentation] GSTP1 rs1695 is a predictive indicator of both hematological toxicity and prognosis of ovarian cancer treated with paclitaxel plus carboplatin (2018)
  • Author(s): Tomoko Yoshihama, Akira Hirasawa, Hiroyuki Nomura, Tomoko Akahane, Fumio Kataoka, Wataru Yamagami, Taisei Mushiroda, Mamoru Tanaka, Daisuke Aoki
  • Organizer: 第70回日本産科婦人科学会学術講演会
• [Presentation] BRCA1/2変異卵巣癌の血縁者における乳癌および卵巣癌の罹患に関する検討 (2017)
  • Author(s): 岩佐尚美,平沢 晃,野村弘行,赤羽智子,千代田達幸,山上 亘,片岡史夫,井本逸勢,青木大輔
  • Organizer: 第27回日本乳癌検診学会学術総会
• [Presentation] 腹水卵巣癌細胞のCD44各アイソフォーム発現量と化学療法の効果との関連性の検討 (2017)
  • Author(s): 蔦 幸児,冨永英一郎,戸澤晃子,赤羽智子,大原 樹,小林佑介,平沢 晃,阪埜浩司, 鈴木 直,青木大輔
  • Organizer: 第58回日本臨床細胞学会総会（春期大会）
• [Presentation] BBRCA1遺伝子病的変異陽性例であり耳下腺癌を発症した１症例 (2017)
  • Author(s): 赤羽智子, 平沢 晃, 増田健太, 野村弘行, 片岡史夫, 阪埜浩司, 進 伸幸, 亀山香織, 清水 哲, 青木大輔
  • Organizer: 第58回日本臨床細胞学会総会（春期大会）
• [Presentation] The contribution of germline pathogenic variants of cancer susceptibility genes for primary ovarian, fallopian tube, and peritoneal cancers in Japanese (2017)
  • Author(s): Hirasawa A,Issei I,Naruto T,Akahane T,Yamagami W,Nomura H,Masuda K,Susumu N,Tsuda H,Aoki D
  • Organizer: AACR 2017 Addressing Critical Questions in Ovarian Cancer Research and Treatment
  • Int'l Joint Research
• [Presentation] Ascites-derived and tissue-derived ovarian cancer cell primary 3D cultures aimed for personalized medicine (2017)
  • Author(s): Nanki Y,Hirasawa A,Nomura H,Okubo A,Itoh M,Akahane A,Chiyoda T,Kataoka F,Tominaga E,Aoki D
  • Organizer: AACR 2017 Addressing Critical Questions in Ovarian Cancer Research and Treatment
  • Int'l Joint Research
• [Presentation] UGT1A1 polymorphism may be a prognostic indicator of stage I ovarian clear cell carcinoma patients treated with irinotecan (2017)
  • Author(s): Yoshihama T,Hirasawa A,Nomura H,Akahane T,Nanki Y,Yamagami W,Kataoka F,Tominaga E,Susumu N,Mushiroda T,Aoki D
  • Organizer: 15th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology
  • Int'l Joint Research
• [Presentation] Polymorphisms of the genes ESR1, UGT2B17, and UGT1A1 associated with estrogen metabolism are not associated with osteoporosis in Japanese women after artificial menopause (2017)
  • Author(s): Yokota M,Hirasawa A,Kazuya K,Akahane T,Sakai K,Makabe T,Horiba Y,Yamagami W,Ogawa M,Iwata T,Yanamoto S,Deshimaru R,Banno K,Susumu N,Aoki D
  • Organizer: 6th Scientific Meeting of the Asia Pacific Menopause Federation
  • Int'l Joint Research
• [Presentation] The contribution of deleterious germ-line mutations of susceptibility genes to ovarian, fallopian tube, and peritoneal cancers in Japanese (2017)
  • Author(s): Hirasawa A,Imoto I,Naruto T,Akahane T,Yamagami W,Susumu N,Tsuda H,Aoki D
  • Organizer: AACR Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] 血縁腫瘍歴聴取票を用いた婦人科関連遺伝性腫瘍のスクリーニングに関する検討. (2016)
  • Author(s): 平野卓朗，平沢 晃，真壁 健, 坂井健良, 赤羽智子，増田健太，小林佑介, 山上 亘，野村弘行，片岡史夫，冨永英一郎, 阪埜浩司，進 伸幸，青木大輔.
  • Organizer: 第2回日本産科婦人科遺伝診療学会学術講演会
  • Place of Presentation: 京都府京都市メルパルク京都
  • Year and Date: 2016-12-16
• [Presentation] 腹水細胞中から樹立したヒト悪性腹膜中皮腫由来細胞株の特性に関する検討. (2016)
  • Author(s): 赤羽智子, 冨永英一郎, 平沢 晃, 青木大輔.
  • Organizer: 第55回日本臨床細胞学会秋期大会
  • Place of Presentation: 大分県別府市別府国際コンベンショナルセンター
  • Year and Date: 2016-11-18
• [Presentation] 自己記入式がん家族歴聴取票を使用した遺伝高リスク家系の抽出. (2016)
  • Author(s): 國富晴子, 増田健太, 平沢 晃, 赤羽智子, 小林佑介, 山上 亘, 野村弘行, 片岡史夫, 冨永英一郎, 阪埜浩司, 進 伸幸, 青木大輔.
  • Organizer: 第22回日本家族性腫瘍学会学術集会
  • Place of Presentation: 愛知県松山市ひめぎんホール
  • Year and Date: 2016-06-03
• [Presentation] TAS-117, a novel allosteric AKT inhibitor, shows potent antitumor activity on ovarian clear cell adenocarcinoma cells from fresh surgical samples in 3-dimentional culture. (2016)
  • Author(s): Tsuta K, Tominaga E, Tozawa A, Akahane T, Uekawa A, Ohara T, Nomura H, Kataoka F, Hirasawa A, Bonno K, Suzuki N, Aoki D.
  • Organizer: 第68回日本産科婦人科学会学術講演会
  • Place of Presentation: 東京都 東京国際フォーラム
  • Year and Date: 2016-04-22