molecular and epidemiological analysis for new carcinogenesis mechanism in hereditary gynecological cancer

• Project/Area Number: 18K16812
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Keio University
• Principal Investigator: Tsuji Kosuke 慶應義塾大学, 医学部(信濃町), 助教 (70528166)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: リンチ症候群 / 卵巣癌 / 子宮体癌 / 重複癌 / マイクロサテライト不安定性 / 高腫瘍変異量 / 子宮内膜癌 / Lynch症候群 / 腫瘍遺伝子変異量 / 腫瘍ゲノム / 遺伝性婦人科腫瘍 / ミスマッチ修復

Outline of Final Research Achievements

The characteristic feature of Lynch syndrome, one of a hereditary gynecological tumors, is microsatellite instability (MSI), which has been attracting attention as a companion diagnostics for immune checkpoint inhibitors. We proved the usefulness of the SGO criteria as a diagnostic tool for Lynch syndrome in ovarian cancer. In addition, Lynch syndrome is common in 7/33 (21.2%) cases of double cancer of ovarian and endometrial cancer. In addition, genomic analysis of these tumors revealed tumor mutation burden-high (> 10 mutations/ Mb) in both endometrial cancer and ovarian cancer. Further analysis of these mutated genes is expected to reveal the carcinogenic mechanism of each primary cancer. In addition, MSI analysis of advanced or recurrent gynecological cancers showed that MSI-high was not observed in cervical cancer.

Academic Significance and Societal Importance of the Research Achievements

近年の研究によって、遺伝性腫瘍は比較的一般的な頻度で認められることが分かってきており、本研究によって、遺伝性腫瘍であるリンチ症候群が、卵巣癌、特に卵巣癌子宮体癌の重複例において高率に認められることが分かり、婦人科癌診療における遺伝的関与の可能性に注意すべきであることを示している。また、治療選択におけるMSI検査においても、子宮体癌、卵巣癌において陽性結果が多く、若年者にも多い子宮頸癌における遺伝性の関与が少ないことが示され、社会的にインパクトがあると考える。

Research Products

• [Journal Article] Upregulation of IGF2R evades lysosomal dysfunction-induced apoptosis of cervical cancer cells via transport of cathepsins (2019)
  • Author(s): Takeda Takashi, Komatsu Masayuki, Chiwaki Fumiko, Komatsuzaki Rie, Nakamura Kanako, Tsuji Kosuke, Kobayashi Yusuke, Tominaga Eiichiro, Ono Masaya, Banno Kouji, Aoki Daisuke, Sasaki Hiroki.
  • Journal Title: Cell Death & Disease Volume: 10(876) Issue: 12 Pages: 1-17
  • DOI: 10.1038/s41419-019-2117-9
  • Peer Reviewed / Open Access
• [Journal Article] Primary malignant melanoma of the uterine cervix or vagina which were successfully treated with nivolumab (2019)
  • Author(s): Anko Mayuka、Nakamura Masaru、Kobayashi Yusuke、Tsuji Kosuke、Nakada Sakura、Nakamura Yoshio、Funakoshi Takeru、Banno Kouji、Aoki Daisuke
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 46 Issue: 1 Pages: 190-195
  • DOI: 10.1111/jog.14136
  • Peer Reviewed
• [Journal Article] Synchronous endometrial and ovarian cancer in Lynch syndrome with a MSH2 germline mutation: A case report. (2018)
  • Author(s): Takeda T, Banno K, Yanokura M, Anko M, Kobayashi A, Sera A, Takahashi T, Adachi M, Kobayashi Y, Hayashi S, Nomura H, Hirasawa A, Tominaga E, Aoki D.
  • Journal Title: Mol Clin Oncol Volume: Nov;9(5) Pages: 479-484
  • DOI: 10.3892/mco.2018.1723
  • Peer Reviewed / Open Access
• [Presentation] 当院における子宮癌肉腫症例の術前子宮内膜細胞診に関する臨床的検討 (2019)
  • Author(s): 永井晋平, 辻 浩介, 安康真由香, 高橋孝幸, 小林佑介, 山上 亘, 岩田 卓, 冨永英一郎, 阪埜浩司, 青木大輔
  • Organizer: 第60回 日本臨床細胞学会総会(春期大会）
• [Presentation] ヒト子宮頸癌細胞に対する量子線治療による免疫調節因子の発現変化 (2019)
  • Author(s): 飯島茂異人, 阪埜浩司, 辻 浩介, 小林佑介, 冨永英一郎, 長谷川純崇, 青木大輔
  • Organizer: 第37回 日本ヒト細胞学会学術集会
• [Presentation] Postirradiation PD-L1 expression and low tumor-infiltrating CD8+ cytotoxic lymphocytes are predictors of an improved prognosis after carbon ion radiotherapy for uterine cervical adenocarcinoma (2019)
  • Author(s): Iijima M, Okonogi N, Banno K, Tsuji K, Kobayashi Y, Tominaga E, Hasegawa S, Aoki D
  • Organizer: Royal College of Obstetricians & Gynaecologists (RCOG) World Congress 2019
• [Presentation] Insulin like growth factor 2 receptor act as a prognostic biomarker and behaves as an oncogene escaping from lysosomal dysfunction-induced apoptosis in cervical cancer (2019)
  • Author(s): Takeda T, Komatsu M, Banno K, Tsuji K, Kobayashi Y, Tominaga E, Sasaki H, Tanaka M, Aoki D
  • Organizer: Royal College of Obstetricians & Gynaecologists (RCOG) World Congress 2019
• [Presentation] Targeting casein kinase 2 disrupts intracellular trafficking of IGF2R and lysosomal homeostasis and induced cell death in cervical cancer (2019)
  • Author(s): Takeda T, Komatsu M, Chiwaki F, Sera A, Tsuji K, Kobayashi Y, Tominaga E, Banno K, Sasaki H, Aoki D
  • Organizer: The 6th Biennial Meeting of Asian Society of Gynecologic Oncology (ASGO 2019)
• [Presentation] Post-irradiation PD-L1 expression predicts better prognosis after carbon ion radiotherapy in uterine cervical adenocarcinoma (2019)
  • Author(s): Iijima M, Okonogi N, Banno K, Tsuji K, Kobayashi Y, Tominaga E, Hasegawa S, Aoki D
  • Organizer: The 6th Biennial Meeting of Asian Society of Gynecologic Oncology (ASGO 2019)
• [Presentation] 卵巣癌における家族歴を用いたLynch症候群の拾い上げおよび臨床病理学的検討 (2018)
  • Author(s): 竹田 貴
  • Organizer: 第24回 日本家族性腫瘍学会 学術講演会