Functional analysis of HPV E7 gene mutations and CIN3 progression using cohort samples

• Project/Area Number: 19K07636
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Mori-Uchino Mayuyo 東京大学, 医学部附属病院, 講師 (30570452)
• Co-Investigator(Kenkyū-buntansha): 田口 歩 東京大学, 医学部附属病院, 助教 (60756782)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: HPVタイプ / CIN / 子宮頸がん / Human papillomavirus / 子宮頸部異形成 / HPV / コホート研究 / Human Papillomavirus / L1 / バイオマーカー

Outline of Research at the Start

子宮頸癌やその前がん病変である子宮頸部異形成(CIN)はHPV感染に起因し、その進展・退縮バイオ マーカーとしてはHPVジェノタイプが信頼性が高く注目されているが、正確に予測することは困難である。CINの予後を予測できるバイオ マーカーの探索は喫緊の課題である。この中でHPV由来癌遺伝子であるE7領域の変異導入が CIN進展と関連する可能性のあるマーカーとして着目されている。本研究では、1. 日本にお けるコホート検体を用いて、HPV E7遺伝子変異とCIN3以上への進展との関連を検証し、2. E7遺伝子変異検出の簡易化を行い、3. HPV E7変異導入のCIN3進展における機能解析を行う。

Outline of Final Research Achievements

In the "Study of HPV expression profile using CIN cohort samples," we examined the expression of HPV-derived E6/E6*, E1^E4, and L1 in HPV types 16, 18, 52, and 58 and found that HPV type 18 positive cases showed loss of L1 expression, while HPV type 52 positive cases showed L1 expression even in CIN3 In contrast, in HPV52-positive cases, L1 expression was observed even in CIN3. In "Prediction of CIN Prognosis Using the Markov Model," we analyzed the Markov model, a statistical model that can reflect the natural history of CIN with repeated progression and regression, and found that HPV type 16 shows rapid development of cervical dysplasia in a stepwise manner, while HPV types 52 and 58 are associated with persistent infection and mild to moderate dysplasia. HPV types 52 and 58 are characterized by persistent infection and mild to moderate dysplasia.

Academic Significance and Societal Importance of the Research Achievements

子宮頸部異形成（CIN）の適切な管理のためには、CINの進展退縮を予測することが必要である。CINの予後は感染HPVタイプにより異なる。HPVタイプ毎の特徴を理解することがCINの進展や退縮を予測するには不可欠である。本研究の結果により、HPVタイプ毎の特徴を見出したことにより、HPVタイプ毎の治療方針に反映させることが可能となる。これにより子宮頸部円錐切除術といった侵襲的な治療を回避することや、待機することが可能となり、患者の負担軽減に繋がり、非常に社会的意義が高いと考えられる。

Research Products

• [Journal Article] History of whole pelvis plus para-aortic radiation is a risk factor associated with febrile neutropenia during chemotherapy for recurrent cervical cancer (2021)
  • Author(s): Nara Katsuhiko、Taguchi Ayumi、Tojima Yuri、Miyamoto Yuichiro、Tanikawa Michihiro、Sone Kenbun、Mori Mayuyo、Tsuruga Tetsushi、Yamamoto Takehito、Takenaka Ryosuke、Takada Tappei、Osuga Yutaka、Suzuki Hiroshi
  • Journal Title: International Journal of Clinical Oncology Volume: 26 Issue: 9 Pages: 1759-1766
  • DOI: 10.1007/s10147-021-01950-8
  • Peer Reviewed / Open Access
• [Journal Article] A low preoperative albumin-to-globulin ratio is a negative prognostic factor in patients with surgically treated cervical cancer (2021)
  • Author(s): Kawata Akira、Taguchi Ayumi、Baba Satoshi、Miyamoto Yuichiro、Tanikawa Michihiro、Sone Kenbun、Tsuruga Tetsushi、Mori Mayuyo、Oda Katsutoshi、Kawana Kei、Osuga Yutaka、Fujii Tomoyuki
  • Journal Title: International Journal of Clinical Oncology Volume: 26 Issue: 5 Pages: 980-985
  • DOI: 10.1007/s10147-021-01861-8
  • Peer Reviewed / Open Access
• [Journal Article] Establishment and Molecular Phenotyping of Organoids from the Squamocolumnar Junction Region of the Uterine Cervix (2020)
  • Author(s): Maru Y, Kawata A, Taguchi A, Ishii Y, Baba S, Mori M, Nagamatsu T, Oda K, Kukimoto I, Osuga Y, Fujii T, Hippo Y.
  • Journal Title: Cancers (Basel) Volume: 12 Issue: 3 Pages: 694-694
  • DOI: 10.3390/cancers12030694
  • Peer Reviewed / Open Access
• [Journal Article] Differential expression of human papillomavirus 16-, 18-, 52-, and 58-derived transcripts in cervical intraepithelial neoplasia (2020)
  • Author(s): Baba S, Taguchi A, Kawata A, Hara K, Eguchi S, Mori M, Adachi K, Mori S, Iwata T, Mitsuhashi A, Maeda D, Komatsu A, Nagamatsu T, Oda K, Kukimoto I, Osuga Y, Fujii T, Kawana K.
  • Journal Title: Virol J Volume: 17 Issue: 1 Pages: 32-32
  • DOI: 10.1186/s12985-020-01306-0
  • NAID: 120007089054
  • Peer Reviewed / Open Access
• [Journal Article] Multistate Markov Model to Predict the Prognosis of High-Risk Human Papillomavirus-Related Cervical Lesions. (2020)
  • Author(s): Taguchi A, Hara K, Tomio J, Kawana K, Tanaka T, Baba S, Kawata A, Eguchi S, Tsuruga T, Mori M, Adachi K, Nagamatsu T, Oda K, Yasugi T, Osuga Y, Fujii T.
  • Journal Title: Cancers (Basel). Volume: 12 Issue: 2 Pages: 1-15
  • DOI: 10.3390/cancers12020270
  • Peer Reviewed / Open Access