Analysis of HPV genome variations using next generation sequencer: in association with cervical carcinogenesis

• Project/Area Number: 15K10701
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Showa University (2016-2018); University of Tsukuba (2015)
• Principal Investigator: ONUKI MAMIKO 昭和大学, 医学部, 講師 (20573744)
• Co-Investigator(Kenkyū-buntansha): 柊元 巌 国立感染症研究所, 病原体ゲノム解析研究センター, 室長 (70291127)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ヒトパピローマウイルス / 子宮頸癌 / 子宮頸部上皮内病変 / 全ゲノム解析 / 全ゲノム増幅 / 準種解析 / HPV全ゲノム増幅

Outline of Final Research Achievements

There are concomitant genetic changes in the HPV genome during viral infection, so-called "variant" or "quasispecies". Among the HPV52/58-positive specimens from Japanese women with CIN/ICC, the variant distributions were strongly biased toward lineage B for HPV52 and lineage A for HPV58 across histological categories. Among women with HPV16 positive lesion, sublineage A4 are dominant in cervical cancer patients. The relative risk of sublineage A4 for cervical cancer development was significantly higher compared to sublineages A1/A2/A3. We also found new sublineage, A5. Among the within-host variations, C-to-T transitions, a characteristic change mediated by cellular APOBEC cytosine deaminases, were predominantly detected throughout the whole viral genome, most strikingly in low-grade CIN lesions.

Academic Significance and Societal Importance of the Research Achievements

持続感染してゆくためにウイルス遺伝子は変異しバリアントや準種が存在すると考えられている。本研究では日本人女性の子宮頸癌やその前癌病変で多くみられるHPV16,52,58型を対象に、そのバリアントや準種を解析・分類した。ウイルス遺伝子の配列には様々な臓器で発がんと関連するアポベック蛋白とも関係するものが多く含まれていることがわかった。さらにHPV 16陽性に限定し病変別に比較すると子宮頸癌に多く含まれる特定のバリアントが存在した。これらは今後感染したHPV遺伝子を調べることで子宮頸癌や前癌病変になる可能性が予測できたり、このバリアントに対する予防・治療を考える材料になり得る。

Research Products

• [Journal Article] Whole-Genome Analysis of Human Papillomavirus Type 16 Prevalent in Japanese Women with or without Cervical Lesions. (2019)
  • Author(s): Hirose Y, Onuki M, Tenjimbayashi Y, Yamaguchi-Naka M, Mori S, Tasaka N, Satoh T, Morisada T, Iwata T, Kiyono T, Mimura T, Sekizawa A, Matsumoto K, Kukimoto I.
  • Journal Title: Viruses Volume: 11 Issue: 4 Pages: 350-350
  • DOI: 10.3390/v11040350
  • NAID: 120007133500
  • Peer Reviewed / Open Access
• [Journal Article] Human papillomavirus genotype and prognosis of cervical cancer: Favorable survival of patients with HPV16-positive tumors (2018)
  • Author(s): Onuki Mamiko、Matsumoto Koji、Tenjimbayashi Yuri、Tasaka Nobutaka、Akiyama Azusa、Sakurai Manabu、Minaguchi Takeo、Oki Akinori、Satoh Toyomi、Yoshikawa Hiroyuki
  • Journal Title: Papillomavirus Research Volume: 6 Pages: 41-45
  • DOI: 10.1016/j.pvr.2018.10.005
  • NAID: 120007128286
  • Peer Reviewed / Open Access
• [Journal Article] Within-Host Variations of Human Papillomavirus Reveal APOBEC-Signature Mutagenesis in the Viral Genome (2018)
  • Author(s): Hirose Yusuke、Onuki Mamiko、Tenjimbayashi Yuri、Mori Seiichiro、Ishii Yoshiyuki、Takeuchi Takamasa、Tasaka Nobutaka、Satoh Toyomi、Morisada Tohru、Iwata Takashi、Miyamoto Shingo、Matsumoto Koji、Sekizawa Akihiko、Kukimoto Iwao
  • Journal Title: Journal of Virology Volume: 印刷中 Issue: 12
  • DOI: 10.1128/jvi.00017-18
  • Peer Reviewed / Open Access
• [Journal Article] 子宮頸がんとHPVゲノム変異 (2018)
  • Author(s): 小貫麻美子、松本光司
  • Journal Title: 臨床婦人科産科 Volume: 72(3) Pages: 387-393
  • NAID: 40021520260
• [Journal Article] Whole-genome analysis of human papillomavirus genotypes 52 and 58 isolated from Japanese women with cervical intraepithelial neoplasia and invasive cervical cancer (2017)
  • Author(s): Tenjimbayashi Yuri、Onuki Mamiko、Hirose Yusuke、Mori Seiichiro、Ishii Yoshiyuki、Takeuchi Takamasa、Tasaka Nobutaka、Satoh Toyomi、Morisada Tohru、Iwata Takashi、Miyamoto Shingo、Matsumoto Koji、Sekizawa Akihiko、Kukimoto Iwao
  • Journal Title: Infectious Agents and Cancer Volume: 12 Issue: 1 Pages: 44-44
  • DOI: 10.1186/s13027-017-0155-4
  • NAID: 120007128848
  • Peer Reviewed / Open Access
• [Journal Article] Posttreatment human papillomavirus testing for residual or recurrent high-grade cervical intra-epithelial neoplasia: a pooled analysis (2016)
  • Author(s): Onuki M, Matsumoto K, Sakurai M, Ochi H, Minaguchi T, Satoh T, Yoshikawa H.
  • Journal Title: Journal of Gynecologic Oncology Volume: 27 Issue: 1
  • DOI: 10.3802/jgo.2016.27.e3
  • NAID: 120007135489
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Human papillomavirus genotype and prognosis of cervical cancer: favorable survival of patients with HPV16-positive tumors (2018)
  • Author(s): M. Onuki, K. Matsumoto, Y. Tenjimbayashi, N. Tasaka, T. Satoh, H. Yoshikawa
  • Organizer: 32ND international papillomavirus conference
  • Int'l Joint Research
• [Presentation] APOBEC signature mutagenesis in HPV16/52/58 genomes and its relevance to cervical carcinogenesis (2018)
  • Author(s): Y.HIrose, Y. Tejimbayashi, M. Onuki, T. Iwata, K. Matsumoto, I. Kukimoto
  • Organizer: 32ND international papillomavirus conference
  • Int'l Joint Research
• [Presentation] Whole-genome analysis of HPV52/58 isolated from Japanese women with cervical intraepithelial neoplasia and invasive cervical cancer (2018)
  • Author(s): Y. Tejimbayashi, Y. HIrose, M. Onuki, T. Iwata, K. Matsumoto, I. Kukimoto
  • Organizer: 32ND international papillomavirus conference
  • Int'l Joint Research
• [Presentation] Post-treatment human papillomavirus testing for residual or recurrent high-grade cervical neoplasia: a pooled analysis (2018)
  • Author(s): Onuki M, Matsumoto K
  • Organizer: 第70回日本産科婦人科学会学術講演会
• [Presentation] Analysis of biological differences of human papillomavirus 58 E7 variants (2018)
  • Author(s): 天神林友梨、廣瀬佑輔、小貫麻美子、松本光司、柊元巌
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] APOBEC signature mutagenesis in the genome of human papillomavirus and its relevance to cervical carcinogenesis (2018)
  • Author(s): 廣瀬佑輔、天神林友梨、小貫麻美子、岩田 卓、松本光司、柊元巌
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 日本人女性から検出されるHPV52/58の全ゲノム解析 (2017)
  • Author(s): 天神林 友梨, 廣瀬 佑輔, 小貫 麻美子, 中尾 砂理, 岩田 卓, 松本 光司, 柊元 巌
  • Organizer: 第76回日本癌学会
• [Presentation] 次世代シークエンサーによるヒトパピローマウイルスゲノムの患者内多様性の解析 (2017)
  • Author(s): 廣瀬 佑輔,天神林 友梨,小貫 麻美子,水口剛雄, 岩田 卓, 松本 光司, 柊元 巌
  • Organizer: 第76回日本癌学会
• [Presentation] HPV16 positivity is a possible prognostic factor for favorable survival in advanced cervical cancer. (2016)
  • Author(s): Mamiko Onuki, Koji Matsumoto, Yuri Tenjimbayashi, Sari Nakao, Manabu Sakurai, Hiroyuki Ochi, Takeo Minaguchi, Katsumi Someya, Hiroyuki Yoshikawa, Toyomi Satoh
  • Organizer: The 16th Biennial Meeting of the International Gynecologic Cancer Society (IGCS 2016)
  • Place of Presentation: Lisbon, Portugal
  • Year and Date: 2016-10-29
  • Int'l Joint Research