HPV感染と子宮頚部発がんに関するコホート研究

• Project/Area Number: 12218102
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: University of Tsukuba
• Principal Investigator: 吉川 裕之 筑波大学, 大学院・人間総合科学研究科, 教授 (40158415)
• Co-Investigator(Kenkyū-buntansha): 岩坂 剛 佐賀大学, 医学部, 教授 (60117067) ; 八重樫 伸生 東北大学, 大学院・医学系研究科, 教授 (00241597) ; 関谷 宗英 千葉大学, 医学部, 教授 (00092065) ; 藤井 多久磨 慶應義塾大学, 医学部, 助手 (10218969) ; 金澤 浩二 琉球大学, 医学部, 教授 (50092680) ; 神田 忠仁 国立感染症研究所, 遺伝子解析室, 室長 (60134615) ; 星合 昊 近畿大学, 医学部, 教授 (50111290) ; 平井 康夫 癌研究会附属病院, 副部長 (00260076) ; 永田 知里 岐阜大学, 医学部, 助教授 (30283295)
• Project Period (FY): 2000 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥119,800,000 (Direct Cost: ¥119,800,000); Fiscal Year 2004: ¥23,800,000 (Direct Cost: ¥23,800,000); Fiscal Year 2003: ¥24,000,000 (Direct Cost: ¥24,000,000); Fiscal Year 2002: ¥25,000,000 (Direct Cost: ¥25,000,000); Fiscal Year 2001: ¥24,000,000 (Direct Cost: ¥24,000,000); Fiscal Year 2000: ¥23,000,000 (Direct Cost: ¥23,000,000)
• Keywords: 子宮頸がん / CIN / HPV / コホート研究 / HLA / クラミジア抗体 / CMV抗体 / パートナー数 / 中央病理診断 / HPV抗体 / VLP抗体 / E6 / 子宮頸癌 / ワクチン / 子宮頚癌 / L2

Research Abstract

CINの癌への進展に関与する因子を解明するため、CINI/II症例のコホート研究を行っている。CIN IIIへの進展例が急増しており、平成16年度中の解析が期待できる。登録数は900例に達し、平成16年6月30日に登録を終了した。今回、厳しく適格規準を設定し、509例において中間解析を行った。
進展しやすい因子は、単変量解析では、年齢(30歳代),CIN grade(I), HLA DR1302,sexual partners(多)、HPV16/18/33/52/58感染が有意な因子として抽出された。有意にならなかったがその傾向のあるものとしてCMV IgG陽性,Chlamydia IgG陽性があった。観察を続けることで有意になる可能性がある。HPVはHPV16/18/33/52/58では有意に進展に関連があった。多変量解析ではCIN grade(p<0.05), sexual partners(p<0.05), DR1302(p<0.05), HPV16/18/33/52/58(p<0.05)だけが有意な因子として残った。DR1302が進展に対してprotectiveに働くことをコホート研究で立証したのは、本研究が初めてである。
消退しにくい(継続しやすい)因子は、単変量解析では、年齢(>30歳),CIN grade(I),HPV16/18/33/52/58,CMV IgG(陽性),Chlamydia IgG(陽性),smoking(喫煙),marital status(既婚),sexual partner number(>4)が有意なものとして抽出され、多変量解析では年齢(p<0.01)、HPV16/18/33/52/58(p<0.01)、sexual partners(p<0.01)、CIN grade(p=0.06marginal)が残った。

Research Products

• [Journal Article] Association of PTEN mutation with HPV-negative adenocarcinoma of the uterine cervix. (2004)
  • Author(s): Minaguchi T, Yoshikawa H, et al.
  • Journal Title: Cancer Lett. 210(1) Pages: 57-62
• [Journal Article] Dominant human papillomavirus 16 infection in cervical neoplasia in young Japanese women ; study of 881 outpatients. (2004)
  • Author(s): Masumoto N, Fujii T, et al.
  • Journal Title: Gynecol Oncol. 94(2) Pages: 509-514
• [Journal Article] A large case-control study of cervical cancer risk associated with human papillomavirus infection in Japan, by nucleotide sequencing-based genotyping. (2004)
  • Author(s): Asato T, Kanazawa K, et al.
  • Journal Title: J Infect Dis. 189(10) Pages: 1829-1832
• [Journal Article] Putative gene loci associated with carcinogenesis and metastasis of endocervical adenocarcinomas of uterus determined by conventional and array-based CGH. (2004)
  • Author(s): Hirai Y, et al.
  • Journal Title: Am J Obstet Gynecol. 191(4) Pages: 1173-1182
• [Journal Article] Keratinocyte-specific POU transcription factor hSkn-1a represses the growth of cervical cancer cell lines. (2004)
  • Author(s): Enomoto Y, Kanda T, et al.
  • Journal Title: Oncogene. 23(29) Pages: 5014-5022
• [Journal Article] IgG antibodies to HPV16,52,58 and 6 L1-capsids and spontaneous regression of cervical intraepithelial neoplasia.
  • Author(s): Matsumoto K, Yoshikawa H, et al.
  • Journal Title: Cancer Lett. (In press)
• [Publications] Matsumoto K, Yoshikawa H.: "IgG antibodies to human papillomavirus 16, 52, 58, and 6 L1 capsids : Case-control study of cervical intraepithelial neoplasia In Japan"J Med Virol. 69(3). 441-446 (2003)
• [Publications] Yokoyama M, Yoshikawa H: "Prognostic factors associated with the clinical outcome of cervical intraepithelial neoplasia : a cohort study in Japan"Cancer Lett.. 192(2). 171-179 (2003)
• [Publications] Furuta R, Yoshikawa H.: "Ectopic chromosome around centrosome in metaphase cells as a marker of high-risk human papillomavirus-associated cervical intraepithelial neoplasias"Int J Cancer. 106(2). 167-171 (2003)
• [Publications] Matsumoto K, Yoshikawa H.: "Human papillomavirus type 16 E6 variants and HLA class II alleles among Japanese women with cervical cancer"Int J Cancer. 106(2). 919-922 (2003)
• [Publications] Matsumoto K, Yoshikawa H.: "Are smoking and chlamydial infection risk factors for CIN? : Different results after adjustment for HPV DNA and antibodies"Br J Cancer. 89(5). 831-833 (2003)
• [Publications] Kawana K, Yoshikawa H.: "Safety and immunogenicity of a peptide containing the cross-neutralization epitope of HPV16L2 administered nasally in healthy volunteers"Vaccine. 21(27-30). 4256-4260 (2003)
• [Publications] Kawana K.: "Neutralizing antibodies against oncogenic human papillomavirus as a possible determinant of the fate of low-grade cervical intraepithelial neoplasia"BBRC. 296・1. 102-105 (2002)
• [Publications] Horie K.: "SUMO-1 conjugation to intact DNA topoisomerase I amplifies cleavable complex formation induced by camptothecin"Oncogene. 21・52. 7913-7922 (2002)
• [Publications] Hasumi Y.: "Soluble FLT-1 expression suppresses carcinomatous ascites in nude mice bearing ovarian cancer"Cancer Res.. 62・7. 2019-2023 (2002)
• [Publications] Matsumoto K.: "IgG antibodies to human papillomavirus 16,52,58,and 6 L1 capsids : Case-control study of cervical intraepithelial neoplasia in Japan"J Med Virol.. 69・3. 441-446 (2003)
• [Publications] Ohara K.: "Nonoperative assessment of nodal status for locally advanced cervical squamous cell carcinoma treated by radiotherapy with regard to patterns of treatment failure"Int J Radiat Oncol Biol Phys.. 55・2. 354-361 (2003)
• [Publications] Yokoyama M.: "Prognostic factors associated with the clinical outcome of cervical intraepithelial neolasia : a cohort study in Japan"Cancer Lett.. (in press).
• [Publications] Kawana K.: "Nasal immunization of mice with peptide having a cross-neutralization epitope on minor capsid protein L2 of human papillomavirus type 16 elicit systemic and mucosal antibodies."Vaccine. 19・11-12. 1496-1502 (2001)
• [Publications] Kawana K.: "Human papillomavirus type 16 minor capsid protein L2 N-terminal region containing a common neutralization epitope binds to cell surface and enters the cytoplasm"J.Virology. 75・5. 2331-2336 (2001)
• [Publications] Watanabe M.: "A subtamily of RHA-binding DEAD-box proteins acts as an estrogen receptor alpha coactivator through the N-terminal activation domain (AF-1) with an RNA coactivator, SRA"EMBO J.. 20・6. 1341-1352 (2001)
• [Publications] Xin CY.: "Analysis of E6 variants of human papillomavirus type 33,52 and 58 in Japanese women with cervical intraepithelial neoplasia/cervical cancer in relation to their oncogenic potential"Cancer Lett.. 170. 19-24 (2001)
• [Publications] Minaguchi T.: "PTEN mutation located only outside exons 5,6 and 7 is an idependent predictor of favorable survival in endometrial carcinomas"Clin.Cancer Res.. 7. 2636-2642 (2001)
• [Publications] Kukimoto I.: "Displacement of YY1 by Differentiation Specific Transcription Factor hSkn-la Activates P670 Promoter of Human Papillomavirus Type 16"J.Virol.. 75. 9302-9311 (2001)
• [Publications] Nakagawa S,Yoshikawa H: "Ubiquitous presence of E6 and E7 transcripts in human papillomavirus-positive cervical carcinomas regardless of its type."J Med Virol.. 62. 251-258 (2000)
• [Publications] Ishiwata I,YoshikawaH: "Human papillomavirus types 56 and 59 in novel cervical cancer cell lines."Hum Cell. 13. 55-56 (2000)
• [Publications] Matsumoto K,YoshikawaH: "Enhanced oncogenicitv of human papillomavirus type 16 (HPV16) variants in Japanese population."Cancer Lett.. 156. 159-165 (2000)
• [Publications] Kawana Y,Yoshikawa,H: "Human papillomavirus 16 minor capsid protein L2 N-terminal region containing a common neutralizing epitope binds to the cell surface and enters the cytoplasm."J Virology. (in press).
• [Publications] Kawana K,Yoshikawa H: "Nasal immunization of mice with peptide having a cross-neutralization epitope on minor capsid protein L2 of human papillomavirus type 16 elicit systemic and mucosal antibodies. "Vaccine. 19. 1496-1502 (2000)