Identification and clinical Application of the Genes Associated with Carc nogenesis of the Uterine Cervix

• Project/Area Number: 14571561
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Osaka University
• Principal Investigator: ENOMOTO Takayuki Osaka University, Graduate School of Medicine, Lecturer, 医学系研究科, 講師 (90283754)
• Co-Investigator(Kenkyū-buntansha): UEDA Yutaka Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (10346215) ; NAKASHIMA Ryuichi Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70335347)
• Project Period (FY): 2002 – 2003
• Project Status: Completed (Fiscal Year 2003)
• Budget Amount: ¥3,400,000 (Direct Cost: ¥3,400,000); Fiscal Year 2003: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 2002: ¥2,300,000 (Direct Cost: ¥2,300,000)
• Keywords: TSC4O3 / IGFBP-5 / Clonality / HighRisk Type HPV / LKB1 / 子宮頸部悪性腺腫 / Peutz-Jeghers Syndrome / STK11(LKB1) / クロナリティー解析 / 遺伝子診断

Research Abstract

(1)Identification of the genes associated with carcinogenesis of the uterine cervix
We showed overexpression of the TSC403 gene was a late event in cervical carcinogenesis, and that TSC403 was associated with invasion and metastasis of cervical carcinoma. Cervical carcinomas with overexpression of TSC403 were demonstrated to have significantly poorer prognosis than those without overexpression (p<0.05).
We also identified 20 genes and ESTs specifically upregtdated or down-regulated in cervical carcinoma compared with normal cervical tissue by gene expression profiling study using DNA microarray. As one of the 20 gene and ESTs, IGFBP-5 was demonstrated to be expressed in the keratinizing layer of normal cervical squamous epithelium specifically and to be suppressed in cervical carcinoma, implying that IGFBP-5 is associated with proliferation or differentiation in cervical carcinogenesis.
We showed that monoclonal or highrisk type HPV-infected GINs were more likely to progress or persist th an polyclonal or high-risk type HPV-negative ones (p=0.009 for monoclonal vs. polyclonal, p=O.O24 for high-risk type HPV positive vs. negative). Moreover, the combination of clonal status and high-risk type HPV infection were demonstrated to be significantly correlated with clinical outcome (p=0.003). These facts show clonal status and high-risk type HPV infection are useful biomarkers predicting the outcome of CIN.
(3)Identification of the genes characterizing Minimal Deviation Adenocarcinoma (MDA) of the cervix
LKB1 has been identified as the tumor suppressor gene responsible for Peutz-Jeghars Syndrome (PJS). We showed somatic mutations of the LKB1 gene occurred in 6 (55%) of 11 MDAs and that MDAs with LKB1 mutations had significantly poor prognosis than without the mutaions (p<0.05). We also demonstrated Pylolic gland metaplasia of the uterine cervical glands, resembling MDAs in histopathology, were able to be ruled out in the points that the composition of the lesions were polyclonal and had no mutations of LKB1.

Research Products

• [Publications] 榎本隆之, 中嶌竜一, 上田 豊, 他: "Mutations in the STK11 gene characterize minimal deviation adenocarcinoma of the uterine cervix"Laboratory Investigation. 83(1). 35-45 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] 上田 豊, 榎本隆之, 中嶌竜一, 他: "Monoclonal expansion with integration of high-risk type human papillomaviruses is an initial step for cervical carcinogenesis: association of clonal status and human papillomavirus infection with clinical outcome in Cervical Intraepithelial Neoplasia"Laboratory Investigation. 83(10). 1517-1527 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kuragaki, C., Enomoto, T., Ueno, Y, Sun, H.Fujita, M., Nakashima, R., Ueda, Y., Wada, H., Murata, Y., Toki, T., Konishi, I., Fujii, S.: "Mutations in the STK11 gene characterize minimal deviation adenocarcinoma of the uterine cervix"Laboratory Investigation. 83(1). 35-45 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Ueda, Y., Enomoto, T., Miyatake, T., Ozaki, K., Yoshizaki, T., Kanao, H., Ueno, Y, Nakashima, R., Shroyer, K.R., Murata, Y.: "Monoclonal expansion with integration of high-risk type human papillomaviruses is an initial step for cervical carcinogenesis: association of clonal status and human papillomavirus infection with clinical outcome cervical"Laboratory Investigation. 83(10). 1517-1527 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 榎本隆之, 中嶌竜一, 上田 豊 他: "Mutations in the STK11 gene characterize minimal deviation adenocarcinoma of the uterine cervix"Laboratory Investigation. 83(1). 35-45 (2003)
• [Publications] 上田 豊, 榎本隆之, 中嶌竜一 他: "Monoclonal expansion with integration of high-risk type human papillomaviruses is an initial step for cervical carcinogenesis : association of clonal status and human papillomavirus infection with clinical outcome in cervical intraepithelial neoplasia"Laboratory Investigation. 83(10). 1517-1527 (2003)