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

宫颈癌发生相关基因的鉴定及临床应用

• 批准号: 14571561
• 负责人: ENOMOTO Takayuki
• 金额: $ 2.18万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571561/
• 关键词: 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

(1)Identification of the genes associated with carcinogenesis of the uterine cervixWe 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 … More 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 cervixLKB1 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. Less

（1）宫颈癌发生相关基因的鉴定结果表明，TSC 403基因的过表达是宫颈癌发生的晚期事件，与宫颈癌的浸润和转移有关。应用基因表达谱芯片技术，我们还发现了20个基因和EST在宫颈癌组织中的表达与正常宫颈组织相比发生了特异性的上调或下调。IGFBP-5作为20个基因和EST之一，在正常宫颈鳞状上皮的角化层特异表达，在宫颈癌中表达被抑制，提示IGFBP-5与宫颈癌的增殖或分化有关。我们发现，单克隆或高危型HPV感染的GIN更容易进展或持续，IGFBP-5在宫颈癌中的表达与宫颈癌的发生、发展和分化有关。 ...更多信息 多克隆或高危型HPV阴性（单克隆对多克隆p=0.009，高危型HPV阳性对阴性p= 0.024）。此外，克隆状态和高危型HPV感染的组合被证明与临床结果显著相关（p=0.003）。这些事实表明克隆状态和高危型HPV感染是预测CIN结局的有用生物标志物。（3）宫颈微小偏差腺癌（Minimal Deviation Adenocarcinoma，MDA）基因的鉴定LKB 1基因被鉴定为与Peutz-Jeghars综合征（Peutz-Jeghars Syndrome，PJS）相关的抑癌基因。我们发现，11例MDA中有6例（55%）发生LKB 1基因体细胞突变，并且具有LKB 1突变的MDA的预后明显低于没有突变的MDA（p<0.05）。我们还证明了子宫颈腺体的幽门腺化生，类似于组织病理学中的MDA，能够被排除在病变的组成是多克隆的并且没有LKB 1突变的点之外。少

项目成果

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 Intraepi

Yutaka Ueda、Takayuki Enomoto、Ryuichi Nakajima 等人：“单克隆扩增与高危型人乳头瘤病毒整合是宫颈癌发生的第一步：克隆状态和人乳头瘤病毒感染与宫颈内皮临床结果的关联

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: as

Ueda, Y.、Enomoto, T.、Miyatake, T.、Ozaki, K.、Yoshizaki, T.、Kanao, H.、Ueno, Y、Nakashima, R.、Shroyer, K.R.、Murata, Y.：“单克隆抗体

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)

Takayuki Enomoto、Ryuichi Nakajima、Yutaka Ueda 等：“表征子宫颈最小偏差腺癌的 STK11 基因突变”实验室调查 83(1)。

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 Investigati

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