Developing New Approaches for Cervical Cancer Control

描述(申请人提供)：浸润性宫颈癌(ICC)是一种艾滋病定义的疾病[CDC更新，1993]。我们的研究表明，感染HIV-2或HIV-I的妇女患ICC和发展为宫颈上皮内瘤变3/原位癌(CIN 3/CIS)的风险增加。基于细胞学、人乳头瘤病毒(HPV)检测和宫颈可视化的筛查程序都被提议用于资源匮乏的环境，然而，这些方法都不是在艾滋病毒流行地区控制宫颈癌的实用方法。必须开发新的方法来识别和治疗艾滋病毒流行地区的ICC高危妇女。我们假设，与大多数感染致癌型HPV的HIV血清阴性妇女不同，HIV血清阳性与致癌型HPV共感染的妇女获得了允许的分子变化，并与进展到ICC相关，甚至在细胞学变化被检测到之前，或者当只有轻微的变化，如CIN1存在时。我们进一步假设，这种预测ICC风险增加的分子变化是可以识别的，并可以作为敏感和特异的分析的基础，具有很高的预测价值，用于早期识别HIV感染的ICC高危妇女。我们开发相关分子分析的方法是基于这样一种知识，即正常细胞的一组表达基因或“表达谱”不同于同一组织类型的癌症和发育不良细胞的表达基因集[Fields，1994]。我们建议对感染致癌HPV型和不同程度宫颈病变异常(CIN 1、CIN 2/3、CIS、ICC)的HIV血清阳性和HIV血清阴性妇女进行活检，并检测这些不同病变的表达谱，以确定具有恶性肿瘤特征但发生在ICC之前的基因表达变化(即在CIS中)。一旦确定了这样的特征，我们将确定并比较在HIV血清阳性和HIV血清阴性妇女的早期前驱病变中异常表达基因的频率。将对其他样本进行验证，并对随后发生和没有发展为CIN 3/CIS的妇女存储的纵向样本进行原则证明测试。这将为今后开发检测过表达基因的蛋白质产物的“低技术”酶联免疫吸附试验提供理论基础，并为证明这一方法的实用性的纵向研究提供理论基础。

DESCRIPTION (provided by applicant): Invasive cervical cancer (ICC) is an AIDS defining disease [CDC Update, 1993]. Our studies show that women with HIV-2 or HIV- I infection are at increased risk of ICC and development of cervical intraepithelial neoplasia 3/carcinoma in situ (CIN 3/CIS). Screening programs based upon cytology, detection of human papillomavirus (HPV), and visualization of the cervix have all been proposed for use in resource poor settings, however, none of these methods are practical approaches to cervical cancer control in areas of endemic HIV infection. Novel approaches must be developed to identify and treat women at high risk for ICC in HIV endemic areas. We hypothesize that, in contrast to most HIV seronegative women who are infected with oncogenic types of HPV; HIV seropositive women co-infected with oncogenic types of HPV acquired the molecular changes which permit, and are associated with progression to ICC even before cytologic changes are detected, or when only mild changes such as CIN 1 are present. We further hypothesize that such molecular changes, which are predictive of increased ICC risk can be identified and could serve as the basis for sensitive and specific assays, with high predictive value, for the early identification of HIV, infected women at high risk of ICC. Our approach to developing relevant molecular assays is based on the knowledge that the set of expressed genes, or "expression profile" of normal cells differs from that of cancer and dysplastic cells of the same tissue type [Fields, 1994]. We propose to biopsy HIV seropositive and HIV seronegative women infected with oncogenic HPV types and with varying grades of cervical lesion abnormalities (CIN 1, CIN 2/3, CIS, ICC) and examine the expression profiles of these different lesions to identify changes in gene expression that are characteristic of malignancy but occur prior to ICC (i.e., in CIS). Once such profiles are identified, we will determine and compare the frequency with which abnormally expressed genes are present in earlier precursor lesions among HIV seropositive and HIV seronegative women. Validation on additional samples, and proof of principle testing on stored longitudinal samples from women who did and did not subsequently develop CIN 3/CIS, will be performed. This will provide the rationale for future development of "low tech" ELISA assays for detection of the protein products of the over-expressed genes of interest and for longitudinal studies demonstrating the utility of this approach.