Developing New Approaches for Cervical Cancer Control

描述（由申请人提供）：浸润性宫颈癌（ICC）是一种艾滋病定义疾病[CDC更新，1993]。我们的研究表明，感染HIV-2或HIV- 1的女性发生ICC和宫颈上皮内瘤变/原位癌（CIN 3/CIS）的风险增加。基于细胞学、人乳头瘤病毒（HPV）检测和子宫颈可视化的筛查方案都被建议用于资源贫乏的环境，然而，这些方法都不是在地方性HIV感染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患ICC的高风险妇女。我们假设，与大多数感染了致癌型HPV的HIV血清阴性妇女相反；HIV血清阳性的女性同时感染了致癌型HPV，获得了允许并与ICC进展相关的分子变化，甚至在检测到细胞学变化之前，或者当只有轻微的变化（如CIN 1）时。我们进一步假设，这种预测ICC风险增加的分子变化可以被识别出来，并可以作为敏感和特异性检测的基础，具有高预测价值，用于早期识别感染艾滋病毒的高风险ICC妇女。我们开发相关分子检测的方法是基于正常细胞的表达基因集或“表达谱”不同于同一组织类型的癌症和发育不良细胞的知识[Fields， 1994]。我们建议对感染了致瘤性HPV类型和不同级别宫颈病变异常（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，并检查这些不同病变的表达谱，以确定恶性肿瘤特征的基因表达变化，但发生在ICC之前（即CIS）。一旦确定了这些特征，我们将确定并比较在艾滋病毒血清阳性和艾滋病毒血清阴性妇女的早期前体病变中异常表达基因的频率。将对其他样本进行验证，并对储存的纵向样本进行原则测试证明，这些样本来自患有或未患CIN 3/CIS的妇女。这将为未来发展“低技术”ELISA检测感兴趣的过表达基因的蛋白质产物和纵向研究证明这种方法的实用性提供理论依据。

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.