Cervical Carcinoma (CC) is preceded by distinct preneoplastic changes called""""""""cervical intraepithelial neoplasia"""""""" (CIN). CC provides a prototype system for studying evolution of genetic mutations in progression because of its characteristic preinvasive stages. The biological behavior of CINs varies in their progression to invasive cancer and the genetic basis of it is poorly understood. Molecular genetic studies to date in CC have identified amplification of oncogenes such as ERBB2, c-myc genes and frequent allelic imbalances affecting multiple chromosomal arms such as 2q, 3p, 4q, 5p, 6p, and 11q. Reports indicate the occurrence of similar genetic alterations in precancerous lesions, suggesting that these changes play crucial role in the progression of CC. However, the sequence of genetic alterations and their role in predisposition of CINs to invasive cancer is unclear. To address these questions, we propose to undertake a systematic study of genetic alterations through the spectrum of tumor progression with the following specific aims: Characterization of genetic changes in invasive and preinvasive cervical cancerous lesions. We propose a detailed study of the genetic alterations of gene amplification and deletion mapping utilizing the techniques such as laser microdissection, comparative genomic hybridization, microarray cDNA chips, and loss of heterozygosity. The study is expected to generate gene amplification profiles, and allelic deletions through the spectrum of CC development. This will enable us to define the temporal relationship of genetic alterations with various stages of progression that might provide insights into the genetic mechanisms of CC. 2. Development of a genetic prognostic model for identifying high-risk dysplastic lesions. The data generated from these studies will be used to determine the clinical significance and to develop a genetic prognostic model for identifying high-risk CINs that progress into invasive cancer.
