Investigations Into The Molecular Pathogenesis Of Cervical Glandular Neoplasias

ABSTRACT More than 12,000 women are diagnosed with cervical cancer, an HPV-associated malignancy, annually in the U.S. There are two major histologic forms of cervix cancer: squamous cell carcinoma (SCC) and adenocarcinoma (ADENO). Importantly, SCC can be prevented through cervical cytology screening programs, whereas ADENO cannot. While there is a prophylactic vaccine against HPV, uptake of HPV vaccination in the U.S. has been poor and there are several generations of women who are already exposed to HPV infection and will not be helped by HPV vaccination. Therefore, cervical screening at a cost of over $6 billion per year will be needed for several decades at least. Understanding the molecular pathogenesis of ADENO has important public health value in order to facilitate the prevention of ADENO, for which current screening strategies are inadequate. In the US and Europe, HPV16, 18, and 45 infections account for >95% of AIS/ADENO. We examined viral methylation of HPV16/18/45 AIS (n=27) and cervical intraepithelial neoplasia grade 3 (CIN3) (n=63) cases compared to 90 HPV16/18/45 control infections with 20,000) in whom the vast majority of ADENO occur, to measure host and HPV viral methylation changes and HPV viral integration to molecularly define the natural history of ADENO. We will compare and contrast these findings with the better known natural history of SCC. Ultimately, we will develop a risk-prediction model for AIS/ADENO precursors using HPV genotypes, HPV viral and host gene epigenetics, and HPV viral integration.