Human Papilloma Virus Genotype and Management of Cervical Cancer---Molecular Targets Discovery and Novel Treatment Strategies

Human papillomavirus (HPV) infection has been established as an etiologic agent for cervical cancer (CC). HPV-18 is a predictor of poor prognosis in stage I-IIA CC patients receiving primary surgery, while ?7-related HPVs (HPV 18, 39, 45) are predictors of poor outcomes in patients with locally advanced CC undergoing primary radiotherapy or concurrent chemoradiation. Significant improvement in survival in the CCRT group for HPV18-positive and HPV58-positive patients compared with the RT alone group, while no such differences were observed among HPV16-positive or HPV33-positive tumors in stages IIB to IVA squamous cervical cancer (SCC) patients (1993-2000). We also found that HPV-16 negativity indicated poor prognosis in cervical adeno-adenosquamous carcinoma (AD/ASC), especially for those treated with primary RT/CCRT. Patients with HPV-16-negative AD/ASCs might better be treated with primary surgery (e.g., primary radical hysterectomy for stage I-II and pelvic exenteration for stage IVA). If the finding of a single institutional study could be substantiated in a large population, different treatment modalities for patients with HPV genotypes and validated in prospective trials, which may change treatment guidelines for cancer of uterine cervix. Epigenetic alterations including DNA methylation and chromatin architectural disruption are recognized as a universial feature of malignancies. In this study, we will verify that HPV genotypes differentially impact prognosis of adding chemotherapy to radiotherapy for SCC in another cohort (2001-2014) and compare the genomic and epigenetic profiles (using Human Transcriptome array 2.0 (HTA v2.0), OncoScan Array, methylome, microRNA profiling, and ChIP-seq ) of tumor HPV genotypes in different response (outcome) to RT/CCRT and discover predictive biomarkers. If genomes and epigenomes of cervical SCC can be characterized, which results may lead to the discovery of predicting biomarkers and novel therapeutic targets for poor prognostic SCC. In the following 3 years: we aim to: The first to second year: Aim 1: To verify that HPV genotypes differentially impact prognosis of adding chemotherapy to radiotherapy for SCC Aim 2: To compare the genomic and epigenetic profiles of tumor HPV genotypes in different response (outcome) to RT/CCRT and discover predictive biomarkers The second to third year: Aim 3: To validate the predictive value of the molecular profiles in the fresh specimens (tumor, blood, and urine) of the prospective cohort of different outcome.

Project ID:PC10408-2508
External Project ID:MOST104-2314-B182-047-MY3