Human papillomavirus (HPV) infection is the primary cause of cervical carcinoma. Locally advanced cervical cancer (LACC) is incurable with a high recurrence rate after standard-of-care chemoradiation therapy (CRT). High-risk HPV genotypes have evolved complex regulatory strategies to tightly control viral gene expression and alternative splicing. Recent studies indicate that some alternatively spliced HPV genes have different functions in cervical tumor replication and oncogenesis than their full-length oncogene counterparts. The ratio of full-length and alternatively spliced HPV transcripts can vary in cervical tumors harboring different high-risk HPV genotypes. We manually inspected whole transcriptome sequencing (RNA-seq) data and discovered recurrent HPV-human gene fusions containing alternatively spliced HPV transcripts and long intergenic non- protein-coding human RNAs (lncRNA). HPV alternative splicing is important in cervical cancer biology; however, it is still unclear whether alternatively spliced HPV transcripts affect the chemoradiation response in cervical cancer patients. The proposed research will determine whether alternatively spliced HPV transcripts have prognostic and mechanistic significance for patient outcomes in cervical cancer. Specifically, we will determine whether alternatively spliced HPV transcripts modulate radiation response using HPV-transformed cervical cancer cells and telomerase-reverse-transcriptase (hTERT) transformed cervical epithelial cells. We will also evaluate whether alternatively spliced HPV transcripts can serve as biomarkers for different HPV genotypes using cDNA capture sequencing data and clinical data from an established cohort of LACC patients uniformly treated with curative-intent CRT. Finally, we will develop novel algorithms to identify viral-host gene fusions and examine their functional consequences using RNA-seq data and clinical outcome data. Successful completion of this translational research will identify alternatively spliced HPV transcripts as accurate prognostic molecular biomarkers and suitable novel targets in LACC. Establishing the mechanistic function of HPV alternative splicing in cervical cancer radiation response will ultimately facilitate the development of optimized therapies and improve patient outcomes.

Public Health Relevance

Patients with locally advanced cervical cancer (LACC) are commonly treated with standard-of-care chemoradiation therapy (CRT), but more than one-third of these LACC patients experience disease recurrence with extremely poor prognosis. Human papillomavirus (HPV) is the primary cause of cervical carcinoma and recent studies indicate that HPV alternative splicing has an important role in cervical cancer replication and oncogenesis; however, it is unknown whether alternative splicing of HPV transcripts affects CRT response. This proposal will answer these questions by performing in vitro experiments, conducting data analyses of patient cohort data, and developing novel algorithms to examine the prognostic and mechanistic significance of HPV alternative splicing in cervical cancer radiation response.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Career Transition Award (K22)
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Subcommittee I - Transistion to Independence (NCI)
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Jakowlew, Sonia B
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Washington University
Schools of Medicine
Saint Louis
United States
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