Genomic Characterization and Therapeutic Targeting of HPV Undetected Cervical Carcinomas

SIMPLE SUMMARY: Persistent HPV infection is a known driver of cervical carcinogenesis, but the existence and biological relevance of HPV undetected (HPV(U)) cervical cancer has been debated. Here we report the results of detailed molecular classification of HPV(U) cervical cancer, and validate HPV(U) as a biomarker of poor outcomes. We identify that HPV(U) cervical cancer tumors harbor mutations affecting cell cycle progression, and in vitro experiments reveal HPV(U), but not HPV(+), cells are sensitive to palbociclib monotherapy. HPV(U) status can be translated into the clinic as a predictive biomarker of poor patient response to standard of care treatments and these patients may benefit from personalized treatment plans. Our results identify palbociclib as a lead candidate as an alternative treatment strategy for HPV(U) cervical cancer patients. We also suggest that primary cervix tumors be routinely tested for HPV prior to treatment to identify patients who will benefit from more aggressive precision-driven therapy. ABSTRACT: Cervical cancer tumors with undetectable HPV (HPV(U)) have been underappreciated in clinical decision making. In this study, two independent CC datasets were used to characterize the largest cohort of HPV(U) tumors to date (HPV(U) = 35, HPV(+) = 430). Genomic and transcriptome tumor profiles and patient survival outcomes were compared between HPV(+) and HPV(U) tumors. In vitro analyses were done to determine efficacy of the selective CDK4/6 inhibitor palbociclib on HPV(U) cancer cell lines. Patients with HPV(U) CC tumors had worse progression-free and overall survival outcomes compared to HPV(+) patients. TP53, ARID1A, PTEN, ARID5B, CTNNB1, CTCF, and CCND1 were identified as significantly mutated genes (SMGs) enriched in HPV(U) tumors, with converging functional roles in cell cycle progression. In vitro HPV(U), but not HPV(+), cancer cell lines with wild type RB1 were sensitive to palbociclib monotherapy. These results indicate that HPV(U) status can be translated into the clinic as a predictive biomarker of poor patient response to standard of care treatments. We suggest primary cervix tumors be routinely tested for HPV prior to treatment to identify patients who will benefit from more aggressive precision-driven therapy. Our results identify palbociclib as a lead candidate as an alternative treatment strategy for HPV(U) CC patients.