Genomic characterization and therapeutic targeting of hpv undetected cervical carcinomas

Fiona J. Ruiz, Aishwarya Sundaresan, Jin Zhang, Chandra S. Pedamallu, Mari K. Halle, Vinodh Srinivasasainagendra, Jianqing Zhang, Naoshad Muhammad, Jennifer Stanley, Stephanie Markovina, Hemant K. Tiwari, Perry W. Grigsby, Camilla Krakstad, Julie K. Schwarz, Akinyemi I. Ojesina

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Cervical cancer tumors with undetectable HPV (HPVU) have been underappreciated in clinical decision making. In this study, two independent CC datasets were used to characterize the largest cohort of HPVU tumors to date (HPVU = 35, HPV+ = 430). Genomic and transcriptome tumor profiles and patient survival outcomes were compared between HPV+ and HPVU tumors. In vitro analyses were done to determine efficacy of the selective CDK4/6 inhibitor palbociclib on HPVU cancer cell lines. Patients with HPVU 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 HPVU tumors, with converging functional roles in cell cycle progression. In vitro HPVU, but not HPV+, cancer cell lines with wild type RB1 were sensitive to palbociclib monotherapy. These results indicate that HPVU 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 HPVU CC patients.

Original languageEnglish
Article number4551
JournalCancers
Volume13
Issue number18
DOIs
StatePublished - Sep 2021

Keywords

  • Cervix
  • HPV
  • Palbociclib

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