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

doi:10.3390/cancers13184551

Genomic Characterization and Therapeutic Targeting of HPV Undetected Cervical Carcinomas

Cancers (Basel). 2021 Sep 10;13(18):4551. doi: 10.3390/cancers13184551.

Authors

Fiona J Ruiz^{1

2}, Aishwarya Sundaresan³, Jin Zhang^{2

4

5}, Chandra S Pedamallu⁶, Mari K Halle^{6

7

8}, Vinodh Srinivasasainagendra³, Jianqing Zhang^{6

9}, Naoshad Muhammad², Jennifer Stanley^{2

5}, Stephanie Markovina^{2

5}, Hemant K Tiwari³, Perry W Grigsby^{2

5}, Camilla Krakstad^{7

8}, Julie K Schwarz^{1

2

5

10}, Akinyemi I Ojesina^{6

9

11}

Affiliations

¹ Division of Biological and Biomedical Sciences Molecular Cell Biology, Washington University School of Medicine, St. Louis, MO 63108, USA.
² Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA.
³ Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
⁴ Institute for Informatics, Washington University School of Medicine, St. Louis, MO 63108, USA.
⁵ Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63108, USA.
⁶ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
⁷ Department of Obstetrics and Gynaecology, Haukeland University Hospital, 5021 Bergen, Norway.
⁸ Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway.
⁹ O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
¹⁰ Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63108, USA.
¹¹ HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.

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.

Keywords: HPV; cervix; palbociclib.

Abstract

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