Genomic Characterization and Therapeutic Targeting of HPV Undetected Cervical Carcinomas

Cancers

Aishwarya Sundaresan¹  Vinodh Srinivasasainagendra¹  Hemant K. Tiwari¹  Chandra S. Pedamallu²  Jianqing Zhang²  Mari K. Halle²  Akinyemi I. Ojesina²  Camilla Krakstad³  Perry W. Grigsby⁴  Stephanie Markovina⁴  Jin Zhang⁴  Naoshad Muhammad⁴  Jennifer Stanley⁴  Julie K. Schwarz⁵  Fiona J. Ruiz⁵ 

[1] Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35294, USA;Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;Department of Obstetrics and Gynaecology, Haukeland University Hospital, 5021 Bergen, Norway;Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA;Division of Biological and Biomedical Sciences Molecular Cell Biology, Washington University School of Medicine, St. Louis, MO 63108, USA;

关键词: HPV;    palbociclib;    cervix;   

DOI  :  10.3390/cancers13184551

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown