Ruiz Fiona J, Sundaresan Aishwarya, Zhang Jin, Pedamallu Chandra S, Halle Mari K, Srinivasasainagendra Vinodh, Zhang Jianqing, Muhammad Naoshad, Stanley Jennifer, Markovina Stephanie, Tiwari Hemant K, Grigsby Perry W, Krakstad Camilla, Schwarz Julie K, Ojesina Akinyemi I
Division of Biological and Biomedical Sciences Molecular Cell Biology, Washington University School of Medicine, St. Louis, MO 63108, USA.
Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA.
Cancers (Basel). 2021 Sep 10;13(18):4551. doi: 10.3390/cancers13184551.
Cervical cancer tumors with undetectable HPV (HPV) have been underappreciated in clinical decision making. In this study, two independent CC datasets were used to characterize the largest cohort of HPV tumors to date (HPV = 35, HPV = 430). Genomic and transcriptome tumor profiles and patient survival outcomes were compared between HPV and HPV tumors. In vitro analyses were done to determine efficacy of the selective CDK4/6 inhibitor palbociclib on HPV cancer cell lines. Patients with HPV CC tumors had worse progression-free and overall survival outcomes compared to HPV patients. , , , , , , and were identified as significantly mutated genes (SMGs) enriched in HPV tumors, with converging functional roles in cell cycle progression. In vitro HPV, but not HPV, cancer cell lines with wild type were sensitive to palbociclib monotherapy. These results indicate that HPV 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 CC patients.
人乳头瘤病毒（HPV）检测不到的宫颈癌肿瘤在临床决策中一直未得到充分重视。在本研究中，使用了两个独立的宫颈癌数据集来表征迄今为止最大的HPV肿瘤队列（HPV阴性 = 35例，HPV阳性 = 430例）。比较了HPV阴性和HPV阳性肿瘤之间的基因组和转录组肿瘤谱以及患者生存结果。进行了体外分析以确定选择性细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂帕博西尼对HPV阴性癌细胞系的疗效。与HPV阳性患者相比，HPV阴性宫颈癌肿瘤患者的无进展生存期和总生存期更差。 、 、 、 、 、 和 被确定为在HPV阴性肿瘤中富集的显著突变基因（SMGs），在细胞周期进程中具有趋同的功能作用。体外实验表明，具有野生型 的HPV阴性而非HPV阳性癌细胞系对帕博西尼单药治疗敏感。这些结果表明，HPV状态可作为患者对标准治疗反应不佳的预测生物标志物应用于临床。我们建议在治疗前对原发性宫颈肿瘤进行常规HPV检测，以识别将从更积极的精准驱动治疗中获益的患者。我们的结果确定帕博西尼作为HPV阴性宫颈癌患者替代治疗策略的主要候选药物。
