Introduction/Background Cervical cancers are one of the most threatening female reproductive system tumors worldwide. Of whom, Non-HPV-associated cervical cancers (NHPV-CCs) are rare and poorly understood, yet associated with poorer outcomes compared to HPV-associated cervical cancers. To shed light on the molecular tumorigenesis of NHPV-CCs, we performed an integrated genomic and transcriptomic analysis to identify the characteristics of NHPV-CCs.
Methodology Twenty-five out of 1010 cervical cancer patients were identified to be HPV-negative by PCR, RT-PCR, and RNA-seq in our cancer center in 5 years. Genomic alterations and transcriptomic differences were profiled by whole exome sequencing (WES) and RNA-seq in all 25 patients. The TCGA-CESC cohort was analyzed for validation. The efficacy of PI3Kα inhibitor BYL719 in NHPV-CCs was detected in cell lines and patient-derived xenografts (PDX).
Results NHPV-CCs were characterized by poor prognosis and high tumor mutation burden compared to HPV-associated cervical cancers, as PIK3CA listing the top genomic alteration(36%). The PI3K/AKT signaling and FGFR signaling were significantly enriched in NHPV-CCs in both cohorts. The PI3Kα specific inhibitor BYL719 demonstrated superior tumor inhibitory efficacy in both the NHPV-CC cell line and PDX models. Furthermore, based on gene expression profiles, we identified two subtypes of NHPV-CCs: the metabolism subtype characterized by fatty acid metabolism, and the immune-suppression subtype characterized by upregulation of PD-1 and NOTCH signaling.
Conclusion We clarified the prevalence of NHPV-CCs and compared the clinicopathology and molecular features of NHPV-CCs. Our findings highlight the significance of PIK3CA mutation and PI3K/AKT pathway in NHPV-CC tumorigenesis, suggesting the clinical potential of PI3Ka inhibitor in NHPV-CCs patients.
Disclosures There are no financial conflicts of interest to disclose.
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