Integrated genomic and transcriptomic analysis reveals the activation of PI3K signaling pathway in HPV-independent cervical cancers
Menée à partir de données génomiques et transcriptomiques portant sur des échantillons tumoraux issus de 1 010 patientes atteintes d'un cancer du col de l'utérus non associé au papillomavirus humain, cette étude met en évidence le rôle de la voie de signalisation de la kinase PI3K dans la tumorigenèse
Background : HPV-independent cervical cancers (HPV-ind CCs) are uncommon with worse prognosis and poorly understood. This study investigated the molecular characteristics of HPV-ind CCs, aiming to explore new strategies for HPV-ind CCs. Methods : HPV status of 1010 cervical cancer patients were detected by RT-PCR, PCR and RNA-sequencing (RNA-seq). Whole exome sequencing (WES) and RNA-seq were performed in identified HPV-ind CCs. The efficacy of PI3K
α inhibitor BYL719 in HPV-ind CCs was evaluated in cell lines, patient-derived organoids (PDOs) and patient-derived xenografts (PDXs). Results
:
Twenty-five CCs were identified as HPV-ind, which were more common seen in older, adenocarcinoma patients and exhibited poorer prognosis as well as higher tumor mutation burden compared to HPV-associated CCs. HPV-ind CCs were featured with highly activated PI3K/AKT signaling pathway, particularly, PIK3CA being the most predominant genomic alteration (36%). BYL719 demonstrated superior tumor suppression in vitro and in vivo. Furthermore, HPV-ind CCs were classified into two subtypes according to distinct prognosis by gene expression profiles, the metabolism subtype and immune subtype. Conclusions
:
This study reveals the prevalence, clinicopathology, and molecular features of HPV-ind CCs and emphasizes the importance of PIK3CA mutations and PI3K pathway activation in tumorigenesis, which suggests the potential significance of PI3Kα inhibitors in HPV-ind CC patients.