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RNAscope for In situ Detection of Transcriptionally Active Human Papillomavirus in Head and Neck Squamous Cell Carcinoma
Published on: March 11, 2014
Integrated genomic and transcriptomic analysis reveals the activation of PI3K signaling pathway in HPV-independent
Yi Wang1,2, Misi He3,4,5, Tiancong He6
1Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
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 PI3Kα 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.
Insights
Human papillomavirus (HPV)-independent cervical cancers (HPV-ind CCs) are rare and aggressive. This study identified PIK3CA mutations and PI3K pathway activation in HPV-ind CCs, suggesting PI3Kα inhibitors as a potential treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Human papillomavirus (HPV)-independent cervical cancers (HPV-ind CCs) represent a rare subset of cervical malignancies.
- These cancers are characterized by a poorer prognosis and remain poorly understood.
- Investigating the molecular underpinnings of HPV-ind CCs is crucial for developing targeted therapeutic strategies.
Purpose of the Study:
- To elucidate the molecular characteristics of HPV-independent cervical cancers.
- To identify potential therapeutic targets and strategies for HPV-ind CCs.
Main Methods:
- HPV status was determined in 1010 cervical cancer patients using RT-PCR, PCR, and RNA-sequencing (RNA-seq).
- Whole exome sequencing (WES) and RNA-seq were performed on identified HPV-ind CCs.
- The efficacy of the PI3Kα inhibitor BYL719 was evaluated in vitro and in vivo models.
Main Results:
- Twenty-five HPV-ind CCs were identified, associated with older age, adenocarcinoma histology, poorer prognosis, and higher tumor mutation burden.
- A hallmark of HPV-ind CCs is the highly activated PI3K/AKT signaling pathway, with PIK3CA mutations being the most frequent genomic alteration (36%).
- BYL719 demonstrated significant tumor suppression capabilities in various models, and HPV-ind CCs were classified into metabolism and immune subtypes.
Conclusions:
- This study highlights the prevalence, clinicopathological features, and molecular landscape of HPV-ind CCs.
- PIK3CA mutations and PI3K pathway activation are critical drivers of tumorigenesis in HPV-ind CCs.
- PI3Kα inhibitors represent a promising therapeutic avenue for patients with HPV-ind cervical cancer.
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