spot_imgspot_img

Intratumor Heterogeneity of HPV Integration in HPV linked Cancer

Human papillomavirus (HPV) integration into human host genomedrives HPV + head & neck cancers. Tumor whole-genome seq identified intratumor clonal heterogeneity & genomic instability. Published in: Nature Communications


Key Highlights:

  1. HPV Integration and Genomic Instability:
    • Integration of human papillomavirus (HPV) into the host genome is a critical driver of HPV-positive head and neck squamous cell carcinoma (HPV+ HNSCC).
    • Whole-genome sequencing of 51 tumors revealed significant intratumor heterogeneity of HPV integration, with 44% of HPV integration breakpoints being subclonal.
    • Integration events were linked to broad and focal genomic instability, with structural variants frequently observed at integration sites.
  2. Physical States of HPV:
    • Four distinct physical states of HPV were identified in tumors.
    • At least 49% of tumors progressed without HPV integration, maintaining episomal HPV genomes. These tumors displayed unique mutational patterns.
  3. APOBEC Signature and Cancer Evolution:
    • APOBEC signature mutations were strongly associated with HPV integration events and occurred at various stages of cancer progression.
  4. Mutational Pathways and Oncogenic Activation:
    • Tumors with clonal HPV integration exhibited JAK-STAT pathway activation, while those without integration predominantly showed NF-κB pathway activation.
    • PI3K pathway activation was identified as the major oncogenic driver, typically occurring early in carcinogenesis.
  5. ATM Haploinsufficiency and Carcinogenesis:
    • Heterozygous loss of the ataxia-telangiectasia mutated (ATM) gene was observed in 67% of tumors.
    • Downregulation of ATM was confirmed through single-cell RNA sequencing and immunohistochemistry, indicating its contribution to genomic instability and tumor progression.
  6. Smoking-Induced Mutational Signatures:
    • HPV+ HNSCC tumors exhibited almost no smoking-induced mutational signatures, underscoring the distinct etiology of these cancers.

Implications:

  • Role of Episomal HPV:
    Tumors that progressed without integration exhibited distinct mechanisms of carcinogenesis, highlighting the significance of studying both episomal and integrated HPV states.
  • Prognostic Insights:
    While previously observed associations between URI1/OMSR gains and poor prognosis were validated, no clear somatic mutations were identified as definitive indicators of prognosis.
  • Future Directions:
    Further studies, including long-read sequencing and analyses of distant metastases, are needed to better understand the implications of HPV integration heterogeneity and its role in cancer progression.

This study highlights the complexity of HPV integration in HPV+ HNSCC, emphasizing the interplay between integration events, APOBEC-associated mutations, and somatic changes like ATM loss and PI3K activation. These findings advance our understanding of HPV-driven carcinogenesis and pave the way for deeper investigations into therapeutic and prognostic biomarkers.

Source: https://www.nature.com/articles/s41467-025-56150-z#Abs1

Get in Touch

LEAVE A REPLY

Please enter your comment!
Please enter your name here

spot_imgspot_img

Related Articles

spot_img

Get in Touch

588FansLike
520FollowersFollow
4,100FollowersFollow
780SubscribersSubscribe

Latest Posts