Intratumoral Heterogeneity and Clonal Evolution Induced by HPV Integration

Area of Science:

• Genomics
• Cancer Biology
• Virology

Background:

• Human papillomavirus (HPV) integration into host DNA is common in HPV-positive cancers.
• The impact of HPV integration on chromosomal integrity remains largely unknown.
• Understanding these genomic alterations is crucial for cancer research.

Purpose of the Study:

• To investigate the consequences of HPV genome integration on host DNA.
• To identify and characterize novel forms of structural variation in HPV-positive cancers.
• To elucidate the role of these variations in tumor evolution and heterogeneity.

Main Methods:

• Utilized continuous long-read sequencing on oropharyngeal cancer samples and cell lines.
• Analyzed structural variations, focusing on repetitive patterns of viral and host DNA concatemers.
• Reconstructed the evolutionary pathways of structural variants using shared breakpoints.

Main Results:

• Identified a new structural variation termed "heterocateny," characterized by diverse, interrelated concatemers of HPV and host DNA.
• Demonstrated that virus-host concatemers are unstable, facilitating host DNA capture, amplification, and recombination.
• Observed heterocateny in both extrachromosomal and intrachromosomal DNA within tumors.

Conclusions:

• Heterocateny is driven by aberrant replication and recombination of oncogenic HPV DNA.
• This process promotes intratumoral heterogeneity and clonal evolution in HPV-positive cancers.
• Extends the known consequences of HPV integration beyond simple DNA insertion.