HPV integration landscape in precancerous lesion of cervical cancer

Vollständiger Abstract

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Persistent high-risk Human Papillomavirus (HPV) infection is the major cause of cervical cancer. The integration of HPV DNA into human genome is key event during cervical carcinogenesis. However, the viral integration profiles in precancerous lesion samples remain incompletely characterized. Here, this study identified HPV-human genome integration breakpoints in cervical precancerous lesion through high-risk HPV genome capture sequencing of 500 Thinprep Cytologic Test (TCT) samples. After sequencing reads alignment, breakpoints identification, contamination removal, and functional annotation, this study profiled 476 recurrent integration hotspot genes in our samples. After assigning hotspot genes to different lesion grade, patient age group, and infected HPV subtype according to the recurrent frequency of hotspot genes, this paper further compared the integration profile between above groups. In the comparison of lesion grades, high-grade lesions were more involved in mesenchymal development and membrane structure-related processes, while low-grade lesions were more involved in adhesion connections, cadherin proteins, and β-catenin-related functions. In the age group comparison, muscle cell development and protein kinase C binding were more enriched in elder group, while the genes in younger group were more involved in cell adhesion, catenin complex, and synaptic-related functions. In the HPV type comparison, HPV16/18-related genes mainly involved bicarbonate transport, one-carbon metabolism, and chromatin DNA binding, while other HPV type-related genes more involved cell adhesion, development, and membrane signal-related functions. These findings provide an overview of recurrent HPV integration-related hotspot genes and identify functional themes that may inform further studies of HPV-associated cervical precancerous lesions.