Integrated analysis of virus and host transcriptomes in cervical cancer in Asian and Western populations

Background: HPV-associated cervical cancer is the second most-frequent cause of death among female cancers worldwide. Race may influence vulnerability to HPV and have an effect on cervical cancer survival independent of socioeconomic status. Integration of the virus and host transcriptomes from different populations provides an unprecedented opportunity to understand these racial disparities in the prevalence of HPV and its associated cervical cancers in addition to fundamentally advancing the knowledge of HPV-induced cervical carcinogenesis and progression.Results: We performed RNA sequencing (RNA-Seq) analysis of 90 tumors and 39 adjacent normal tissues from cervical cancer patients recruited at Zhejiang University (ZJU) in China, and conducted a comparative analysis with RNA-Seq data of 286 cervical cancers from The Cancer Genome Atlas (TCGA). We found a significantly higher rate of HPV positives and HPV integration in TCGA group than in ZJU group. In addition to LINC00393 and HSPB3 as the new common integration hotspots in both populations, we found new hotspots such as SH2D3C and CASC8 in TCGA, and SCGB1A1 and ABCA1 in ZJU. There is a significant correspondence of increased expression levels between an integrated gene and its adjacent genes. We describe the first, to our knowledge, virus transcriptome-based classification of cervical cancer that is highly predictive of clinical outcome. In particular, patients with expressed E5 performed better than those without E5 expression. However, the constituents of these virus transcriptome-based tumor subtypes differ dramatically between the two populations. We further characterized the immune infiltration landscapes between different HPV statuses and revealed significantly elevated levels of regulatory T cells and M0 macrophages in the HPV positive tumors, which were associated with poor prognosis.Conclusions: These findings provide new insights into HPV-associated cervical carcinogenesis and progression and have important implications in the classification of tumor subtypes, prognosis, and anti-cancer immunotherapy in cervical cancer.