Multi‐omics data reveals novel impacts of human papillomavirus integration on the epigenomic and transcriptomic signatures of cervical tumorigenesis

Abstract

Integration of human papilloma virus (HPV) DNA into the human genome may progressively contribute to cervical carcinogenesis. To explore how HPV integration affects gene expression by altering DNA methylation during carcinogenesis, we analyzed a multiomics dataset for cervical cancer. We obtained multiomics data by HPV-capture sequencing, RNA sequencing, and Whole Genome Bisulfite Sequencing from 50 patients with cervical cancer. We detected 985 and 485 HPVintegration sites in matched tumor and adjacent paratumor tissues. Of these, LINC00486 (n = 19), LINC02425 (n = 11), LLPH (n = 11), PROS1 (n = 5), KLF5 (n = 4), LINC00392 (n = 3), MIR205HG (n = 3) and NRG1 (n = 3) were identified as highfrequency HPV-integrated genes, including five novel recurrent genes. Patients at clinical stage II had the highest number of HPV integrations. E6 and E7 genes of HPV16 but not HPV18 showed significantly fewer breakpoints than random distribution. HPV integrations occurring in exons were associated with altered gene expression in tumor tissues but not in paratumor tissues. A list of HPV-integrated genes regulated at transcriptomic or epigenetic level was reported. We also carefully checked the candidate genes with regulation pattern correlated in both levels. HPV fragments integrated at MIR205HG mainly came from the L1 gene of HPV16. RNA expression of PROS1 was downregulated when HPV integrated in its upstream region. RNA expression of MIR205HG was elevated when HPV integrated into its enhancer. The promoter methylation levels of PROS1 and MIR205HG were all negatively correlated with their gene expressions. Further experimental validations proved that upregulation of MIR205HG could promote the proliferative and migrative abilities of cervical cancer cells. Our data provides a new atlas for epigenetic and transcriptomic regulations regarding HPV integrations in cervical cancer genome. We demonstrate that HPV integration may affect gene expression

Machine learning predicts metastatic progression using novel differentially expressed lncRNAs as potential markers in pancreatic cancer

“…For the upregulated lncRNAs, AC010789.1, as previously stated, had a report regarding its function in colorectal cancer 55,63 . LINC00486, RF00019, LINC01115, and AC133530.1 all lack validation studies in PC, but other reports indicate involvement in several diseases, including cancer [64][65][66][67] .…”

“…For the upregulated lncRNAs, AC010789.1, as previously stated, had a report regarding its function in colorectal cancer 55,63 . LINC00486, RF00019, LINC01115, and AC133530.1 all lack validation studies in PC, but other reports indicate involvement in several diseases, including cancer [64][65][66][67] . As these novel lncRNAs lack studies regarding their functions, GSEA of the selected MSigDB collections returned no significant enrichment but in one transcription factors collection.…”

Cervical Cancer Stages, Human Papillomavirus Integration, and Malignant Genetic Mutations: Integrative Analysis of Datasets from Four Different Cohorts

“…Pathways significantly associated with mutated genes were also found to corroborate the roles of the corresponding proteins in productive HPV integration, viral carcinogenesis, and cancer-related conditions. Multi-omics data obtained by HPV capture sequencing, RNA sequencing, and whole-genome bisulfite sequencing showed that patients at clinical stage II had the highest number of HPV integrations [44]. The phenomenon of co-localization of HPV integration events and mutations may lead to changes in crucial cancer gene functions [43].…”

Human papillomavirus associated cervical lesion: pathogenesis and therapeutic interventions

“…In addition to direct insertions between genes, HPV integration can also affect gene expression via long‐range or short‐range cis‐interactions, involving the expression of various tumor suppressors 224 . Moreover, HPV integration can modify gene expression by altering DNA methylation and advancing carcinogenesis progression 225 . While most studies suggest that HPV integration activates nearby oncogenes in cervical cancer, a recent study demonstrated that effective virus‐cell fusion transcripts typically do not produce endogenous human proteins or alter the expression of nearby genes 214 .…”

“… 224 Moreover, HPV integration can modify gene expression by altering DNA methylation and advancing carcinogenesis progression. 225 While most studies suggest that HPV integration activates nearby oncogenes in cervical cancer, a recent study demonstrated that effective virus‐cell fusion transcripts typically do not produce endogenous human proteins or alter the expression of nearby genes. 214 Subsequent research is essential for investigating the impact of HPV integration on genome structure and expression.…”