Characteristics of HPV integration in cervical adenocarcinoma and squamous carcinoma

Abstract

Purpose HPV integration usually occurs in HPV-related cancer, and is the main cause of cancer. But the carcinogenic mechanism of HPV integration is unclear. The study aims to provide a theoretical basis for understanding the pathogenesis of cervical adenocarcinoma (AC) and cervical squamous carcinoma (SCC). Methods We used HPV capture sequencing to obtain HPV integration sites in AC and SCC, and analyzed cytobands, distribution of genetic and genomic elements, identified integration hotspot genes, clinicopathological parameters, breakpoints of HPV16 and performed pathway analysis. Then we conducted immunohistochemical (IHC) assay to preliminarily verify the expression of most frequently integrated genes in AC, STARD3 and ERBB2. Results The results revealed that the most frequently observed integrated cytoband was 17q12 in AC and 21p11.2 in SCC, respectively. The breakpoints in both AC and SCC were more tended to occur within gene regions, compared to intergenetic regions. Compared to SCC samples, AC samples had a higher prevalence of genomic elements. In AC, HPV integration has no significantly difference with clinicopathological parameters, but in SCC integration correlated with differentiation (P < 0.05). Breakpoints of HPV in SCC located in LCR more frequently compared to AC, which destroyed the activation of promoter p97. Hotspot genes of HPV integration were STARD3 and ERBB2 in AC, and RNA45S rDNA and MIR3648-1 in SCC, respectively. Meanwhile, we preliminarily proved that the expression of STARD3 and ERBB2, the most frequently integrated genes, would increase after integration. Conclusion These results suggested that HPV may utilize the powerful hosts’ promoters to express viral oncogenes and overexpression of viral oncogenes plays a significant role in the carcinogenesis of SCC. In AC, HPV integration may affect hosts’ oncogenes, and the dysregulation of oncogenes may primarily contribute to progression of AC.

HPV, HBV, and HIV-1 Viral Integration Site Mapping: A Streamlined Workflow from NGS to Genomic Insights of Carcinogenesis

“…The primary locations of viral–host integration identified herein for the SiHa, HeLa, CaSki, SCC154, and ACH-2 cell lines were consistent with prior investigations, although some differences in minor integration sites were noted [ 24 , 42 , 44 , 45 , 48 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ]. The discrepant results may be attributed to differences in sequencing methods, software platforms, parameters, and cut-off definitions.…”

“…Chromosomal regions (chr. 13q22.1, 8q24, and 21p11.2) associated with carcinogenesis were also identified in the cell lines [ 44 , 45 , 46 , 47 , 48 , 49 ]. The median number of integration events at/near a cytoband or gene associated with carcinogenesis per sample was 2 (range, 2 to 10).…”

“…The median number of integration events at/near a cytoband or gene associated with carcinogenesis per sample was 2 (range, 2 to 10). Host genes adjacent to the VIS, which have been identified in the literature as oncogenes, tumor suppressor genes, or cancer-associated genes, were denoted in Table 2 by superscripted numerals [ 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ]. Taken together, the findings offer valuable insights into the intricate relationship between viral integration, chromosomal location, and genetic alterations that contribute to carcinogenesis.…”

“…1 Chromosomal region and band recognized as a human common fragile site [41]. 2 Chromosomal region and band associated with carcinogenesis [44][45][46][47][48][49]. 3 Chromosomal region and band recognized as an HPV integration hotspot (i.e., 2q22.…”

Bioinformatics Analysis of Human Papillomavirus 16 Integration in Cervical Cancer: Changes in MAGI-1 Expression in Premalignant Lesions and Invasive Carcinoma

“…It is recognized that most HR-HPV infections are transient and revert in less than two years [ 4 ]. However, the persistence of HPV 16 infection increases the risk of progression of premalignant lesions to invasive carcinoma due to the integration of the viral genome into the host cell genome [ 5 ], which induces overexpression of its E6/E7 oncoproteins, deregulating the cell cycle and thereby increasing deregulated cell proliferation, cell death avoidance, angiogenesis activation, activation of metastatic phenotype, migration, and invasion [ 6 ]. Although integration is not part of the normal life cycle of HPV 16, as in the case of retroviruses, which possess an integrase that promotes the insertion of their genome into the host cell genome [ 7 ], for HPV 16 integration to occur, there must be damage to the DNA of both the host cell and the virus that can be produced via exposure to reactive oxygen and nitrogen species (ROS/NOS) generated as part of E1/E2-mediated viral replication [ 8 ]; during this process, the HPV 16 genome binds to host-cell DNA through the formation of the E2 complex with bromodomain protein 4 (E2-BRD4), a chromatin reader protein that recognizes and binds to acetylated histones through cell division, regulating transcription at common fragile sites [ 9 ].…”