Viral Load, E2 Gene Disruption Status, and Lineage of Human Papillomavirus Type 16 Infection in Cervical Neoplasia

Abstract

The clinical utility of human papillomavirus (HPV) load and integration status remains unclear. We applied refined methods to delineate the viral load, integration status, and lineage of 104 women with HPV-16 monotype infection, including 19 with normal cervices, 9 with histologically proven cervical intraepithelial neoplasia (CIN) 1, 24 with CIN 2, 27 with CIN 3, and 25 with squamous cell carcinoma (SCC). Higher crude viral load, as determined by real-time polymerase chain reaction (PCR) targeting the E7 gene, was observed for SCC but became insignificant after normalization for cell content. Integration was located and quantified by real-time PCRs targeting, respectively, the carboxyl, amino, and hinge domains of the E2 gene. Pure episomal, integrated, and mixed forms were observed in all disease groups. Most E2 gene disruptions involved the amino-terminal, but sparing the hinge region that has been frequently used as a surrogate marker of integration. Large-fragment disruption involving all 3 E2 regions was observed only in the CIN 3 and SCC groups. Altogether, 33.3% of the CIN 3 group and 28.0% of the SCC group harbored pure episomal genomes. The Asian lineage was associated with a higher risk for CIN 3/SCC than the European lineage, and 6 of the 7 large-fragment E2 disruptions were from Asian lineage. The link between viral lineage, integration pattern, and oncogenesis deserves further study.

State of HPV16 integration in Lithuanian women with cervical neoplasia

“…The opinions and data concerning the relationship between the HPV integration and the level of cervical intraepithelial lesions differ according to various authors. Some researchers suggest that integration of HPV is an early event of carcinogenesis [25,26], while others believe that integration is more frequently detected in already existing significant intraepithelial changes [8,9]. However, there is no doubt about the importance of HPV integration and its influence on cervical changes.…”

“…Therefore, recently, more attention has been focused on molecular markers, such as virus activity markers (HPV mRNR), gene expression (for instance, p16), and DNA methylation changes [6,7]. The deletion of the HPV E2 gene plays many important roles, such as the integration of HPV DNA into a host cell genome and, referring to other researchers [8,9], provides the possibility of a more rapid progression of cervical intraepithelial lesions from low to high and faster progression to invasive cervical cancer.…”

“…Despite the fact that the deletion of various parts of the virus genome is detected in virus integrated transcripts, constant deletion of some certain genes is also found in the transcripts. On numerous occasions, E2 gene deletion can be identified [9].…”

Type‐specific human papillomavirus oncogene messenger RNA levels correlate with the severity of cervical neoplasia

“…[30][31][32][33] In contrast, there are no differences in this study between HR-HPV (types 16, 18, 52, 58, 31 and 33) loads and severity of cervical lesions observed in other studies. 5,34 Another issue concerning viral load is that until now, the measurement of viral load has not been justified in clinical settings due to the wide variations in viral load within disease grades and the fact that most studies have been limited to measuring HPV 16 viral load only.…”

Human Papillomavirus in Cervical Cancer Screening: Important Role as Biomarker

“…For now, it remains largely unclear whether the measurement of HPV integration status could be a useful biomarker for progressive disease. Several studies suggest that identification of integrated viral forms could support HPVbased screening and triage strategies (2,(69)(70)(71)(72)(73)(74)(75).…”