Type-Dependent Integration Frequency of Human Papillomavirus Genomes in Cervical Lesions

Abstract

Chromosomal integration of high-risk human papillomavirus (HR-HPV) genomes is believed to represent a significant event in the pathogenesis of cervical cancer associated with progression from preneoplastic lesions to invasive carcinomas. This hypothesis is based on experimental data suggesting that integration-dependent disruption of HR-HPV E2 gene functions is important to achieve neoplastic transformation and on clinical data gathered by analyzing lesions induced by human papillomavirus (HPV) 16 and 18 that revealed integrated viral genome copies in the vast majority of cervical cancer cells. However, a substantial fraction of cervical cancers is associated with other HR-HPV types for which virtually no data concerning their integration status have been reported so far. Here, we compared integration frequencies of the five most common oncogenic HPV types (HPV16, 18, 31, 33, and 45) in a series of 835 cervical samples using a specific mRNA-based PCR assay (Amplification of Papillomavirus Oncogene Transcripts). Most precancerous lesions displayed exclusively episomal viral genomes, whereas 62% of the carcinomas had integrated viral genomes. However, the frequency of integrated HR-HPV genomes showed marked differences for individual HR-HPV types. HPV16, 18, and 45 were found substantially more often in the integrated state compared with HPV types 31 and 33. The analysis of the median age of patients with high-grade precancerous lesions and invasive cancers suggests that precancers induced by HPV types 18, 16, and 45 progress to invasive cervical cancer in substantially less time compared with precancers induced by HPV types 31 and 33. These findings suggest that integration of oncogenic HPV genomes in cervical lesions is a consequence rather than the cause of chromosomal instability induced by deregulated HR-HPV E6-E7 oncogene expression. Distinct HR-HPV types apparently provoke chromosomal instability in their host cells to a different extent than is reflected by their integration frequencies in advanced lesions and the time required for CIN 3 lesions to progress to invasive cancer.

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

“…27 Other reports reveal that HPV 16, 18 and 45 are substantially found more often in an integrated state compared with HPV 31 and 33 and that precancerous states induced by HPV 16,18 and 45 progress to invasive cervical cancer in less time compared with those induced by HPV 31 and 33. 28 This is consistent with the current results, which reveal that levels of oncogenic expression of HPV 16, 18, 52 and 58 have been increasing with the degree of cervical dysplasia and progression to cervical cancer but not for HPV 31 and 33.…”

Human papillomavirus is frequently detected in gefitinib-responsive lung adenocarcinomas

“…Such a mechanism can explain the observation that only small portions of virustransformed cells harbored viral genome as was reported by studies on cell transformation by bovine papillomavirus (27) and HPV-18 (28). It was also hypothesized that the deregulated high-risk HPV E6-E7 expression induces chromosomal instability, resulting in HPV genome integration in the affected cell (29). It is suspected that the chromosome instability may give rise to more malignant cancer cells with a selective growth advantage (30).…”

Molecular Markers Implicating Early Malignant Events in Cervical Carcinogenesis

“…E6 and E7 are overexpressed in most CC cases (2,11,12), which has been suggested to associate with the integration of HPV DNA into the host-cell genome conjoined with the disruption of the viral E2 gene. Its protein product, E2, normally downregulates the expression of E6 and E7 (13)(14)(15). In the majority of HPV16-and HPV18-positive CCs, the virus has been detected in an integrated form (15)(16)(17)(18), although there are also HPV-positive CCs in which the virus is either in a mixed form or only in episomes (15,18).…”

“…Its protein product, E2, normally downregulates the expression of E6 and E7 (13)(14)(15). In the majority of HPV16-and HPV18-positive CCs, the virus has been detected in an integrated form (15)(16)(17)(18), although there are also HPV-positive CCs in which the virus is either in a mixed form or only in episomes (15,18).…”