Variants of the long control region and the E6 oncogene in European human papillomavirus type 16 isolates: implications for cervical disease

Abstract

High-risk human papillomavirus types, especially type 16, are risk factors for cervical cancer. Preliminary studies suggest that HPV16 polymorphisms in the long control region or in the E6 gene may alter the oncogenic potential of the virus. This could partially explain why some lesions progress to cancer while others do not. A systematic study combining the long control region and E6 has not been undertaken. This prompted us to investigate the long control region and the E6 in northern European women infected with human papillomavirus 16. We identified the sequence variations of both regions and investigated the long control region promoter activity among various isolates. In addition, we correlated the distribution of long control region and E6 polymorphisms with disease status. We analyzed 45 samples from Swedish and Finnish women. The long control region and the E6 gene were sequenced after polymerase chain reaction long control region fragments of six European isolates covering the majority of polymorphisms in this region were ligated into the pALuc vector and used for luciferase assays. In European HPV16 isolates, polymorphisms in the long control region are more frequent than in the E6 gene. Nevertheless, the promoter function was slightly increased in only one of the tested European long control region variants. In addition, we found a specific European E6 variant, L83V, to be enriched in high-grade lesions and cancer rather than a specific European long control region variant. The difference in oncogenicity between European HPV16 genotypes is more probably due to an altered property of the corresponding E6 proteins rather than to an altered activity of the P97 promoter.

Mutation Detection of E6 and LCR Genes from HPV 16 Associated with Carcinogenesis

“…These results agree with previous studies (Brady et al, 1990;Ho et al, 1991;Andersson et al, 2000;Kammer et al, 2002;Sichero et al, 2012), which have described this modification as the most frequent one in the E6 sequence in E sublineage (Cornet et al, 2013). Noteworthy, we detected this mutation in all of the Ep sublineage samples, but in none of the Ea ones.…”

“…The mutation most frequently observed in LCR was G7521A in the binding site of the transcription factor YY1 (Pande et al, 2008). In this study, in accordance to other authors (Yamada et al, 1997;Schmidt et al, 2001;Kammer et al, 2002;Pande et al, 2008;Shang et al, 2011), the mutation most frequently detected in the LCR region was G7521A, found in the African lineages and most European ones. Thus, only 20% of analyzed samples presented homology with the prototype sequence.…”

Human Papillomavirus Type 16 Genetic Variants: Phylogeny and Classification Based on E6 and LCR

“…The phylogenetic tree segregated into four major branches (i.e., lineages) that could be recognized by the nomenclature of previous studies: (i) EAS, including the European (EUR) and Asian (As) sublineages, (ii) African 1 (AFR1), including two sublineages that we tentatively defined as AFR1a and AFR1b, (iii) African 2 (AFR2), including two sublineages that we tentatively defined as AFR2a and AFR2b, and (iv) AA/NA, including the North American (NA), Asian-American-1 (AA1), and Asian-American-2 (AA2) sublineages. A second, larger, phylogenetic tree was generated including all 353 unique E6/LCR variants from the present study, as well as additional novel published E6/LCR sequences retrieved from the work of Kammer (1,15,20) (Fig. 2).…”

Risk for High-Grade Cervical Intraepithelial Neoplasia Associated with Variants of Human Papillomavirus Types 16 and 18

“…A classification of the variants on the basis of the presence of a single nucleotide alteration usually yielded inconsistent findings (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Although data from studies comparing European (prototype-like) with non-European (non -prototype-like) variants have been relatively consistent, with non-European variants being associated with an increased risk of cervical lesions (24)(25)(26)(27)(28), a lack of association has also been reported (29)(30)(31).…”