Increased Risk for Cervical Disease Progression of French Women Infected with the Human Papillomavirus Type 16 E6-350G Variant

Abstract

To test the significance of human papillomavirus (HPV) type 16 and HPV16 E6 variants as risk factors for viral persistence and progression to high-grade lesion, we did a nested case-control study within a cohort study of >15,000 Caucasian French women. Three groups infected with highrisk HPV were compared: (a) women with cleared infection (controls, n = 201), (b) women with persistent infection (cases, n = 87), and (c) women who progressed into highgrade lesion (cases, n = 58 A subgroup of human papillomaviruses (HPV), referred to as high-risk types, are the etiologic agents of cervical cancer (1). Among the high-risk types HPV16 is the most prevalent type in premalignant and malignant cervical lesions worldwide (2, 3). Persistence of viral infection has a key role in cervical cancer development (4, 5). HPV16 is likelier to persist (6) and to cause progression into cervical intraepithelial neoplasia (CIN) than other high-risk HPV types (7,8). Nucleic acid sequencing of HPV16 genomes has revealed the existence of numerous natural variants that differ from the original European prototype sequence (9) up to 2% in the coding region and/or up to 5% in the noncoding region (10). HPV16 variants have been classified as five major phylogenetic clusters (or lineages): European, Asian, Asian American, African, and North American. For each lineage, several subclasses have been identified (summarized in ref. 11). Interestingly, three codon sites in the HPV16 E6 open reading frame coding for amino acids 10, 14, and 83 were shown to be under selective pressure (12). Variants at these residues lead to changes from arginine to glycine or isoleucine (R10G or R10I) at codon 10, from glutamine to histidine or aspartic acid (Q14H or Q14D) at codon 14, and from leucine to valine (L83V) at codon 83. Recent studies suggest that HPV16 E6 variants are involved in determining persistence of the viral infection and the development of cervical lesions (13-20). Some of these have shown that non-European HPV16 variants are more associated with disease progression than the European variants (21, 22).By using cross-sectional analyses of several European populations, we have previously shown that within the European lineage, the L83V E6 variant harboring a nucleotide substitution at position 350 (HPV16 350G) alone or in combination with other polymorphisms is more prevalent in cervical cancer than in . This phenomenon may be explained by the fact that natural variants alter the immunogenic and/or carcinogenic properties of the virus. In this study, we have used a large French cohort to elucidate further whether HPV16 and HPV16-specific variants are predictors for persistence of infection and progression into high-grade lesion.We did a nested case-control study within a large cohort study of >15,000 Caucasian French women ages between 18 and 76 years (median = 34 years). They had been recruited between 1997 and 2003 among women who underwent their biennial or triennial routine screening in the Department of Obstetrics and Gynaecology at t...

Risks for Persistence and Progression by Human Papillomavirus Type 16 Variant Lineages Among a Population-Based Sample of Danish Women

“…In a previous study of 95 HPV16-positive women identified through routine screening in France (23), no statistically significant differences in risk for HPV16 persistence were identified by variant status. However, the definition of HPV16 persistence was less well defined than in the present study (i.e., persistent at 2 years) and 95% confidence intervals remain compatible with the present findings.…”

“…The most common individual polymorphism in E6 is 350G that leads to a change from leucine to valine at codon 83 (L83V), which defines two distinct sublineages within the EUR lineage (20,21). Some studies have suggested that the EUR-350G and EUR-350T sublineages vary in their distribution between cervical cancers and controls (22,23).…”

The immortalizing and transforming ability of two common human papillomavirus 16 E6 variants with different prevalences in cervical cancer

“…These differences have been elucidated most clearly for HPV16. Multiple studies have shown that HPV16 variants differ in their association with cervical cancer (Tidy et al, 1989;Berumen et al, 2001;Zehbe et al, 1998aZehbe et al, , b, 2001Kammer et al, 2002;Xi et al, 2007), viral persistence (Grodzki et al, 2006;Xi et al, 2006;Lee et al, 2008) and the frequency of recurrence of cervical disease (Xi et al, 2007). Increased risk of anal cancers has also been reported for certain HPV16 variants (Xi et al, 1998).…”

Characterization of a cluster of oncogenic mutations in E6 of a human papillomavirus 83 variant isolated from a high-grade squamous intraepithelial lesion

“…Independent genetic and epidemiological studies have demonstrated the existence of natural variations in the HPV genome. These HPV16 variants seem to be risk factors for viral persistence; this is probably because of modification of the immunogenic properties of the virus (Grodzki et al, 2006). In fact, differential pathogenicity of HPV16 variants with mutations in E6 has been reported for cervical high-grade squamous intraepithelial lesions (HSIL), invasive cervical cancer and anal HSIL (Da Costa et al, 2002;Grodzki et al, 2006;Wu et al, 2006;Zehbe et al, 1998;Zuna et al, 2009 HPV16 induce markedly faster dividing when grown as organotypic raft cultures (Asadurian et al, 2007;Zehbe et al, 2009).…”