Association of HPV16 E6 variants with diagnostic severity in cervical cytology samples of 354 women in a US population

Abstract

It has been suggested that DNA sequence variants of HPV16 contribute to differences in the behavior of individual cervical lesions. To address this question, we have analyzed the association of HPV16 variants with diagnostic severity in 354 HPV16-positive Oklahoman women. HPV16 variant status was determined by PCR amplification and DNA sequencing of the E6 open reading frame. European sequences were identified in 86% of samples and 14% were non-European. Of the 51 nonEuropean cases, 61% were Asian-American, 23% African and 16% were Native American variants. European prototype and related variants were present in comparable numbers (43% each) but the relative proportion of each differed with diagnostic category. In general, the proportion of European variants and non-European variants increased with diagnostic severity while the European prototype decreased. When adjusted for age and race (white, black or Hispanic), the increased risk for carcinoma/severe dysplasia for non-European variants was statistically significant with an odds ratio of 3.8 (1.3-10.7). However, the analogous comparison for the European variants, although also showing increased association with carcinoma/ severe dysplasia, did not reach statistical significance (OR 5 1.6 (95% CI 0.7-3.6). Overall, HPV16 European sequences (both prototype and related variants), were predominant in Oklahoman women including those with cancers. This suggests that while there appear to be differences among the HPV16-variant categories in risk for progression to invasive cancer, all variant categories are associated with the development of invasive cancer. ' UICCKey words: human papillomavirus; cervical carcinogenesis; cervical intraepithelial lesions; HPV variants; cervical neoplasia Intraepithelial lesions and carcinomas of the cervix have been overwhelmingly demonstrated to be associated with human papillomaviruses, with a particularly strong association with HPV16. [1][2][3] However, the fact that only a minority of women infected with HPV16 develop invasive carcinoma suggests that there are as yet undefined factors that affect the biological outcome in the associated lesions. In addition to various host factors, there has been strong interest in the possible role of DNA sequence variation (and hence protein structure/function) in contributing to the biological progression of individual HPV associated lesions. Intratype HPV variants have been defined as showing less than 2% nucleotide variation in the L1 ORF 4 from the original reference or prototype sequence.5 In addition to the L1 sequence changes, the individual variant types have characteristic nucleotide changes in other parts of the viral genome. These have been particularly well characterized for the E6 ORF 6-8 and LCR. 9,10 For HPV16, the E6 sequence changes have been found to accurately assign variant category to individual isolates. 8,11 The first HPV16 sequence 5 identified was from a European woman and was termed ''European prototype''. Studies performed on a worldwide basis have identified sever...

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

“…In combination with the fact that HPV83m was isolated from an HSIL from a cervical smear, these results are strongly indicative of the oncogenic potential of this new variant, HPV83m. This idea is consistent with other studies that have reported the impact of E6 variants of HPV16 on the natural history of an infection (Asadurian et al, 2007;Da Costa et al, 2002;Grodzki et al, 2006;Richard et al, 2010;Wu et al, 2006;Zehbe et al, 1998;Zuna et al, 2009). In addition, we have demonstrated, by reverting the mutations in the second zinc-finger region of E6m, the importance of these mutations to this induction of host-cell proliferation; we show that cells expressing E6r-E7 of HPV83r exhibited the same proliferation as cells expressing E6-E7 of HPV6 and were not able to form colonies in soft agar cultures.…”

“…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). …”

Unique variants of human papillomavirus genotypes 52 and 58 and risk of cervical neoplasia

“…A study suggested that there appeared to be differences among the HPV16 variant categories in the risk for progression to cervical cancer, but all variant categories were associated with the development of cancer. 30 However, the mechanism of different variants to cause the development of cervical neoplasia remains unknown, although the carcinogenetic potential of HPV variants might be altered due to differences in the biological behavior of variant. In addition, the potential oncogenicity of variants might be dependent on host genetic differences between populations.…”

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

“…Factors favoring HPV persistence versus clearance are still poorly understood, but several studies have suggested that intratype genetic variations may influence persistence and clinical outcome (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). This phenomenon may be explained by natural variants that alter the immunogenic and/or carcinogenic properties of the virus.…”