Variants of HPV16 Appear to Confer Differing Risks of Cervical Cancer Precursor Lesions

Variants of HPV16 Appear to Confer Differing Risks of Cervical Cancer Precursor Lesions

Naturally occurring variants in human papillomavirus type 16 (HPV16) may put infected women at differing levels of risk for high grade cervical intraepithelial neoplasia (CIN 2-3), a precursor of invasive cervical cancer, according to a report in the June 4 Journal of the National Cancer Institute.

Long Fu Xi, PhD, University of Washington, Seattle, and colleagues explain that HPV16, one of the HPV types most strongly associated with risk for high grade CIN and cervical cancer, is also the most commonly occurring HPV type in the normal (ie, cervical disease-free) population. It is known, say the authors, that only a minority of women infected with HPV16 develop cervical cancer and, moreover, that not all women with CIN 2-3 will develop the cancer. Laboratory studies have shown that certain nucleotide alterations in HPV 16 affect its cancer-promoting potential, they note, and the presence of multiple variant forms of HPV16 has been demonstrated in all human populations studied. These findings, add Xi and co-workers, suggest that the natural variants of HPV16 in a given population may not have the same biologic behavior.

This study was designed to assess the association between natural variants of HPV16 and the risk of biopsy-confirmed CIN 2 or 3. Prospective studies were conducted with two populations: female university students aged 18 to 20 years and females aged 16 to 47 years who sought treatment at a sexually transmitted disease (STD) clinic. All study participants were interviewed to obtain information on demographic characteristics, sexual behaviors, and history of STDs. Vaginal and cervical cell samples for HPV detection and typing were collected at enrollment and approximately every 4 months thereafter. HPV16 variants found in the samples taken from study participants were characterized according to their similarity to a reference, or prototype, HPV 16 sample. Variants with relatively few nucleotide alterations different from the prototype were called prototype-like, while those with a greater number of alterations unlike the prototype were designated nonprototype-like.

A total of 123 women who met the study criteria (not having CIN 2-3 at study entry and having at least one HPV16-positive visit either at study entry or during follow-up) were included in the analysis. Prototype-like variants accounted for 79% of the HPV 16 detected in the university students and 86% of the virus detected in patients attending the STD clinic. CIN 2-3 was confirmed by biopsy in nine of 57 HPV16-positive females attending the university and in 10 of 66 HPV16-positive females at the STD clinic. Among university students, those with HPV16 nonprototype-like variants were 6.5 times more likely to develop CIN 2-3 than those with prototype-like variants. A similar association was observed among females at the STD clinic.

These results, say the authors, suggest that the risk of developing CIN 2-3 is not the same with all variants of HPV 16 and that nonprototype-like variants confer a greater risk compared with prototype-like variants. However, add Xi and colleagues, the important genetic differences in these HPV16 variants that underlie this increased risk of CIN 2-3 remain to be determined.

In the editorial accompanying this report, Allan Hildesheim, PhD, of the National Cancer Institute, suggests that the findings by Xi et al, though based on a small sample, may have important implications both for our understanding of the natural history of HPV-related anal and genital diseases and for our efforts to develop HPV vaccines. Hildesheim notes that, since HPV infection has been confirmed as the main causal agent in cervical cancer, recent research has focused on identifying factors that influence the progression of HPV infection, including external and lifestyle factors (eg, other infectious agents, oral contraceptives); the current results suggest that viral variants may impart different risks of disease.

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