GENOMIC VARIATION OF HUMAN PAPILLOMAVIRUS TYPE-16 AND RISK FOR HIGH-GRADE CERVICAL INTRAEPITHELIAL NEOPLASIA

Background: Epidemiologic studies have demonstrated strong and consist ent associations between the detection of human papillomavirus (HPV) t ype 16 DNA and the risk of cervical intraepithelial neoplasia (CIN) an d cervical cancer, However, HPV16 is also the most common type of HPV in the normal population, and only a minority of women with HPV16 infe ction develop cervical cancer. Studies of genomic heterogeneity in HPV 16 have demonstrated the presence of multiple variant forms in all hum an populations examined to date, It is conceivable that the natural va riants of HPV16 in a given population may not have the same biologic b ehavior, Purpose: This study was designed to determine the association between natural variants of HPV16 and the risk of biopsy-confirmed CI N 2 or 3, the most important precancerous lesions of the uterine cervi x. Methods: Prospective studies were conducted among 1) women attendin g a university and 2) women presenting to a sexually transmitted disea se clinic, Subjects were eligible for inclusion in this investigation if the initial cytologic findings did not reveal CIN 2-3 and HPV16 DNA was detected by means of a polymerase chain reaction (PCR)-based meth od in one or more cervical or vulvovaginal samples, Eligible subjects were followed every 4 months with cervical Pap smears and colposcopic examinations. Women were referred for biopsy if cytology or colposcopy suggested CIN 2-3. Two groups of HPV16 variants, prototype-like and n onprototype-like, were determined by means of single-strand conformati on polymorphism (SSCP) analysis of PCR products from the noncoding reg ion of the viral genome. Representative SSCP patterns from HPV16 varia nts were further characterized by direct DNA sequencing of the PCR pro ducts. Relative risks (RRs) and 95% confidence intervals (CIs) were ca lculated by Cox regression analysis. Results: Prototype-like variants accounted for 79% of the HPV16 detected in university students and 86% of the virus detected in patients presenting to the sexually transmit ted disease clinic. CIN 2-3 was confirmed by biopsy in nine of 57 HPV1 6-positive women attending the university and in 10 of 66 HPV16-positi ve women presenting to the sexually transmitted disease clinic. Among university students, those with HPV16 nonprototype-like variants were 6.5 (95% CI = 1.6-27.2) times more likely to develop CIN 2-3 than thos e with prototype-like variants. A similar association was observed amo ng women presenting to the sexually transmitted disease clinic (RR = 4 .5; 95% CI = 0.9-23.8). Conclusions: This study suggests that the risk of developing CIN 2-3 is not the same with all variants of HPV16 and that nonprototype-like variants confer a greater risk compared with pr ototype-like variants. The important genomic differences underlying th is increased risk of CIN 2-3 remain to be determined.