Lf. Xi et al., GENOMIC VARIATION OF HUMAN PAPILLOMAVIRUS TYPE-16 AND RISK FOR HIGH-GRADE CERVICAL INTRAEPITHELIAL NEOPLASIA, Journal of the National Cancer Institute, 89(11), 1997, pp. 796-802
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.