DESCRIPTION (Adapted from applicant's abstract): Human papillomaviruses (HPVs)
are classified into "types," "subtypes," and variants." HPV16 and 18 are types
known to be central to the pathogenesis of most invasive cervical cancers (ICC)
and their precursor lesion, cervical intraepithelial neoplasia (CIN) grade 2-3.
However, many women acquire and spontaneously resolve cervical infections with
these HPV types. We hypothesize that certain HPV 1 6 and 18 variants differ in
their biologic behavior and risk of cervical neoplasia. A number of small
studies have examined associations between HPV 1 6 and 18 variants and risk of
cervical neoplasia and many, but not all, suggest differences in biologic
behaviors. Confirmation of these findings in large, more representative
populations is essential. We propose to efficiently examine these issues by
performing additional assays on a subset of samples collected during the
ongoing NCI-sponsored, multi-center randomized clinical trial: ASCUS/LSIL
Triage Study (ALTS). This study, which includes 5,086 women from four different
regions of the country, is examining how to best manage women referred with a
cytologic diagnosis of atypical squamous cells of uncertain significance
(ASCUS) or low- grade squamous intraepithelial lesions (LSIL) of the cervix.
The ALTS dataset is extremely rich with results from standardized collection
and testing of clinical specimens, detailed questionnaires with information on
potential confounders, and histologic and colposcopic diagnoses provided by
expert panel review. By including data from only those women enrolled in the
immediate colposcopy arm of ALTS, we will develop precise estimates of the
association between HPV 1 6 and IS variants and cervical neoplasia (aims 1 and
2), and determine whether those variants that are associated with CIN 2-3 have
increased DNA levels or specific nucleotide changes in the LCR and E6 regions
of the genome (aim 4). Furthermore, using data from women enrolled in the
immediate colposcopy and conservative management arms, we will provide the
first observations on the relationship between HPV 1 6 variants and risk for
recurrence after treatment for CIN 2-3 (aim 3). To address these aims, we will
perform PCR-based assays for detection and typing of 7,290 samples, classify
(by DNA sequencing) HPV variants present in samples from women infected with
HPV16 (n=548) or 18 (n=222), and quantify (by a PCR-based kinetic thermocycling
assay) the amount of HPV DNA present in the 1,915 HPV16-positive and 222
HPV18-positive samples. The proposed study is likely to make important
contributions to our understanding of the role of HPV 16 and 18 variants in the
pathogenesis of cervical cancer.
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