Grant Details
Grant Number: |
3R01CA061197-03S1 Interpret this number |
Primary Investigator: |
Adami, Hans-Olov |
Organization: |
Karolinska Institute |
Project Title: |
HPV and Cervix Neoplasia-a Case Control Study |
Fiscal Year: |
1999 |
Abstract
DESCRIPTION: (Adpated from the Applicant's Abstract): The applicants'
objective is to advance the understanding of the role played by genital
human papillomavirus (HPV) in the etiology of carcinoma in situ (CIS) -- and
inferentially invasive cancer -- of the cervix. While a causal role of HPV
is likely, no large population-based, prospective study has examined its
role in the natural history from normal epithelium to CIS, nor the role of
cell-mediated immunity (as determined by HLA haplotype), microheterogeneity
(or mutations) in the HPV genome, or of other factors that may determine
transience/persistence of HPV infection. Nor has the purported orderly
progression or monoclonal origin of cervix neoplasia been established. They
propose a broad, interdisciplinary case-control study, nested in a
population-based cohort. This study uses unique Swedish opportunities for a
stringent study base definition, long-term follow-up and retrieval of smears
and histopathologic specimens; it has an extensive morphologic and molecular
component.
The main specific questions relate to 1) determinants of progression:
long-term pattern of infection (transience, persistence, reinfection) by HPV
type, concordance between HPV in smears and CIS lesions, microheterogeneity
or acquired mutations in the HPV genome, effect modification by HLA
haplotype and/or smoking; 2) progression and clonality: correlation between
HPV and the morphology as well as mono- or polyclonality of concomitant
lesions as indicated by x-chromosome inactivation.
They will follow up through 1993 a population-based cohort of women whose
first PAP smear after 1969 was normal. At least 400 incident cases of CIS
and 400 matched controls will be included and subjected to a telephone
interview. On average five sequential smears from each subject (a total of
about 4,000 smears) will undergo DNA extraction and PCR-based analyses
including typing of 19 HPV-types, and of HLA class II haplotypes (HLA-DQB1
and HLA-DRB1) in one smear per individual. Also, in a selected set (about
100 cases) sequencing of a proportion of the HPV genome will be performed to
study microheterogeneity. Detailed studies of progression and clonality
will be carried out; the specimens from about 50 cases of CIS with multiple
discrete lesions will be microdissected, followed by DNA extraction and
analysis of HPV as well as X-chromosome inactivation. These data will be
used on a number of different analyses including conditional logistic
regression.
Publications
None. See parent grant details.