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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA061197-02
Application #
2458102
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Project Start
1996-09-30
Project End
1999-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Karolinska Institute
Department
Type
DUNS #
350582235
City
Stockholm
State
Country
Sweden
Zip Code
171 7-7
Lu, Donghao; Sundström, Karin; Sparén, Pär et al. (2016) Bereavement Is Associated with an Increased Risk of HPV Infection and Cervical Cancer: An Epidemiological Study in Sweden. Cancer Res 76:643-51
Beskow, Anna H; Moberg, Martin; Gyllensten, Ulf B (2005) HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri. Int J Cancer 117:510-4
Beskow, Anna H; Gyllensten, Ulf B (2002) Host genetic control of HPV 16 titer in carcinoma in situ of the cervix uteri. Int J Cancer 101:526-31
Hu, Xinrong; Pang, Tianyun; Asplund, Anna et al. (2002) Clonality analysis of synchronous lesions of cervical carcinoma based on X chromosome inactivation polymorphism, human papillomavirus type 16 genome mutations, and loss of heterozygosity. J Exp Med 195:845-54
Beskow, A H; Josefsson, A M; Gyllensten, U B (2001) HLA class II alleles associated with infection by HPV16 in cervical cancer in situ. Int J Cancer 93:817-22
Hu, X; Pang, T; Guo, Z et al. (2001) HPV16 E6 gene variations in invasive cervical squamous cell carcinoma and cancer in situ from Russian patients. Br J Cancer 84:791-5
Hu, X; Pang, T; Guo, Z et al. (2001) Oncogene lineages of human papillomavirus type 16 E6, E7 and E5 in preinvasive and invasive cervical squamous cell carcinoma. J Pathol 195:307-11
Guo, Z; Wu, F; Asplund, A et al. (2001) Analysis of intratumoral heterogeneity of chromosome 3p deletions and genetic evidence of polyclonal origin of cervical squamous carcinoma. Mod Pathol 14:54-61
Josefsson, A M; Magnusson, P K; Ylitalo, N et al. (2000) Viral load of human papilloma virus 16 as a determinant for development of cervical carcinoma in situ: a nested case-control study. Lancet 355:2189-93
Guo, Z; Hu, X; Afink, G et al. (2000) Comparison of chromosome 3p deletions between cervical precancers synchronous with and without invasive cancer. Int J Cancer 86:518-23

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