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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
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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.

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Publications

HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri.
Authors: Beskow AH, Moberg M, Gyllensten UB
Source: Int J Cancer, 2005 Nov 10;117(3), p. 510-4.
PMID: 15906352
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Host genetic control of HPV 16 titer in carcinoma in situ of the cervix uteri.
Authors: Beskow AH, Gyllensten UB
Source: Int J Cancer, 2002 Oct 20;101(6), p. 526-31.
PMID: 12237892
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Clonality analysis of synchronous lesions of cervical carcinoma based on X chromosome inactivation polymorphism, human papillomavirus type 16 genome mutations, and loss of heterozygosity.
Authors: Hu X, Pang T, Asplund A, PontÚn J, NistÚr M
Source: J Exp Med, 2002 Apr 1;195(7), p. 845-54.
PMID: 11927629
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Oncogene lineages of human papillomavirus type 16 E6, E7 and E5 in preinvasive and invasive cervical squamous cell carcinoma.
Authors: Hu X, Pang T, Guo Z, PontÚn J, NistÚr M, Bernard Afink G
Source: J Pathol, 2001 Oct;195(3), p. 307-11.
PMID: 11673827
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HLA class II alleles associated with infection by HPV16 in cervical cancer in situ.
Authors: Beskow AH, Josefsson AM, Gyllensten UB
Source: Int J Cancer, 2001 Sep;93(6), p. 817-22.
PMID: 11519043
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HPV16 E6 gene variations in invasive cervical squamous cell carcinoma and cancer in situ from Russian patients.
Authors: Hu X, Pang T, Guo Z, Mazurenko N, Kisseljov F, PontÚn J, NistÚr M
Source: Br J Cancer, 2001 Mar 23;84(6), p. 791-5.
PMID: 11259093
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Analysis of intratumoral heterogeneity of chromosome 3p deletions and genetic evidence of polyclonal origin of cervical squamous carcinoma.
Authors: Guo Z, Wu F, Asplund A, Hu X, Mazurenko N, Kisseljov F, PontÚn J, Wilander E
Source: Mod Pathol, 2001 Feb;14(2), p. 54-61.
PMID: 11235906
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A prospective study showing long-term infection with human papillomavirus 16 before the development of cervical carcinoma in situ.
Authors: Ylitalo N, Josefsson A, Melbye M, S÷rensen P, Frisch M, Andersen PK, SparÚn P, Gustafsson M, Magnusson P, PontÚn J, Gyllensten U, Adami HO
Source: Cancer Res, 2000 Nov 1;60(21), p. 6027-32.
PMID: 11085523
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Viral load of human papilloma virus 16 as a determinant for development of cervical carcinoma in situ: a nested case-control study.
Authors: Josefsson AM, Magnusson PK, Ylitalo N, S°rensen P, Qwarforth-Tubbin P, Andersen PK, Melbye M, Adami HO, Gyllensten UB
Source: Lancet, 2000 Jun 24;355(9222), p. 2189-93.
PMID: 10881891
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Clonality of precursors of cervical cancer and their genetical links to invasive cancer.
Authors: Guo Z, PontÚn F, Wilander E, PontÚn J
Source: Mod Pathol, 2000 Jun;13(6), p. 606-13.
PMID: 10874663
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Comparison of chromosome 3p deletions between cervical precancers synchronous with and without invasive cancer.
Authors: Guo Z, Hu X, Afink G, PontÚn F, Wilander E, PontÚn J
Source: Int J Cancer, 2000 May 15;86(4), p. 518-23.
PMID: 10797265
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HPV typing and HPV16 E6-sequence variations in synchronous lesions of cervical squamous-cell carcinoma from Swedish patients.
Authors: Hu X, Guo Z, Tianyun P, PontÚn F, Wilander E, Andersson S, PontÚn J
Source: Int J Cancer, 1999 Sep 24;83(1), p. 34-7.
PMID: 10449604
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Detection and quantitation of human papillomavirus by using the fluorescent 5' exonuclease assay.
Authors: Josefsson A, Livak K, Gyllensten U
Source: J Clin Microbiol, 1999 Mar;37(3), p. 490-6.
PMID: 9986801
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