Invasive cervical cancer (ICC) is an AIDS defining disease [CDC Update, 1993]. Our studies show that women with HIV-2 or HIV- I infection are at increased risk of ICC and development of cervical intraepithelial neoplasia 3/carcinoma in situ (CIN 3/CIS). Screening programs based upon cytology, detection of human papillomavirus (HPV), and visualization of the cervix have all been proposed for use in resource poor settings, however, none of these methods are practical approaches to cervical cancer control in areas of endemic HIV infection. Novel approaches must be developed to identify and treat women at high risk for ICC in HIV endemic areas. We hypothesize that, in contrast to most HIV seronegative women who are infected with oncogenic types of HPV; HIV seropositive women co-infected with oncogenic types of HPV acquired the molecular changes which permit, and are associated with progression to ICC even before cytologic changes are detected, or when only mild changes such as CIN 1 are present. We further hypothesize that such molecular changes, which are predictive of increased ICC risk can be identified and could serve as the basis for sensitive and specific assays, with high predictive value, for the early identification of HIV, infected women at high risk of ICC. Our approach to developing relevant molecular assays is based on the knowledge that the set of expressed genes, or """"""""expression profile"""""""" of normal cells differs from that of cancer and dysplastic cells of the same tissue type [Fields, 1994]. We propose to biopsy HIV seropositive and HIV seronegative women infected with oncogenic HPV types and with varying grades of cervical lesion abnormalities (CIN 1, CIN 2/3, CIS, ICC) and examine the expression profiles of these different lesions to identify changes in gene expression that are characteristic of malignancy but occur prior to ICC (i.e., in CIS). Once such profiles are identified, we will determine and compare the frequency with which abnormally expressed genes are present in earlier precursor lesions among HIV seropositive and HIV seronegative women. Validation on additional samples, and proof of principle testing on stored longitudinal samples from women who did and did not subsequently develop CIN 3/CIS, will be performed. This will provide the rationale for future development of """"""""low tech"""""""" ELISA assays for detection of the protein products of the over-expressed genes of interest and for longitudinal studies demonstrating the utility of this approach.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA097275-02
Application #
6647638
Study Section
Special Emphasis Panel (ZRG1-SNEM-5 (02))
Program Officer
Starks, Vaurice
Project Start
2002-08-16
Project End
2007-07-31
Budget Start
2003-08-25
Budget End
2004-07-31
Support Year
2
Fiscal Year
2003
Total Cost
$547,547
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Hanisch, Rachel A; Cherne, Stephen L; Sow, Papa Salif et al. (2014) Human papillomavirus type 16 viral load in relation to HIV infection, cervical neoplasia and cancer in Senegal. Cancer Epidemiol 38:369-75
Hanisch, R A; Sow, P S; Toure, M et al. (2013) Influence of HIV-1 and/or HIV-2 infection and CD4 count on cervical HPV DNA detection in women from Senegal, West Africa. J Clin Virol 58:696-702
Heitzinger, K; Sow, P S; Dia Badiane, N M et al. (2012) Trends of HIV-1, HIV-2 and dual infection in women attending outpatient clinics in Senegal, 1990-2009. Int J STD AIDS 23:710-6
Holmes, Rebecca S; Hawes, Stephen E; Toure, Papa et al. (2009) HIV infection as a risk factor for cervical cancer and cervical intraepithelial neoplasia in Senegal. Cancer Epidemiol Biomarkers Prev 18:2442-6
Mair, C; Hawes, S E; Agne, H D et al. (2008) Factors associated with CD4 lymphocyte counts in HIV-negative Senegalese individuals. Clin Exp Immunol 151:432-40
Rowhani-Rahbar, Ali; Hawes, Stephen E; Sow, Papa Salif et al. (2007) The impact of HIV status and type on the clearance of human papillomavirus infection among Senegalese women. J Infect Dis 196:887-94
Hawes, Stephen E; Critchlow, Cathy W; Sow, Papa Salif et al. (2006) Incident high-grade squamous intraepithelial lesions in Senegalese women with and without human immunodeficiency virus type 1 (HIV-1) and HIV-2. J Natl Cancer Inst 98:100-9
Sova, Pavel; Feng, Qinghua; Geiss, Gary et al. (2006) Discovery of novel methylation biomarkers in cervical carcinoma by global demethylation and microarray analysis. Cancer Epidemiol Biomarkers Prev 15:114-23