Infection with oncogenic human papillomaviruses (HPV) is necessary, but not sufficient, for development of ICC and exposure to other co-carcinogens is required for progression to malignancy. After adjusting for the presence of oncogenic HPV, multiple studies report C. trachomatis, a non-oncogenic, obligate intracellular pathogen is a risk factor for ICC. We hypothesize that C. trachomatis infection increases risk of malignancy as a result of inducing aberrant DNA methylation in the promoter region of a variety of genes, including some relevant to the pathogenesis of ICC. Aberrant DNA methylation, widely accepted as important in the pathogenesis of cancers, including ICC, is an epigenetic change associated with the abnormal silencing or activation of gene transcription, and we have previously identified 30 hypermethylated ICC associated genes. Support for our hypothesis includes: 1) C. trachomatis elicits prolonged chronic inflammation which produces high levels of reactive oxygen species, known to damage DNA and alter cellular methylation. 2) C. trachomatis is an obligate intracellular pathogen, which can establish persistent infection. In vitro studies have shown that, even in the absence of integration, intracellular pathogens alter patterns of cellular methylation. 3) A review of our recent in-vitro studies describing alterations of cellular gene transcription associated with C. trachomatis infection revealed that a substantial number of the 30 genes we have shown are aberrantly methylated in association with ICC were down regulated as a result of C. trachomatis infection [Preliminary Studies]. To determine whether C. trachomatis contributes to the pathogenesis of ICC by inducing aberrant DNA methylation, we are proposing a study based in West Africa, where cervical cancer is, and is likely to remain, a major public health problem. We hypothesize that a subset of our 30 ICC-associated hypermethylated genes will be associated with serologic evidence of C. trachomatis infection among women with, and without, ICC. Complementary in vitro studies in HPV 16 E6/E7 immortalized ectocervical cells will provide insights into the molecular basis and natural history of such changes. This study will provide information about the well established, but not well understood association between infection, inflammation, and cancer, and, may support the development of novel treatment approaches based on alteration of aberrant patterns of methylation, which in phase one trials appear promising.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA115713-04
Application #
7630390
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Blair, Donald G
Project Start
2006-07-13
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
4
Fiscal Year
2009
Total Cost
$490,342
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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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
Deftereos, Georgios; Corrie, Simon R; Feng, Qinghua et al. (2011) Expression of mir-21 and mir-143 in cervical specimens ranging from histologically normal through to invasive cervical cancer. PLoS One 6:e28423