Our long-standing goal is to understand the role that human papillomaviruses (HPVs) play in the etiology of cancer, and to identify other risk factors that cause only some HPV infected individuals to progress to cancer. Previously we have focused on a group of high-risk genus alpha HPVs and have showed that they have a causal role in anogenital cancers. In addition, we identified immunogenetic factors that influenced the development of cervical cancer. We also identified a number of factors that were known or thought to be associated with immunosuppression, such as smoking and corticosteroid use that were common among the squamous cell anogenital cancers. This prompted us to direct our attention to the possibility that a different set of HPVs, known as genus beta- or EV HPVs, are involved (together with immunosuppression and UV damage) in the etiology of squamous cell cancer of the skin (SCSC). To test this hypothesis Project 1 will establish a nested case control study of SCSC among organ transplant recipients (OTR). We will identify the genus beta HPV types present in SCSC tumor tissue, the types and viral load resident in hair follicles of cases and controls, and HPV antibodies in blood samples drawn prior to transplantation. Associations with HPV markers will be estimated accounting for other SCSC risk factors such as immunosuppressive drugs, sunlight exposure and other characteristics. In a parallel longitudinal study, Project 1 will also examine the natural history of genus beta HPVs in the OTR population. Project 2 will focus on the mechanisms by which the genus beta E6 and E7 proteins contribute to malignancy by studying their ability to bypass UV damage checkpoints, inhibit apoptosis, disrupt p53 function and stimulate proliferation. We hypothesize that infection with genus beta HPVs can lead to increased proliferation of squamous cells, and that the HPV oncoproteins inhibit the normal response to UV-induced DNA damage, i.e. repair or apoptosis, allowing cells with mutations in tumor suppressors or oncogenes to accumulate changes that lead to cancer. Project 3 will focus on identifying genetic risk factors for HPV related cancers. For SCSC in OTRs, polymorphisms in genes in both the innate and adaptive immune response pathways will be interrogated, as well as genes in the UV-induced DNA damage repair pathway. We will also study polymorphisms in genes in the Toll-like receptor pathway in cervical and vulvar cancers, taking advantage of our large population-based cases and controls accrued in prior funding periods. Four cores will support these three projects: Molecular Biology, Pathology, Data Management and Biostatistics, and Administration. If a strong link between specific HPV types and SCSC can be verified in studies such as the ones we propose, this information will have important translational benefit in diagnosis, therapy and prevention. We bring an experienced, highly integrated, multidisciplinary team to address this important problem.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA042792-23
Application #
8118874
Study Section
Special Emphasis Panel (ZCA1-RPRB-5 (S1))
Program Officer
Starks, Vaurice
Project Start
1997-06-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
23
Fiscal Year
2011
Total Cost
$1,952,686
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Leo, Paul J; Madeleine, Margaret M; Wang, Sophia et al. (2017) Defining the genetic susceptibility to cervical neoplasia-A genome-wide association study. PLoS Genet 13:e1006866
Madeleine, Margaret M; Johnson, Lisa G; Doody, David R et al. (2016) Natural Antibodies to Human Papillomavirus 16 and Recurrence of Vulvar High-Grade Intraepithelial Neoplasia (VIN3). J Low Genit Tract Dis 20:257-60
Hardikar, Sheetal; Johnson, Lisa G; Malkki, Mari et al. (2015) A population-based case-control study of genetic variation in cytokine genes associated with risk of cervical and vulvar cancers. Gynecol Oncol 139:90-6
Wallace, Nicholas A; Robinson, Kristin; Howie, Heather L et al. (2015) ?-HPV 5 and 8 E6 disrupt homology dependent double strand break repair by attenuating BRCA1 and BRCA2 expression and foci formation. PLoS Pathog 11:e1004687
Galloway, Denise A; Laimins, Laimonis A (2015) Human papillomaviruses: shared and distinct pathways for pathogenesis. Curr Opin Virol 14:87-92
Safaeian, Mahboobeh; Johnson, Lisa G; Yu, Kai et al. (2014) Human Leukocyte Antigen Class I and II Alleles and Cervical Adenocarcinoma. Front Oncol 4:119
Madeleine, Margaret M; Carter, Joseph J; Johnson, Lisa G et al. (2014) Risk of squamous cell skin cancer after organ transplant associated with antibodies to cutaneous papillomaviruses, polyomaviruses, and TMC6/8 (EVER1/2) variants. Cancer Med 3:1440-7
Wallace, Nicholas A; Galloway, Denise A (2014) Manipulation of cellular DNA damage repair machinery facilitates propagation of human papillomaviruses. Semin Cancer Biol 26:30-42
Wallace, Nicholas A; Robinson, Kristin; Galloway, Denise A (2014) Beta human papillomavirus E6 expression inhibits stabilization of p53 and increases tolerance of genomic instability. J Virol 88:6112-27
Bodelon, Clara; Madeleine, Margaret M; Johnson, Lisa G et al. (2014) Genetic variation in the TLR and NF-?B pathways and cervical and vulvar cancer risk: a population-based case-control study. Int J Cancer 134:437-44

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