We propose to assess the impact of sex-steroid hormones and prostate cancer (PCa) progression in the context of the recently identified TMPRSS2:ERG translocation, a novel gene fusion of the 5'-untranslated region of the androgen-regulated TMPRSS2 promoter and the ETS transcription factor family member. The TMPRSS2:ERG translocation is a common molecular event in PCa, and emerging data (including our own) suggest men with tumors with the translocation tend to have a worse cancer prognosis. The regulation of TMPRSS2 by androgens and possibly estrogens is intriguing and illuminates a potential mechanism whereby sex hormones could drive tumor growth and proliferation leading to worse cancer survival. We have identified 1,500 men diagnosed with incident PCa in the Physicians'Health Study and Health Professionals Follow-up Study during 1982 to 2006, and will continue prospective follow-up through 2012 for outcomes (175 will have developed metastatic or fatal disease). We have assembled a repository of archival tumor tissue, and will characterize the TMPRSS2:ERG tumor status using fluorescent in situ hybridization. We will explore the role of the TMPRSS2:ERG fusion on PCa progression. Moreover, we will examine whether circulating levels of sex hormones or variation in genes involved in sex hormone signaling or metabolism interact with the fusion to affect progression;we hypothesize that men with fusion positive tumors have a worse prognosis if they are exposed to high sex hormone levels. We will evaluate whether obesity, with its known regulation of the hormonal milieu causing higher levels of estrogen and reduced testosterone, is associated with PCa progression by interacting with the TMPRSS2:ERG fusion. At the tumor level, we will examine the relation between fusion status, alone and in concert with hormones, and extent of tumor angiogenesis, cellular proliferation and apoptosis. Finally, we will evaluate whether men with fusion positive tumors have a more favorable response to androgen deprivation therapy compared to those without the TMPRSS2:ERG fusion. Based on the incidence of PCa in the United States and frequency of the fusion, more than 100,000 men diagnosed each year have a fusion positive PCa. If these tumors are indeed more aggressive, this number reflects a considerable burden of men at risk of progression. As such, an understanding of the TMPRSS2:ERG fusion on PCa survival in light of the hormonal milieu could have significant public health impact, and illuminate opportunities for primary and secondary prevention or improved patient selection for specific therapeutic intervention.

Public Health Relevance

PCa is a significant public health burden with respect to morbidity and mortality among men in the Western World. The recent identification of a common novel translocation in PCa, the TMPRSS2:ERG fusion, may help explain the heterogeneity of this disease, although there is still limited research in this area. Our study seeks to explore the role of the TMPRSS2:ERG translocation in PCa progression within two large, community-based cohorts of men with PCa, and to understand whether genetic factors, hormones or lifestyle factors interact with the fusion to impact cancer mortality.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136578-04
Application #
8210940
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Woodhouse, Elizabeth
Project Start
2009-03-03
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$337,130
Indirect Cost
$109,037
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Ahearn, Thomas U; Pettersson, Andreas; Ebot, Ericka M et al. (2016) A Prospective Investigation of PTEN Loss and ERG Expression in Lethal Prostate Cancer. J Natl Cancer Inst 108:
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Kelly, Rachel S; Vander Heiden, Matthew G; Giovannucci, Edward et al. (2016) Metabolomic Biomarkers of Prostate Cancer: Prediction, Diagnosis, Progression, Prognosis, and Recurrence. Cancer Epidemiol Biomarkers Prev 25:887-906

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