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Grant Details

Grant Number: 7R03CA128038-02 Interpret this number
Primary Investigator: Reisman, David
Organization: University Of Florida
Project Title: Brm Promoter Polymorphism, a Marker for Cancer Risks
Fiscal Year: 2009
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Abstract

DESCRIPTION (provided by applicant): Identifying genetic alterations underlying cancer risk is essential for cancer screening and chemoprevention strategies that can successfully reduce the growing incidence of cancer deaths. This is particularly true with lung cancer, which causes more cancer deaths than breast, colon and prostate cancer combined, and accounts for more than 162,000 deaths annually. To this end, we have found that the loss of the BRM gene may be an important factor underlying cancer risk. BRM is an essential subunit of the chromatin remodeling complex SWI/SNF, which is involved in cell development, differentiation, and growth control. This complex is required by a variety of transcription factors and key cellular proteins. The loss of BRM by abrogation of the SWI/SNF complex will disrupt the function of a number of important antitumorigenic proteins, such as Rb, p53 and BRCA1. In mice, loss of BRM yields cells that display abnormalities in cell cycle control in vitro, while in vivo, loss of BRM significantly potentiates carcinogen-induced tumorigenicity. In humans, we have found that BRM is silenced not only in cancer cell lines but also in a variety of solid tumor types. Moreover, in cells lacking BRM expression, we have found that the BRM gene is epigenetically silenced and can be restored using small molecular inhibitors known to inhibit histone deacetylase proteins. Given that BRM loss can antagonize antitumorigenic pathways and potentiate tumor development in animal models, the loss of BRM expression is likely involved cancer development. Significantly, we found in cancer cell lines that the loss of BRM expression specifically correlates with the presence of two polymorphic 6-7bp insertions within the BRM promoter. These polymorphic sites are highly similar to binding sites of the transcription factor MEF2; thus, the presence of these BRM-promoter polymorphic sites might not only correlate with the loss of BRM but also play a direct role in turning off the BRM gene during cancer development. As the homozygous presence of these polymorphic sites correlates with BRM silencing, we hypothesize that these polymorphic sites increase the risk of BRM silencing and as a consequence may be important markers for predicting cancer risk. The goal of this application is to validate our initial findings by determining in primary lung cancers whether the presence of these polymorphic sites indeed correlates with loss of BRM expression and whether this loss also involves loss of heterozygosity. . In addition, to further test this hypothesis, the goal of this study to determine if these polymorphic sites are associated with increase cancer risk. The establishment of such markers is needed to combat cancer but especially important in lung cancer, as no genetic risk factors have been identified for lung cancer and there is no effective screening test to detect it in its early stages.

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Publications

BRM Promoter Polymorphisms and Survival of Advanced Non-Small Cell Lung Cancer Patients in the Princess Margaret Cohort and CCTG BR.24 Trial.
Authors: Liu G. , Cuffe S. , Liang S. , Azad A.K. , Cheng L. , Brhane Y. , Qiu X. , Cescon D.W. , Bruce J. , Chen Z. , et al. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2017-05-15; 23(10), p. 2460-2470.
EPub date: 2016-11-08.
PMID: 27827316
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Two novel BRM insertion promoter sequence variants are associated with loss of BRM expression and lung cancer risk.
Authors: Liu G. , Gramling S. , Munoz D. , Cheng D. , Azad A.K. , Mirshams M. , Chen Z. , Xu W. , Roberts H. , Shepherd F.A. , et al. .
Source: Oncogene, 2011-07-21; 30(29), p. 3295-304.
EPub date: 2011-04-11.
PMID: 21478907
Related Citations

Pharmacologic reversal of epigenetic silencing of the anticancer protein BRM: a novel targeted treatment strategy.
Authors: Gramling S. , Rogers C. , Liu G. , Reisman D. .
Source: Oncogene, 2011-07-21; 30(29), p. 3289-94.
EPub date: 2011-04-11.
PMID: 21478905
Related Citations




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