We propose to use a molecular epidemiologic approach in a case-control study to identify interindividual differences in susceptibility to tobacco-induced carcinogenesis as predictors of BC risk. This will include assessing susceptibility at several aspects of tobacco-induced carcinogenesis, including the genetically modulated activation and detoxification of tobacco mutagens and chromosome sensitivity to these mutagens. We will accrue 200 patients with superficial BC and 200 patients with invasive BC of any age and ethnicity and of either sex who have not received chemotherapy or radiotherapy. We will also prospectively select 400 controls from a potential large control pool identified from the rosters of the largest multispecialty healthcare group practice in the Houston metropolitan area. These controls will be matched to the patients by sex, age (plus /minus 5 years), and ethnicity. Comprehensive epidemiologic profiles will be constructed for these patients and controls.
The specific aims are: 1) To assess in patients with BC and in controls two mutagen sensitivity susceptibility assays performed in parallel, one that quantifies the number of lymphocytic chromatid breaks induced by in vitro exposure to bleomycin (a radiomimetic agent) and another that quantifies the number of breaks induced by in vitro exposure to benzo[a]pyrene diol-epoxide (BPDE; the activated form of benzo[alpha]pyrene, a tobacco carcinogen). Our hypothesis is that subjects who show increased bleomycin- and BPDE- chromosome sensitivity are at greater risk for BC than are those who do not show these sensitivities. Using the two tobacco mutagen sensitivity assays in parallel will improve our ability to identify populations at high-risk for BC (case-control analysis) and for invasive compared with superficial BC (case-case analysis); 2) To determine in patients and controls the frequencies of polymorphisms in those genes that regulate the metabolism of carcinogens in tobacco smoke, such as cytochrome P450 (CYP) 1A1, CYP2E1, glutathione-S-transferase (GST) mu and theta, epoxide hydrolase 3 (EPHX3) EPHX4, myeloperoxidase (MPO), N-acetyltransferase (NAT)1, and NAT2. Our hypothesis is that an inherent susceptibility to BC is associated with metabolic enzyme genetic polymorphisms that modulate activation and detoxification of tobacco carcinogen. 3) To explore the associations between the cytogenetic and molecular components and epidemiologic covariates (age, sex, ethnicity, cigarette smoking status, alcohol use and dietary intake, and family history of cancer) in risk of BC overall and by subtype. We will integrate epidemiologic data with the genetic data from the studies described in Specific Aims 1 and 2. Our long-term plan is to refine our risk assessment in patients with BC so that we can identify high-risk subgroups of candidates for primary and secondary prevention measures.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA074880-02
Application #
6150311
Study Section
Special Emphasis Panel (ZRG4-EDC-2 (02))
Program Officer
Seminara, Daniela
Project Start
1999-02-22
Project End
2004-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
2
Fiscal Year
2000
Total Cost
$336,827
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Lin, Moubin; Zhang, Liren; Hildebrandt, Michelle A T et al. (2017) Common, germline genetic variations in the novel tumor suppressor BAP1 and risk of developing different types of cancer. Oncotarget 8:74936-74946
Pierzynski, Jeanne A; Hildebrandt, Michelle A; Kamat, Ashish M et al. (2015) Genetic Variants in the Wnt/?-Catenin Signaling Pathway as Indicators of Bladder Cancer Risk. J Urol 194:1771-6
Ke, Hung-Lung; Lin, Jie; Ye, Yuanqing et al. (2015) Genetic Variations in Glutathione Pathway Genes Predict Cancer Recurrence in Patients Treated with Transurethral Resection and Bacillus Calmette-Guerin Instillation for Non-muscle Invasive Bladder Cancer. Ann Surg Oncol 22:4104-10
Figueroa, Jonine D; Ye, Yuanqing; Siddiq, Afshan et al. (2014) Genome-wide association study identifies multiple loci associated with bladder cancer risk. Hum Mol Genet 23:1387-98
Ke, Hung-Lung; Chen, Meng; Ye, Yuanqing et al. (2013) Genetic variations in micro-RNA biogenesis genes and clinical outcomes in non-muscle-invasive bladder cancer. Carcinogenesis 34:1006-11
Wang, J; Wu, X; Kamat, A et al. (2013) Fluid intake, genetic variants of UDP-glucuronosyltransferases, and bladder cancer risk. Br J Cancer 108:2372-80
Fernández, Mario I; Gong, Yilei; Ye, Yuanqing et al. (2013) ?-H2AX level in peripheral blood lymphocytes as a risk predictor for bladder cancer. Carcinogenesis 34:2543-7
Lee, Eugene K; Ye, Yuanquing; Kamat, Ashish M et al. (2013) Genetic variations in regulator of G-protein signaling (RGS) confer risk of bladder cancer. Cancer 119:1643-51
de Maturana, Evangelina López; Ye, Yuanqing; Calle, M Luz et al. (2013) Application of multi-SNP approaches Bayesian LASSO and AUC-RF to detect main effects of inflammatory-gene variants associated with bladder cancer risk. PLoS One 8:e83745
Xing, Jinliang; Dinney, Colin P; Shete, Sanjay et al. (2012) Comprehensive pathway-based interrogation of genetic variations in the nucleotide excision DNA repair pathway and risk of bladder cancer. Cancer 118:205-15

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