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DIVISION OF MOLECULAR EPIDEMIOLOGY F. Kadlubar, Director L. Poirier, Acting Director

MAJOR RESEARCH AREAS : Identification of genetic polymorphisms that influence carcinogen metabolism, DNA repair and individual cancer susceptibility. Chemoprevention. DIVISION OF MOLECULAR EPIDEMIOLOGY F. Kadlubar, Director L. Poirier, Acting Director.

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DIVISION OF MOLECULAR EPIDEMIOLOGY F. Kadlubar, Director L. Poirier, Acting Director

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  1. MAJOR RESEARCH AREAS: Identification of genetic polymorphisms that influence carcinogen metabolism, DNA repair and individual cancer susceptibility. Chemoprevention DIVISION OF MOLECULAR EPIDEMIOLOGYF. Kadlubar, DirectorL. Poirier, Acting Director

  2. Division of Molecular Epidemiology CURRENT STAFF • The Division consists of: • 7 senior staff (6.5 FTEs, including 1 vacant) • 8 postdoctoral appointees • 12 support staff (6 FTEs) • 2 graduate students • 2 administrative staff • Collaboration with UAMS/VA involve shared laboratory resources with Dr. Lang that consist of: • 1 postdoctoral fellow • 8 support staff • 1 graduate student

  3. Principal Investigator: Fred Kadlubar Current Projects:Genetic Polymorphisms, DNA Adduct Detection in Humans, and Molecular Epidemiologic Studies Applications of DNA Microarray Chip to Population-based Studies

  4. STUDY DESIGN • African-American (n=54), Hispanic (n=72), and Caucasian (n=66) girls , 9.5  0.3 years of age were entered into the study. • Dietary intake, weight, BMI, environmental exposures and personal information were obtained. • Onset of puberty was determined from Tanner breast scores, with T2B designated as initial breast growth. • Blood samples were taken and genotypes for CYP17, CYP1A2, CYP1B1, and CYP3A4 were determined.

  5. Genotype Distribution at Onset of Puberty 70 +T2B 60 50 No. of Individuals 40 30 20 10 0 CYP17*A1/*A1 CYP17*A1/*A2 CYP17*A2/*A2 Genotype

  6. Genotype Distribution at Onset of Puberty 80 +T2B 70 60 No. of Individuals 50 40 30 P = 0.012 20 10 0 CYP3A4*1A/*1A CYP3A4*1A/*1B CYP3A4*1B/*1B Genotype

  7. B. Coles Glutathione S-transferase (GST) polymorphism:Susceptibility to cancer and response to chemotherapeutics • Major studies: • Case-control study of colorectal cancer incidence with respect to hGSTA1 polymorphism (F. Kadlubar). • Retrospective case study on survival of breast cancer after chemotherapy with respect to GST genotype and GST phenotype in tumor (C. Ambrosone, C. Sweeney, F. Kadlubar). • Recurrence of colorectal polyps with respect to GST genetic polymorphism, MTHFR & GPX polymorphism (F. Kadlubar).

  8. Expression of GSTA1/GSTA2 in human liver 14 14 A1*A 12 12 10 10 A1*A/*B 8 8 GSTA1 mg/mg cytosolic protein GSTA1 mg/mg cytosolic protein 6 6 A1*B 4 4 2 2 GSTA2 mg/mg cytosolic protein GSTA2 mg/mg cytosolic protein 0 0 2 2 4 4 6 6 8 8 10 10

  9. Expression of GSTA1/GSTA2 in human liver according to hGSTA1 genotype 14 A1*A 12 10 A1*A/*B 8 GSTA1 mg/mg cytosolic protein 6 A1*B 4 2 GSTA2 mg/mg cytosolic protein 0 2 4 6 8 10

  10. Overall Survival among 196 Women with Breast Cancer by GSTA1 Genotype 1 *B/*B 0.8 *A/*B Proportion Surviving 0.6 *A/*A 0.4 0.2 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Years from Diagnosis

  11. B. Coles FUTURE DIRECTIONS • Critical examination of study breast cancer response to chemotherapy: additional study populations; pharmacogenetic variations; alterated enzyme kinetics. • Examination of additional polymorphism in GSTs (protein & gene) and of tissue-specific GST expression as potential factors in susceptibility to disease and chemotherapeutic response. • Continuation of study: GSTs and colorectal neoplasia (Arizona Cancer Center).

  12. Validation of DNA SNP microarray chip for application to population-based studies. Investigation of genetic and epigenetic alterations of specific cells using laser capture microdissection-based approach. Examination of mutations in mitochonrdrial DNA to investigate prospective role of oxidative stress in prostate cancer. Determination of hypermethylation of GSTP1 promoter as an early marker of prostatic cancer. Junjian Chen Somatic Alteration of Prostate Cancer and Precursor Lesions

  13. George HammonsMechanisms of CYP1A2 gene regulation • PROJECTS: • Hepatic DNA methyltransferase activity in smokers (B. Lyn-Cook et al.). • Determination of individual methylation profiles, gene expression , and enzyme activity of CYP1A2 in human livers (B. Lyn-Cook, Y. Yan-Sanders). • ACCOMPLISHMENTS: • Hepatic DNA methyltransferase was significantly higher in smokers than in non-smokers. • Hypermethylation of the promoter region of the CYP1A2 gene was associated with decreased expression.

  14. LIVER CYP1A2 EXPRESSION IN SMOKERS VS. PROMOTER METHYLATION STATUS

  15. B. Lyn-CookIN VITRO STUDIES ON PANCREATIC CANCER AND TOXICITY • Major Projects: • Biomarkers of pancreatic cancer. • Establish biomarkers of cancer in high risk groups, e.g. smokers vs. nonsmokers. • Develop in vitro predictive bioassays for chemopreventive agents. • Toxicity. • Investigate the molecular and cellular effects of nicotine, soy, and tea components on pancreatic cells in culture. • Determine the mechanism of action of such agents.

  16. The effects of Soy components on normal pancreatic cells (HP-43) 80 70 60 50 % Expression of K-ras 40 30 20 10 0 control Coumestrol Equol Genistein Biochanin Treatment

  17. K-ras Expression in Human Pancreatic Tumor Cells: The effects of SoyComponents 500 400 300 % of Expression 200 100 0 Control Coumestrol Equol Genistein Biochanin A Treatment (female cell line)

  18. Undertake mechanistic studies on the biological and pharmacological actions of chemopreventive agents. Conduct site-specific methylation studies on the promoter region of the IGF-1 gene in lymphocytes from a case-control study of colon adenomas. Conduct global methylation studies on H-K-ras methylation patterns in human lymphocytes from a case-control study of colon adenomas. B. Lyn-CookFuture Plans

  19. L. Poirier Major Projects: DNA methylation and cancer risk in humans and experimental animals. Abnormal methyl metabolism in nonneoplastic diseases.

  20. PLASMA HOMOCYSTEINE IN RATS FED A METHYL-DEFICIENT, HOMOCYSTINE-SUPPLEMENTED DIET

  21. INTIMAL HYPERPLASIA AS A FUNCTION OF PLASMA HOMOCYSTEINE LEVELS

  22. Dietary homocystine raises the plasma level of homocysteine in rats and accelerates the formation of atherosclerotic plaques. In diabetics, high plasma levels of homocysteine is accompanied by elevated blood levels of both S-adenosylmethionine (SAM) and S-adenosylhomocysteine. In both humans and rats, SAM availability appears to be inversely proportional to calorie intake. L. PoirierRECENT CORRELATIONS BETWEEN HOMOCYST(E)INE AND GROWTH- AND SAM-RELATED PARAMETERS

  23. Collaborate with NCI on methylation parameters in a case/control colon adenoma study. Extend collaborative studies on DNA and gene methylation in rats undergoing hepatocarcinogenesis by dietary methyl deprivation. Complete collaborative clinical studies on abnormal methyl metabolism associated with nonneoplastic disease. Coorganize trans-HHS Workshop: Diet, DNA Methylation Processes and Health. L. PoirierFUTURE PROJECTS

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