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 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

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

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.

Genotype Distribution at Onset of Puberty T2B No. of Individuals 0 CYP17*A1/*A1CYP17*A1/*A2CYP17*A2/*A2 Genotype

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).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).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).Recurrence of colorectal polyps with respect to GST genetic polymorphism, MTHFR & GPX polymorphism (F. Kadlubar).

GSTA1  g/mg cytosolic protein GSTA2  g/mg cytosolic protein Expression of GSTA1/GSTA2 in human liver A1*A A1*B A1*A/*B GSTA1  g/mg cytosolic protein GSTA2  g/mg cytosolic protein

GSTA1  g/mg cytosolic protein GSTA2  g/mg cytosolic protein Expression of GSTA1/GSTA2 in human liver according to hGSTA1 genotype A1*A A1*B A1*A/*B

Proportion Surviving Years from Diagnosis *A/*A *A/*B *B/*B Overall Survival among 196 Women with Breast Cancer by GSTA1 Genotype

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).

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

George Hammons Mechanisms of CYP1A2 gene regulationPROJECTS: Hepatic DNA methyltransferase activity in smokers (B. Lyn-Cook et al.). 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). 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. 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. Hypermethylation of the promoter region of the CYP1A2 gene was associated with decreased expression.

LIVER CYP1A2 EXPRESSION IN SMOKERS VS. PROMOTER METHYLATION STATUS

B. Lyn-Cook B. Lyn-Cook IN 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.

B. Lyn-Cook Future Plans Undertake mechanistic studies on the biological and pharmacological actions of chemopreventive agents. 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 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. Conduct global methylation studies on H-K-ras methylation patterns in human lymphocytes from a case-control study of colon adenomas.

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

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

INTIMAL HYPERPLASIA AS A FUNCTION OF PLASMA HOMOCYSTEINE LEVELS

CORRELATIONS BETWEEN HOMOCYST(E)INE AND GROWTH- AND SAM-RELATED PARAMETERS L. Poirier RECENT CORRELATIONS BETWEEN HOMOCYST(E)INE AND GROWTH- AND SAM-RELATED PARAMETERS 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.

FUTURE PROJECTS L. Poirier FUTURE PROJECTS Collaborate with NCI on methylation parameters in a case/control colon adenoma study. 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. 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. Complete collaborative clinical studies on abnormal methyl metabolism associated with nonneoplastic disease. Coorganize trans-HHS Workshop: Diet, DNA Methylation Processes and Health. Coorganize trans-HHS Workshop: Diet, DNA Methylation Processes and Health.