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

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DIVISION OF MOLECULAR EPIDEMIOLOGYF. Kadlubar,
DirectorL. Poirier, Acting Director

• MAJOR RESEARCH AREAS
• Identification of genetic polymorphisms that
  influence carcinogen metabolism, DNA repair and
  individual
• cancer susceptibility.
• Chemoprevention

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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

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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
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STUDY DESIGN

• African-American (n54), Hispanic (n72), and
  Caucasian (n66) 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.

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Genotype Distribution at Onset of Puberty
70
T2B
60
50
No. of Individuals
40
30
20
10
0
CYP17A1/A1
CYP17A1/A2
CYP17A2/A2
Genotype
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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).

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Expression of GSTA1/GSTA2 in human liver
14
14
A1A
12
12
10
10
A1A/B
8
8
GSTA1 mg/mg cytosolic protein
GSTA1 mg/mg cytosolic protein
6
6
A1B
4
4
2
2
GSTA2 mg/mg cytosolic protein
GSTA2 mg/mg cytosolic protein
0
2
4
6
8
10
0
2
4
6
8
10
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Expression of GSTA1/GSTA2 in human liver
according to hGSTA1 genotype
14
A1A
12
10
A1A/B
8
GSTA1 mg/mg cytosolic protein
6
A1B
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
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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
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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).

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Junjian Chen Somatic Alteration of Prostate
Cancer and Precursor Lesions

• 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.

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George Hammons Mechanisms 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.

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LIVER CYP1A2 EXPRESSION IN SMOKERS VS. PROMOTER
METHYLATION STATUS
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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.

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B. Lyn-Cook Future Plans

• 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.

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L. Poirier
Major Projects DNA methylation and cancer
risk in humans and experimental
animals. Abnormal methyl metabolism in
nonneoplastic diseases.
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PLASMA HOMOCYSTEINE IN RATS FED A
METHYL-DEFICIENT, HOMOCYSTINE-SUPPLEMENTED DIET
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INTIMAL HYPERPLASIA AS A FUNCTION OF PLASMA
HOMOCYSTEINE LEVELS
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L. PoirierRECENT 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-adenosylhomocyste
  ine.
• In both humans and rats, SAM availability appears
  to be inversely proportional to calorie intake.

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L. Poirier FUTURE PROJECTS

• Collaborate with NCI on methylation parameters in
  a case/control colon adenoma study.
• Extend collaborative studies on DNA and gene
  methylation in rats undergoing hepatocarcinogenesi
  s 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.