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Cancer Molecular Epidemiology

Cancer Molecular Epidemiology. Epidemiology 242 2009. Numbers of Papers/Year Published with Subject Words “Molecular Epidemiology” Using Pubmed Search. Evolution of Epidemiology in History. Systematic collection and analysis of vital statistics

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Cancer Molecular Epidemiology

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  1. Cancer Molecular Epidemiology Epidemiology 242 2009

  2. Numbers of Papers/Year Published with Subject Words “Molecular Epidemiology” Using Pubmed Search

  3. Evolution of Epidemiology in History • Systematic collection and analysis of vital statistics • Defined triad of agent-host-vector for both infectious and chronic disease • Refine exposure assessment such as job-exposure matrix, dietary and nutritional analysis • Defined study design such as case-control and cohort study • Use of the advance of statistical and computational capacities (MLE, Logistic regression, poission regression)

  4. Evolution of Epidemiology • Now, it is the time to add biological variables (physiologic, cellular, subcellular, molecular levels), which can be assayed by technically powerful biological methods • Molecular epidemiology is the use of these biological markers in epidemiology research.

  5. Epidemiology and Molecular Sciences Epidemiology Molecular Sciences • Health effects in grouped people • Observation and inference of association between variables • Macro • Assessment of the individual at the component level • Experimental proof of cause and effects • Micro

  6. Molecular Epidemiology and Traditional Epidemiology • These capacities provide additional tool for epidemiologists studying questions on etiology, prevention and control of diseases • Although molecular epidemiology can be viewed as an evolution step of epidemiology, it generally dose not represent a shift in the basic paradigm of epidemiology

  7. Traditional and Molecular EpidemiologyTraditional Molecular • Association • High exposure and single outcome • Prevention through control of exposure is feasible without understanding cellular process • Mechanisms • Smaller and mixed exposures; multicausal • Intervention through cellular process has the need to understand mechanisms of the process

  8. Basics of Molecular Epidemiology • The term of molecular epidemiology indicates the incorporation of molecular, cellular, and other biological measurements into epidemiologic studies

  9. Molecular Epidemiology • studies utilizing biological markers of exposure, disease and susceptibility • studies which apply current and future generations of biomarkers in epidemiologic research.

  10. Functional Definition of Molecular Epidemiology • The use of biologic markers or biologic measurements in epidemiologic research. Biological markers (or biomarkers) generally include biochemical, molecular, genetic, immunologic, or physiologic signals of events in biologic system.

  11. Molecular Epidemiology • The goal of molecular epidemiology is to supplement and integrate, not to replace, existing methods • Molecular epidemiology can be utilized to enhance capacity of epidemiology to understand disease in terms of the interaction of the environment and heredity.

  12. Capacities of Molecular Epidemiology • Identification of Exposure at the smaller scale • Identification of events earlier in the nature history of disease • Evaluation of gene-environment interaction • In addition, it can be used to reduce misclassification, to indicate mechanisms, and enhance risk assessment

  13. Study of Black Box The concept of a continuum of events between exposure and disease provide opportunities • To ensure that epidemiologic research has a biological basis for hypothesis • To provide the analysis to test these ideas • To generate new epidemiological methods to deal with new challenges

  14. Cancer Epidemiol Biomarkers Prev 2007;16(10). October 2007

  15. Measurement of Biomarkers Biomarkers can be measured quantitatively or qualitatively by biochemical, immunochemical, cytogentic, molecular and genetic techniques.

  16. Materials for Biomarker Measurement Biomarkers can be measured in human biological materials including normal and tumor tissues, blood and urine sample, etc.. Their biological nature can be DNA, RNA, and protein, etc.

  17. Study Questions: Exposure Markers • How reliable are the exposure data obtained by questionnaire and what type of misclassification bias result? • How are the carcinogens metabolized? What are the dynamics and distribution of carcinogen metabolization? • What is the concentration of carcinogens in peripheral blood? What is the exposure level in the target tissue? Can we employ the exposure markers measured in peripheral blood to predict the concentrations of exposure at the target tissue?

  18. Exposure Measurements The powerful tools of molecular biology, analytical chemistry, and related disciplines allow measure smaller amounts of exposures (10-18 -10-21) Reconstruct past exposure doses using molecular measurements (biologic dosimetry)

  19. Exposure Biomarkers Mutagenesis vol. 24,117–125, 2009

  20. Exposure Markers: DNA Adducts • Exposure markers are a group of biomarkers, which can indicate the environmental exposures and can be measured in tumor tissues, or blood or urine specimens. • The presence or concentration of specific environmental carcinogens or other agents can be measured in biological specimens, for example, blood levels of cotinine, polycyclic aromatic hydrocarbon (PAH) -DNA adducts, 4-aminobiphenyl (4-ABP) hemoglobin adducts.

  21. Exposure Markers: DNA Adducts • exposure markers measure biological effective dose, that is, the amount of carcinogens bound to DNA in the target tissue such as DNA-adducts, or surrogate measurements which can represent the exposure levels of the target tissue such as hemoglobin adducts

  22. Exposure Markers • Aromatic Amines and 4-ABP DNA-Adducts. The human bladder carcinogens 2-naphtylamine and 4-aminobiphenyl, as well as the suspected carcinogen o-toluidine, are present in tobacco and certain occupational exposures. DNA adducts of 4-aminobiphenyl were found in tumor samples from smokers indicating that this agent may account for some of the carcinogenicity of tobacco smoke

  23. Exposure Markers • Polycyclic Aromatic Hydrocarbons (PAH) and PAH DNA-Adducts. PAHs are produced by incomplete combustion of organic materials and the sources of environmental PAH include industrial and domestic furnaces, gasoline and diesel engines and tobacco smoke. PAHs are carcinogens requiring metabolic activation to react with cellular macromolecules, the initial step in tumorigenesis

  24. PHIP DNA Adducts

  25. P32 postlabeling

  26. Limitations of Exposure Markers • These markers have to be measured in biological materials, which requires the collection of biological specimens; • Some of exposure markers such as hemoglobin-adducts and blood level of cotinine only represent the current exposure status; • The costs for measurement of exposure markers are generally more expensive than that of questionnaire data.

  27. Study Questions: Susceptibility Genes • Which gene or enzymes are involved? • Is there any metabolic phenotype related to the risk of cancer? • Are there any high risk individuals who are susceptible to cancer and how can we identify them?

  28. Susceptibility Markers • Susceptibility markers represent a group of tumor markers, which may make an individual susceptible to cancer. • These markers may be genetically inherited or determined. • They are independent of environmental exposures.

  29. Susceptibility Markers • Tumor susceptibility markers such as P450s, GSTs, and NATs, act in enzymatic pathways related to metabolizing and eliminating carcinogens.

  30. Susceptibility Markers • The phase I enzymes such as p450 enzyme superfamily metabolize exogenous or endogenous agents or carcinogens to intermediates, which can result in DNA damages and act as risk factors for cancer. • The phase II enzymes such as glutathione S-transferase (GST) system are dealing with detoxification of oxygenated intermediates by conjugation process, acting as a protective factors for cancer.

  31. Case 1 Case 2 Case 3 Case 4 Case 5 GST T1 beta-globin GST M1 Figure. GSTM1 and GSTT1 genotyping from buccal cell DNA. Case 5 is null for the GSTT1 genotype. Case 2 is null for the GSTM1 genotype

  32. Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8 ile/val ile/val ile/ile val/val ile/val ile/ile ile/val ile/ile Figure. GSTP1 polymorphism

  33. 14 13 12 11 10 9 8 7 6 5 4 3 2 1 PCR P450 2E1 after Using Pst1 RFLP

  34. Case 1 Case 2 Case 3 Case 4 Case 5 Arg/Arg Arg/Arg Pro/Pro Arg/Arg Arg/Pro Figure. P53 polymorphism at codon 72 from buccal cell DNA.

  35. Interactions between smoking and GST M1(odds ratios* and 95% confidence intervals) 5.29 (1.81, 15.4) 2.79 (0.97, 7.99) 1.13 (0.32, 3.95) 1.00 *Adjusted for age, sex, race, and level of education

  36. Issues in GWAS Studies • False positive (multiple comparison) • False negative (very small p-value) • Population stratification • Gene-Environmental Interaction

  37. Background • In 2006 and 2007 GWAS studies identified associations between SNPs in the 8q24 region and prostate cancer among Icelandic, Swedish, European American, African American, and the Multiethnic Cohort populations.

  38. Research Questions: Genetic and Molecular Alterations • What kinds of damages do the carcinogens make, and is the damage specific? • Does the DNA repair capacity affect risk and how can we measure it? • Is there any gene-gene interaction and is there any gene-environment interaction?

  39. Identification of Earlier Events • Identification of the patients at a very early stage - for better treatment and prognosis to improve the survival of cancer • Identification of pre-malignant lesions - for intervention and early treatment to reduce the incidence of cancer

  40. Early Biological Response: Molecular Genetic Alterations • Molecular genetic markers are defined as a group of markers which can be induced by certain carcinogens or by some intermediate end-point

  41. Early Biological Response: Molecular Genetic Alterations • cytogenetic markers such as chromosome abnormalities by karyotyping; • oncogenes such as RAS family; • tumor suppressor genes such as TP53 and p16 genes.

  42. P53 Gene Mutations • TP53 Mutations as DNA Fingerprints of Environmental Exposures. The wide range of involvement of TP53 in human tumors and the broad spectrum of mutations make this gene a good candidate for molecular epidemiological studies

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