1. Biological Markers for Exposures Epidemiology 243 Molecular Epidemiology of Cancer

2. Early Studies MacMahon: Geographical correlation of urinary estrogen concentrations with cancer of the breast (1974) Cole & MacMahon: Urinary and blood estrogens and breast cancer in case-control studies (1969,1982, 1983) McMichael: The relationship between cancer mortality and serum cholesterol concentrations (1984)

3. Recent Studies Aflatoxins and hepatitis B on liver cancer in a cohort study, including measurements of urinary metabolites and nucleic acid adducts of aflatoxin (Ross, 1992, 1994) The relationship between HPV and cervical cancer (Munoz, 1992, Bosch, 1995)

4. Application of biomarkers in Epidemiology Molecular markers can be applied to increase the accuracy of measurements of genetic and other acquired susceptibility to disease; of exposures that may cause or prevent disease; of exposures that confound or modify the associations between risk and other exposures of disease itself of factors that may determine the outcome of the disease such as precursors and stages

5. Application of biomarkers in Epidemiology Biomarkers may also be used to reduce the time interval between the relevant exposure and measurement of the putative effect To increase the yield of information on disease pathogenesis To increase the cost-effectiveness of epidemiological studies. More information is gained per unit cost.

6. Biomarker in Epidemiology: Biomarkers of Biological Agents Biological agents associated with chronic infection and subsequent development of cancer are measured using serological or nucleic acid markers.

7. Biomarker in Epidemiology: Biomarkers of Biological Agents HPV DNA by PCR-based assays HPV infection is often transient, especially in young women so that repeated sampling is required to assess persistent HPV infections

16. Classification of Cervical Squamous Neoplasia DysplasiaPapS.CIN scaleBethesda Normal1 Infla. Atypia2aInfla. atypiaNormal Koilocyt.Atypia2bKoilocyto a.LG SIL Mild dysplasia3CIN1LG SIL Moderate dysp.3CIN2HG SIL Severe dysp.3CIN3HG SIL Ca. in situ4CIN3HG SIL Invasive ca.5Invasive ca

17. HPV Testing and Typing HPV infection is the main cause of cervical cancer. Transient in women. Only 10-20% persistent infections are at risk of neoplasia About 70 subtypes, of which 25 are tropic for genital tract. Those are subdivided into three categories:

18. HPV Testing and Typing HPV can be tested and typed by dot blot hybridization, southern blot hybridization, Hybrid Capture and PCR High sensitivity but relatively low specificity, particular among young women HPV typing has great potential as a primary screening tool for cervical cancer.

19. Biomarker in Epidemiology: Biomarkers of Biological Agents HBV infection by serological assays. There are serological markers that distinguish between past and persistent infections. HBV DNA detection in sera further refines the assessment of exposure.

20. HBV

25. Gender Case N % Control N % P Value Male 159 (77.94 ) 287(69.16) 0.0221 Female 45 (22.06)128(30.84) 204 415 Gender distribution among cases and controls

26. Self-reported hepatitis virus infection type Hepatitis History Case N % Control N % Crude OR (95%CI) Adjusted OR (95% CI) No108(60.34)354(90.08) 1 1 HAV 16(8.94) 19(4.84)2.77(1.38~5.57)2.67(1.27~5.60) HBV 55(30.73) 19(4.40)11.30(6.22~20.5)14.52(7.38~28.6) HDV 0 (0) 1(0.26)

27. The relationship between liver cirrhosis and liver cancer Liver cirrhosis Case N % Control N % Crude OR (95%CI) Adjusted OR (95% CI) No149(86.6)355(99.2) Yes 23 (13.4)3 (0.8)18.3(5.40~61.8)22.1(6.11~79.9)

28. The relationship between HBV vaccine and liver cancer HBV vaccine Case N % Control N % Crude OR (95%CI) Adjusted OR (95% CI) No157(96.32) 293(86.14) 1 1 Yes 6(3.68)47(13.9)0.24(0.10~0.57)0.24(0.10~0.60)

29. The distribution of HBsAg among cases and controls HBsAg Case N % Control N % Crude OR (95%CI) Adjusted OR (95% CI) Negative72(35.29)312(75.36) 1 1 Positive132(64.71)102(24.64)5.59(3.95~8.18)5.06(3.45~7.43)

30. HBsAg Case N % Control N % Crude OR (95%CI) Adjusted OR (95% CI) Negative 183(91.04)403(97.11) 1 1 Positive 18 (8.96)12 (2.89) 3.49(1.66~7.33)3.21(1.46~7.06) The distribution of anti-HCV among cases and controls

31. TYPEHBsAgHBsAbHBeAgHBeAbHBcAbCrude OR (95%CI) Adjusted a (95%CI) 2-----1.00 1-+---0.24 (0.09~0.63)*0.23 (0.09~0.61)* 3----+1.00 (0.49~2.03)1.02 (0.49~2.11) 1+--++4.74 (2.48~9.06)* 3.91 (1.99~7.66)* 2+---+8.9 (4.00~19.73)*7.68 (3.23~18.31)* 3+-+-+12.50 (4.78~32.73)* 11.55 (4.18~31.90)* Most frequent HBV infection spectrum in cases and controls

32. Mildewed food intake GSTM1 Case N % Controls N % Crude OR(95% CI) Adjusted OR(95%CI) Further adjusted OR(95%CI) NoNormal45(25.6)126(32.9) 1 1 1 YesNormal17(9.7)29(7.6)1.64(0.82~3.27)1.81(0.87~3.76)2.69(1.15~6.30) NoNull86(48.9)193(50.4)1.25(0.82~1.91)1.20(0.77~1.87)1.38(0.84~2.25) YesNull28(15.9)35(9.1)2.24(1.23~4.09)2.67(1.36~5.23)4.13(1.85~9.24) The possible interaction between GSTM1 and mildewed food

33. The possible interaction between GSTT1 and HBV HBsAg GSTT1 Case N % Control N % Crude OR (95% CI) Adjusted OR (95%CI) Further adjusted OR(95%CI) NoNormal36(19.0)146(37.1) 1 1 1 YesNormal67(35.3)54(13.7)5.03(3.02~8.39)4.49(2.63~7.67)4.48(2.62~7.67) NoNull27(14.2)150(38.1)0.73(0.42~1.26)0.73(0.41~1.29)0.68(0.38~1.22) YesNull60(31.6)44(11.2)5.53(3.25~9.43)4.91(2.81~8.60)5.04(2.85~13.9)

34. Raw water drinking HBsAg Case N % Control N % Crude OR (95% CI) Adjusted OR (95%CI) NoNegative32(17.30)184(51.40) 1 1 YesNegative30(16.22)83(23.18)2.08(1.19~3.64)1.84(1.03~3.28) NoPositive63(34.05)63(17.60)5.75(3.44~9.60)5.25(3.04~9.06) YesPositive60(32.43)28(7.82)12.32(6.86~22.11)9.66(5.22~17.89) The interaction between HBsAg and raw water drinking

35. Mildew food intake HBsAg Case N % Control N % Crude OR (95% CI) Adjusted OR (95%CI) NoNegative46(24.08)151(62.13) 1 1 YesNegative21(10.99)52(12.87)2.20(1.21~4.00)2.47(1.32~4.63) NoPositive97(21.53)87(21.53)6.08(3.97~9.33)5.41(3.46~8.45) YesPositive27(14.14)14(3.47)10.52(5.13~21.58)10.82(5.09~22.98) The interaction between HBsAg and mildewed food intake

36. Alcohol drinking HBsAg Case N % Control N % Crude OR (95% CI) Adjusted OR (95%CI) NoNegative34(17.71)157(38.20) 1 1 YesNegative35(18.23)153(37.23)1.06(0.63~1.78)1.06(0.56~2.00) NoPositive53(27.60)70(36.46)5.00(2.92~8.54)4.36(2.47~7.68) YesPositive49(11.92)52(12.65)6.22(3.71~10.41)6.19(3.13~12.25). The interaction between HBsAg and alcohol drinking

37. Anti-HCV HBsAg Case N % Control N % Crude OR (95% CI) Adjusted OR (95%CI) NoNegative63(31.19)304(73.08) 1 1 YesNegative6(2.97)10(2.40)2.90(1.02~8.26)2.63(0.88~7.85) NoPositive120(59.41)100(24.04)5.79(3.96~8.46)5.20(3.49~7.76) YesPositive13(6.44)2(0.48)31.37(6.91~ 42.44)23.99(5.09~ 13.12) The interaction between HBsAg and anti-HCV

38. The interaction between HBsAg and family history of liver cancer Anti-HCV HBsAg Case N % Control N % Crude OR (95% CI) Adjusted OR (95%CI) NoNegative58(28.29)284(68.27) 1 1 YesNegative14(6.83)30(7.21)2.285(1.41~4.58)2.33(1.13~4.81) NoPositive94(45.85)93(22.36)4.95(3.31~7.40)4.52(2.96~6.92) YesPositive39(19.02)9(2.16)21.22(9.75~46.19)24.14(10.34~ 6.35)

39. Selected Variables OR ( 95%CI ) Age 0.95 (0.93~0.98) Gender 1.71 (0.80~3.65) Education 0.56 (0.38~0.82) Mildewed food intake 2.64 (1.39~4.99) Refrigerator using at home 0.30 (0.13~0.68) Raw water drinking 1.19 (0.65~2.19) Pack-year of smoking 1.00 (0.98~1.03) Alcohol drinking 1.38 (0.72~2.62) Characteristics optimistic 0.40 (0.23~0.69) Depressed 4.35 (1.41~13.45) Family history of liver cancer 4.81 (2.41~9.60) HBsAg 6.93 (4.07~11.78) Anti-HCV 3.49(1.10~11.07) GSTM1 1.87 (1.09~3.21) GSTT1 0.72 (0.43~1.21) Multivariate Logistic Regression Analysis

41. Major Risk Factors for Stomach Cancer in Chinese Population Helicobacter pylori was the first bacterium to be officially recognized as a cancer- causing agent.

42. Major Risk Factors for Stomach Cancer in Chinese Population Helicobacter pylori Infection. Nitrates and nitrites are substances commonly found in cured meats, some drinking water, and certain vegetables, that can be converted by Helicobacter pylori, into compounds that have been found to cause stomach cancer in animals.

51. Figure 1a: H.pylori and gastric cancer - Prospective studies: meta-analysis of non cardia cancer cases.

52. Figure 1b: H.pylori and gastric cancer - Prospective studies: meta-analysis of cardia cancer cases.

53. H. Pylori Infection and Stomach Cancer in Whites at MSKCC H. Pyloricase/controlOR no69/541.00 yes67/153.50 (1.80-6.79) Infection rates: 21.7% in controls 49.3% in cases

54. Biomarker in Epidemiology: Biomarkers of Internal Dose Biomarker of internal dose of external chemical exposures are measurements of a parent compound or its metabolites in an accessible biological matrix, such as serum or urine

55. Biomarker in Epidemiology: Biomarkers of Internal Dose The half-life of the external agent or its metabolites in the body The pattern of the exposure it is measuring (regular exposure or infrequent exposure) Whether the secular trends have occurred in that exposure (e.g., smoking cessation) Direct or indirect influence of the disease

61. Urine Test Kit for Tobacco Use

63. Marker for Internal Dose Fat-soluble substance such as DDT metabolites Persist over time Will not be affected by disease status

64. DDT DDT (dichlorodiphenyltrichloroethane) is a commercial organochlorine insecticide that has been used in countries around the world. It has been used widely on agricultural crops as well as for "vector control" - the control of insects that carry such diseases as malaria and typhus

65. DDT

66. This organochlorine insecticide can be considered as the pesticide of the greatest historical significance, due to its effect on the environment, agriculture, and human health. First synthesized by a German graduate student in 1873, it was rediscovered by Dr. Paul Mueller, a Swiss entomologist, in 1939 while searching for a long-lasting insecticide for the clothes moth.

67. DDT DDT subsequently proved to be extremely effective against flies and mosquitoes, ultimately leading to the award of the Nobel Prize in medicine for Dr. Mueller in 1948. Effective January 1, 1973 the Environmental Protection Agency (EPA) officially canceled all uses of DDT, but not before more than 1 billion kilograms of DDT had been introduced into the United States.

70. Biomarker of Dietary Intake Whether it is a good indicator of intake Whether it is a long- or short-term marker Whether there is a need for multiple measurements Whether it is acceptable for researcher and the subject Whether it is compatible with study design

75. Main component of green Tea Catechins: (-)-Epigallocatechin gallate ((-)EGCg)

76. Adduct as Biomarker Chemicals can bind covalently to cellular macromolecules such as nucleic acids and protein. The product of this addition of a chemical moiety to a macromolecule is termed an “adduct”

77. Adduct as Biomarker Adduct may be highly specific for carcinogen of interest, but not necessarily specific for a given exposure because of multiple sources of carcinogen with environment Adduct formation normally occurs after the metabolic activation of the carcinogen; DNA repair may follow adduct formation

78. Adduct as Biomarker The persistent of the adducts is determined by Chemical stability of the adduct itself The turnover of macromolecule to which the chemical is bound

79. Adduct as Biomarker A half-life of adducts on proteins (HB and albumin): a few weeks to months A half-life of DNA adducts: a few hours to several years depending on cell type concerned

80. Adduct as Biomarker Adducts can be measured at Blood Exfoliated cells Tissue Urine (metabolites of adducts)

81. Group 1: Carcinogenic to Humans Tobacco Smoking Tobacco Products, Smokeless 4-Aminobiphenyl (4-ABP) Benzene Carmium Chromium 2-Naphthylamine (2-NA) Nickel Polonium-210 (Radon) Vinyl Chloride

82. Group 2A: Probably Carcinogenic to Humans Acrylonitrile Benzo[a]pyrene Benzo[a]anthracene 1,3-Butadiene Dibenz(a,h)anthracene Formaldehyde N-Nitrosodiethylamine N-Nitrosodimethylamine

83. PHIP DNA Adducts

84. P32 postlabel ing