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Biological Markers for Exposures Slide 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) Slide 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) Slide 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 Slide 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. Slide 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. Slide 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 Slide 8 Slide 9 Slide 10 Slide 11 Slide 12 Slide 13 Slide 14 Slide 15 Slide 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 Slide 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: Slide 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. Slide 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. Slide 20 HBV Slide 21 Slide 22 Slide 23 Slide 24 Slide 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 Slide 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) Slide 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) Slide 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) Slide 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) Slide 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 Slide 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 Slide 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 Slide 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) Slide 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 Slide 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 Slide 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 Slide 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 Slide 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) Slide 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 Slide 40 Slide 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. Slide 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. Slide 43 Slide 44 Slide 45 Slide 46 Slide 47 Slide 48 Slide 49 Slide 50 Slide 51 Figure 1a: H.pylori and gastric cancer - Prospective studies: meta-analysis of non cardia cancer cases. Slide 52 Figure 1b: H.pylori and gastric cancer - Prospective studies: meta-analysis of cardia cancer cases. Slide 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 Slide 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 Slide 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 Slide 56 Slide 57 Slide 58 Slide 59 Slide 60 Slide 61 Urine Test Kit for Tobacco Use Slide 62 Slide 63 Marker for Internal Dose Fat-soluble substance such as DDT metabolites Persist over time Will not be affected by disease status Slide 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 Slide 65 DDT Slide 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. Slide 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. Slide 68 Slide 69 Slide 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 Slide 71 Slide 72 Slide 73 Slide 74 Slide 75 Main component of green Tea Catechins: (-)-Epigallocatechin gallate ((-)EGCg) Slide 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 Slide 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 Slide 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 Slide 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 Slide 80 Adduct as Biomarker Adducts can be measured at Blood Exfoliated cells Tissue Urine (metabolites of adducts) Slide 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 Slide 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 Slide 83 PHIP DNA Adducts Slide 84 P32 postlabel ing Slide 85