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Susceptibility Markers

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

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Susceptibility Markers

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  1. Susceptibility Markers

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

  3. Biomarker of Genetic Susceptibility • High risk genes • Low risk genes

  4. Mutations with strong influence on risk • Variations with weak functional effect • Low to high frequency in the population (1-50%) • Rare in the population (<1%) • Results in familial clustering • Limited familial clustering • Can be studied in families • Can be studied in populations • e.g. BRCA germline mutations Genetic Susceptibility to Cancer 010205

  5. Frequency Distribution of Breast Cancer Hereditary Familial 10% 20% 70% Unexplained by Family History or Inherited Predisposition

  6. BRCA1 and BRCA2 Mutations in the Ashkenazi Jewish Population An estimated 1 in 40 Ashkenazi Jews carries a BRCA1 or BRCA2 mutation BRCA1 185delAG Prevalence = ~1% 5382insC Prevalence = ~0.15% BRCA2 6174delT Prevalence = ~1.5%

  7. Other genes(16%) BRCA1 (52%) 7-10% Hereditary Hereditary Breast and Ovarian Cancer BRCA2 (32%) Predisposing factor in 15-45% of hereditary breast cancer Sporadic Am J Hum Genet 1998; 62:676-89

  8. Population Risk 0.5% 2% 9% 10%-20% Hereditary Risk BRCA1-2 Mutations Increase the Risk ofEarly-Onset Breast Cancer By age 40 By age 50 By age 70 45%-87% 33%-50%

  9. 1 - 2% 39 - 44% (BRCA1) 11 - 27% (BRCA2) BRCA1-2 Mutations Increase the Risk of Ovarian and Related Cancer By age 70 Population risk Hereditary risk

  10. 2-1. Background: Theoretical model of gene-gene/environmental interaction pathway Tobacco consumption Occupational Exposures Environmental Carcinogens / Procarcinogens Exposures Ile105Val  Ala114Val Null  Environmental Exposure GSTP1 GSTM1 CYP1A1 MspI Ile462Val  PAHs, Xenobiotics, Arene, Alkine, etc Detoxified carcinogens Active carcinogens Tyr113His His139Arg Pro187Ser Tyr113His His139Arg mEH mEH NQO1 Normal cell DNA Damage Arg194Trp, Arg399Gln, Arg280His XRCC1 M G1 G2 P53 P16 Arg72Pro Ala146Thr S Cyclin D1 G870A Programmed cell death Carcinogenesis DNA damage repaired Defected DNA repair gene If DNA damage not repaired G0 If loose cell cycle control

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

  12. Phase I Enzymes 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.

  13. Phase I Genes • The phase I genes encode detoxifying enzymes that recognize a large variety of substrates. • Many drugs, poisons, and other exogenous chemicals, as well as a number of natural endogenous compounds are metabolized by these enzymes.

  14. Phase II Genes • The major function is to detoxify carcinogens • Including GSTs, NATs

  15. 14 13 12 11 10 9 8 7 6 5 4 3 2 1 PCR P450 2E1 after Using Pst1 RFLP

  16. 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

  17. 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.

  18. DNA Repair Genes

  19. Polymorphism of DNA repair genes • DNA repair system maintains the intergrity of the genome by: • Reducing the mutation frequency of cancer-related genes, • minimizing replication errors, • removing DNA damage • Minimizing deleterious rearrangement arising via aberrant recombination • Four pathways for repairing DNA damage • Base excision repair (BER) • Excision of a damaged region  fill-in repair synthesis using opposite strand as template • Nucleotide excisions repair (NER) • Remove photoproducts from UV radiation and bulky adducts • Recombination repair • When both strands are damaged  acts on double-strand breaks and inter-strand links • Mismatch repair • On base mismatches that arise during replication by misincoporation or slippage on the template strand

  20. DNA Repair Genetic Variation in Repair Genes ? DNA Repair Capacity ORs 1.4-75.3 Cancer Occurrence

  21. Base Excision Repair hOGG1 LIG1

  22. hOGG1 • Often deleted in a variety of cancers • Somatically mutated in some cancer cells • Ser326Cys, exon 7: highly polymorphic • 0.2 Caucasian—0.4-0.6 Chinese • Ser326 protein 7-fold greater repair activity • ORs: Lung 2.2-3.4, Orolaryngeal 4.1-6.9

  23. LIG1 • Encodes DNA ligase I, a DNA joining enzyme • Participates in BER, NER, MMR, and HRR • Exon 6, codon 170 polymorphism • 0.5 allele frequency in Caucasians • No studies in esophageal, stomach, liver cancers • No studies in Chinese

  24. Nucleotide Excision Repair • Removes bulky adducts caused by environmental agents • UV radiation • Chemical carcinogens

  25. XPD/ERCC2 ERCC1 LIG1

  26. XPD/ERCC2 • Involved in DNA unwinding during NER • Helps repair genetic damage induced by tobacco and other carcinogens • Exon 10, codon 312 • Exon 23, codon 751 • Most studies of both polymorphisms have been done in lung cancer (most ORs 1.5-3.5)

  27. Homologous Recombinational Repair • One mechanism for repairing double-strand breaks in DNA • Accurately replaces sequence informationby physically exchanging a segment from an homologous intact DNA molecule

  28. XRCC3 LIG1

  29. Adjusted Odds Ratios of Selected DNA Repair Genes for Stomach Cancer

  30. 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 More than multiplicative interaction

  31. Polymorphism of DNA repair genes • DNA repair system maintains the intergrity of the genome by: • Reducing the mutation frequency of cancer-related genes, • minimizing replication errors, • removing DNA damage • Minimizing deleterious rearrangement arising via aberrant recombination • Four pathways for repairing DNA damage • Base excision repair (BER) • Excision of a damaged region  fill-in repair synthesis using opposite strand as template • Nucleotide excisions repair (NER) • Remove photoproducts from UV radiation and bulky adducts • Recombination repair • When both strands are damaged  acts on double-strand breaks and inter-strand links • Mismatch repair • On base mismatches that arise during replication by misincoporation or slippage on the template strand

  32. Lung Cancer Study

  33. Associations between Cigarette Smoking, Selected Susceptibility Genes and Lung Cancer Adjusted for age(continuous),sex and race(white/non-white)

  34. P53 Codon 72 Polymorphism, Smoking, and Lung Cancer

  35. GSTP1 Polymorphism, Smoking and Lung Cancer OR int =1.66 (0.85-3.24)

  36. PCR primers and enzymes

  37. Stomach Cancer Study

  38. Adjusted Odds Ratios of Selected Metabolic and Cell-Cycle Genes for Stomach Cancer

  39. Polymorphism of Susceptibility Genes: Methylenetetrahydrofolate Reductase (MTHFR) • MTHFR gene deals with folate metabolism. • Folate metabolism may play an important role in carcinogenesis through its involvement in both DNA methylation and nucleotide synthesis • A common Ala(222)/Val variant in the methylenetetrahydrofolate reductase (MTHFR) gene leads to a disturbed folate metabolism and is associated with decreased genomic DNA methylation. • Heijmans et al. Cancer Res. 2003 Mar 15;63(6):1249-53

  40. Effects of MTHFR and Green Tea Drinking on the Risk of Stomach Cancer 2.94 (1.3-6.6) 1.48 (0.6-3.5) 2.27 (1.0-4.9) MTHFR CC CT/TT CC CT/TT Green tea Drinker Drinker Non-Drinker Non-Drinker OR for interaction: 0.88 ( 0.3-2.3)

  41. 2-3 Results. Gene-Gene interactions • APEX is involved in the restoration phase of BER: it removes the abasic site after DNA cleavage by OGG1 • Small number • Biologically plausible

  42. 2-3. Results: Multigenetic analyses by pathway Metabolic genestrend p=0.50 DNA repairtrend p=0.83

  43. 2-3. Results: Multigenetic analyses for all genes, and genes with suggestive evidence of effect All genes trend p=0.01 Genes with suggestive effectstrend p=0.02 • (Genes with suggestive effects: NQO1 Pro187Ser, XRCC1 Arg194Trp, OGG1 Ser326Cys, CCND1 G870A) • Suggests that genetic susceptibility depends on multiple loci • Considering variants in different pathways might give a more complete picture of carcinogenesis

  44. ** ** ** ** ** ** ** ** ** ** * 2-3 Results: multigenetic factors by smoking status and packyear ( all genes)

  45. ** ** ** ** ** ** ** ** ** ** * 2-3 Results: multigenetic factors by smoking status and packyear ( genes with suggestive effects) ** **

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