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DNA repair and prostate cancer


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Special Project presentation at George Washington University, 2003

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DNA repair and prostate cancer

  1. 1. Genetic Variants of DNA Repair genes and Prostate Cancer: Department of Epidemiology and Biostatistics George Washington University July 2003 A Population-Based Case-Control Study in China Jamie D. Ritchey
  2. 2. Prostate Cancer <ul><li>The prostate, anatomical location </li></ul><ul><li>International patterns </li></ul><ul><li>Etiology </li></ul><ul><li>Genetic susceptibility, SNPs, and DNA repair </li></ul><ul><li>The Shanghai Prostate Cancer Study </li></ul><ul><li>Objectives </li></ul><ul><li>Methods: genotyping, statistical analysis </li></ul><ul><li>Results </li></ul><ul><li>Strengths and limitations </li></ul><ul><li>Conclusions </li></ul><ul><li>Future Research </li></ul><ul><li>Questions </li></ul>
  3. 3. The Male urinary and reproductive system
  4. 4. International Patterns Hsing, Tsao, and Devesa, International Journal of Cancer, 2000. African American men Chinese men in China
  5. 5. Etiology: Risk factors for prostate cancer <ul><li>Known risk factors: </li></ul><ul><li>Age </li></ul><ul><li>Race </li></ul><ul><li>Family history </li></ul><ul><li>Probable Risk factors: </li></ul><ul><li>Diet, obesity (BMI, WHR, IR), leptin, physical activity </li></ul><ul><li>Diabetes, IGF-1, insulin </li></ul><ul><li>Androgens </li></ul><ul><li>Sexual behavior/sexually transmitted disease, vasectomy </li></ul><ul><li>Smoking </li></ul><ul><li>Alcohol </li></ul><ul><li>Liver cirrhosis </li></ul><ul><li>Low-penetrant Genetic component? </li></ul>ACS, 2003 NCI, 2003
  6. 6. Genetic susceptibility to cancer <ul><li>High penetrant genes 1 </li></ul><ul><li>Rare in the population </li></ul><ul><li>Almost always cause cancer in the individual </li></ul><ul><li>Examples:HPC1, HPC2/ELAC2, HPCX, HPC20, PCAP, CAPB, BRCA1 and BRCA2 </li></ul><ul><li>Low penetrant genes 2 </li></ul><ul><li>More common in population, may be a larger risk factor </li></ul><ul><li>Do not always cause cancer in the individual </li></ul><ul><li>Different Single nucleotide polymorphisms (SNPs) of the same marker may increase or decrease cancer risk </li></ul><ul><li>Hormone: AR, SRD5A2, ER, etc. </li></ul><ul><li>DNA repair genes: XRCC1 , XRCC3 , XRCC5, ERCC1, ERCC2 , MGMT , hOGG1, POLB </li></ul>1Stanford, Epidemiologic Reviews, 2001. 2Greenhut, Kerrigan, and Kelly, , 2003.
  7. 7. Single Nucleotide Polymorphisms (SNPs) Greenhut, Kerrigan, and Kelly, , 2003. Change in shape Altered Cancer Risk SNP: Decreased DNA repair capacity Genomic instability Oncogene activation Inactivate Tumor suppressors Loss of heterozygosity
  8. 8. DNA repair <ul><li>Base Excision Repair (BER) 1,3 </li></ul><ul><li>Direct Damage Reversal 1 </li></ul><ul><li>Nucleotide Excision Repair (NER) 1 </li></ul><ul><li>Non-homologous end-joining and Homologous recombination repair (NHEJ and HR) 1,3 </li></ul><ul><li>Mismatch Repair (MMR) 1,2 </li></ul><ul><li>XRCC1_399 </li></ul><ul><li>MGMT_84 and MGMT_143 </li></ul><ul><li>ERCC2_751 </li></ul><ul><li>XRCC3_241 </li></ul><ul><li>(specifically in HR) </li></ul><ul><li>2 No markers in study, ex: </li></ul><ul><li>MSH2, MLH1, MSH6, PMS2, PMS1, hOGG1 </li></ul>Pathway Marker 1 Poirier, 2002 2 Chen, 2001 3 Goode, 2002
  9. 9. DNA Repair Pathways <ul><li>Reversal of alkyl group </li></ul><ul><li>(-CH 2 -CH 3 , and -CH 3 ) </li></ul><ul><li>DNA Replication or Recombination </li></ul><ul><li>Bulky Adduct </li></ul><ul><li>UV-induced Damage </li></ul><ul><li>Reactive Oxygen, </li></ul><ul><li>Restriction Enzymes, and Normal Cell Process </li></ul><ul><li>Non-Bulky Adduct, </li></ul><ul><li>Oxidative Stress, and </li></ul><ul><li>Ionizing Radiation </li></ul>
  10. 10. Environmental Factors (Diet) + SNP of DNA repair genes = latent effects increasing prostate cancer risk ? Greenhut, Kerrigan, and Kelly, cancer/snps_cancer/snps_ , 2003.
  11. 11. Shanghai Prostate Cancer Study <ul><li>A Population-Based Case control Study </li></ul><ul><li>(Cases collected from: 1993-1995) </li></ul><ul><li>Study components included: </li></ul><ul><li>In-person interview </li></ul><ul><li>Medical record abstraction </li></ul><ul><li>Anthropometric measurements </li></ul><ul><li>Collection of fasting blood </li></ul>
  12. 12. Objectives <ul><li>The primary objective: to investigate whether five different DNA repair markers, specifically: XRCC1_399, XRCC3_241, ERCC2_751, MGMT_84 and MGMT_143 play a role in the etiology of prostate cancer. </li></ul><ul><li>Secondary objectives included: the risk of prostate cancer and the five DNA repair markers by the probable risk factors: </li></ul><ul><li>-Waist to hip ratio, WHR </li></ul><ul><li>-Insulin resistance, IR </li></ul><ul><li>-Diet </li></ul>
  13. 13. Shanghai Prostate Cancer Study Study Design 268 Prostate cancer cases Interview 191 Cases Genotyped 305 controls Genotyped 495 Population Controls 243 cases interviewed 472 controls interviewed 200 cases provided 20 ml fasting blood 330 controls provided 20 ml of fasting blood
  14. 14. Genotyping Blood Buffy coat Purified DNA MALDI-TOF/hME assays XRCC1_399, XRCC3_241, ERCC2_751, MGMT_84, MGMT_143 191 Cases Genotyped 305 controls Genotyped
  15. 15. Statistical Analysis <ul><li>Logistic regression was used to calculate the ORs and the 95% CIs to investigate marker main effects and markers by other potential risk factors </li></ul>
  16. 16. RESULTS
  17. 17. Selected demographic characteristics Characteristic Cases (n=162) Controls (n=251) Age < 69 70-75 > 76 Education None Elementary-high College/ above Other Stage Localized Regional Remote Unknown/unstaged PSA % 19 22 20 N 78 89 84 % 15 12 12 N 61 50 51 12 76 12 ~1 29 191 30 1 9 76 15 0 14 124 24 0 - - - - - - - - 38 31 30 1 61 50 48 2
  18. 19. Genetic Markers and other Factors: Combined Effects XRCC1_399 Waist to Hip Ratio Insulin Resistance Age-Adjusted
  19. 20. Genetic Markers and other Factors: Combined Effects MGMT_84 Waist to hip Ratio Insulin Resistance Age-Adjusted
  20. 21. Genetic Markers and other Factors: Combined Effects XRCC1_399 Total Preserved Food Age-adjusted
  21. 22. Genetic Markers and other Factors: Combined Effects MGMT_84 Total Preserved Food
  22. 23. Genetic Markers and other Factors: Combined Effects XRCC1_399 Allium Vegetable intake
  23. 24. Genetic Markers and other Factors: Combined Effects MGMT_84 Allium Vegetable intake
  24. 25. Study strengths <ul><li>Population-based </li></ul><ul><li>High response rates </li></ul><ul><li>Nearly compete case ascertainment </li></ul><ul><li>Pathology review </li></ul><ul><li>In-person interviews </li></ul><ul><li>High accuracy of Laboratory results </li></ul>
  25. 26. Study limitations <ul><li>Small Sample size </li></ul><ul><li>Generalizability </li></ul>
  26. 27. Conclusions <ul><li>XRCC1_399 AA and the MGMT_84 CT/TT may increase prostate cancer risk </li></ul><ul><li>DNA repair capacity of both markers may be effected by: abdominal obesity, insulin resistance, preserved food consumption and allium vegetables </li></ul><ul><li>No association was seen with alleles of XRCC3_241, ERCC2_241 and MGMT_143, but these may still increase or decrease cancer risk </li></ul>
  27. 28. Future Research <ul><li>Larger Studies </li></ul><ul><ul><li>-- Accrue greater number of cases </li></ul></ul><ul><ul><li>-- Enroll larger set of controls </li></ul></ul><ul><li>Confirmation in Western populations </li></ul><ul><li>Additional markers investigated in each pathway </li></ul>
  28. 29. Acknowledgements <ul><li>National Cancer Institute </li></ul><ul><li>Shanghai Cancer Institute </li></ul><ul><li>Shanghai Tumor Hospital </li></ul><ul><li>George Washington University </li></ul><ul><li>Ann Hsing, Ph.D. </li></ul><ul><li>Joseph Fraumeni, Jr., M.D. </li></ul><ul><li>Gloria Gridley, M.S. </li></ul><ul><li>Yu-Tang Gao, M.D. </li></ul><ul><li>Jie Deng, M.D. </li></ul><ul><li>Ming-Chang Shen, M.D. </li></ul><ul><li>Paul Levine, M.D. </li></ul>