Basic Introduction To The Role Of Genetics In Breast Cancer Development And Treatment

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Basic Introduction To The Role Of Genetics In Breast Cancer Development And Treatment

  1. 1. The role of genetics in the development and treatment of breast cancer?<br />Judith Offman<br />Cancer Prevention Trials Unit <br />WolfsonInstitute of Preventive Medicine<br />Barts and The London School of Medicine and Dentistry<br />
  2. 2. DNA and mutations<br />Types of Mutations<br />Gene<br />X<br />Gene<br />Gene<br />Gene<br />Gene<br />Adopted from http://teampub.wordpress.com/2008/04/08/dna-chromosomes-and-genes-%E2%80%93-an-overview/<br />
  3. 3. Genetic factors associated with breast cancer<br />
  4. 4. Genes associated with breast cancer<br />
  5. 5. BRCA1 and BRCA2 cancer susceptibility genes<br />
  6. 6. Founder effect<br />Adopted from ‘Understanding Cancer Genomics’ by National Cancer Institute<br />
  7. 7. Three mutations common in Ashkenazi Jewish women<br />Adopted from ‘Understanding Cancer Genomics’ by National Cancer Institute<br /><ul><li> Mutations together yield a 2 – 3 % mutation carrier prevalence among US Ashkenazi Jews
  8. 8. High prevalence of BRCA1 mutations in Hispanics</li></li></ul><li>What happens during tumour development?<br />M, maternal; P, paternal <br />Adopted from http://commons.wikimedia.org/wiki/File:Loss_of_heterozygosity.PNG<br />
  9. 9. Tumours start with one mutated cell<br />Adopted from ‘Understanding Cancer Genomics’ by National Cancer Institute<br />
  10. 10. Why are BRCA 1 and 2 important? Why do mutations result in tumours?<br />
  11. 11. Genes make protein<br />Adopted from illustrations by the ‘Human Genome Program’ of the U.S. Department of Energy<br />
  12. 12. DNA damage and repair<br />Cell death or tumour development<br />10,000 events per cell/day<br />DNA repair<br />Mutations<br />
  13. 13. BRCA1 and 2 function<br />Repair breaks in DNA<br />Cell nucleus<br />BRCA1<br />BRCA2<br />gH2AX foci in untreated S-phase cells<br />Mirzoeva and Petrini 2003<br />
  14. 14. Karyotype<br />Human cells contain 23 pairs of chromosomes<br />
  15. 15. Karyotype of BRCA- breast cancer<br />HCC1937 cells (BRCA1-) adopted from Grigorova M., et al.. Cytogenet Genome Res. 2004<br />
  16. 16. Novel treatments and prevention<br />
  17. 17. New cancer treatments for BRCA patients: PARP inhibitors<br />
  18. 18. PARP Inhibitor in Cells<br />BRCA<br />BRCA<br />BRCA<br />BRCA<br />No effect<br />PARP<br />PARP<br />PARP<br />PARP<br />Breast cancer cell: BRCA-/-<br />Non-cancer cell: BRCA+/-<br />X<br />No effect<br />X<br />No effect<br />X<br />X<br />Cell death<br />
  19. 19. In tumours<br />X<br />X<br />X<br />X<br />X<br />X<br />X<br />X<br />X<br />X<br />X<br />X<br />X<br />X<br />X<br />X<br />X<br />X<br />PARP inhibitor<br />
  20. 20. Clinical trials – monotherapy<br />Trials of PARP inhibitors mainly in BRCA1/2 patients<br />
  21. 21. Olaparib in a BRCA1/2 mutation carrier enriched study population<br />
  22. 22. Tumour response to Olaparib in BRCA1/2 mutation carriers<br />19 BRCA mutation carriers evaluated for tumour response. <br />Fong et al. N Engl J Med 2009; 361:123-134<br />
  23. 23. Combination with conventional chemotherapy for sporadic tumours<br />
  24. 24. Combination Trials<br />
  25. 25. Future Directions<br />

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