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BRCA2

BRCA2. By Jordan Masterson March 21, 2006. A little bit about breast cancer…. 1 in every 8 women 10% exhibit the familial pattern of inheritance 30-50% of familial cases involve a mutation in BRCA1 or BRCA2. http://www.breastcancer.org/mammogram_side_d.html. BRCA1 vs. BRCA2. Similarities?

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BRCA2

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  1. BRCA2 By Jordan Masterson March 21, 2006

  2. A little bit about breast cancer… • 1 in every 8 women • 10% exhibit the familial pattern of inheritance • 30-50% of familial cases involve a mutation in BRCA1 or BRCA2 http://www.breastcancer.org/mammogram_side_d.html

  3. BRCA1 vs. BRCA2 • Similarities? • Differences?

  4. BRCA2 Simon N. Powell and Lisa A. Kachnic Marroni et al.

  5. Role of BRCA2 • “…Major biological function is the maintenance of chromosome structure stability in dividing cells by regulation of steps in recombination by homologous DNA strands.”1 • “…Facilitate orderly homologous recombination and thereby maintain genomic integrity.”2 1Luca Pellegrini and Ashok Venkitaraman 2Simon N. Powell and Lisa A Kachnic

  6. DNA repair • 2 mechanisms to repair double-strand breaks: • Non-homologous End Joining (NHEJ) • Homologous Recombination (HR) • Gene conversion • Single strand annealing

  7. BRCA2 + RAD51 Simon N. Powell and Lisa A. Kachnic

  8. In Mouse Models and Human Case studies… • BRCA2 null embryos in mice • Human Heterozygous Carrier Analyses www.scenta.co.uk/_db/ _images/lab_mouse140.jpg Arnold, K et al.

  9. How does BRCA2 cause cancer? • Decreases the amount of proper/effective DNA repair • Increases Genomic Instability

  10. Why breast cancer? • “Heterozygous germline mutations in BRCA2 predispose carriers predominantly to breast and ovarian cancers…the relationship between genotype and phenotype in BRCA2 mutated cells is complex, e.g. an identical mutation can be associated with different cancer phenotypes.”3 3Arnold, K., et al.

  11. References • Pellegrini, Luca and Ashok Venkitaraman. “Emerging functions of BRCA2 in DNA recombination.” TRENDS in Biochemical Sciences 29.6 (2004): 310-316. • Powell, Simon N. and Lisa A. Kachnic. “Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity, and the cellular response to ionizing radiation.” Oncogene 22 (2003): 5784-5791. • Arnold, K. et al. “Lower level of BRCA2 protein in heterozygous mutation carriers is correlated with an increase in DNA double strand breaks and an impaired DSB repair.” Cancer Letters (2006): 1-11. • Kim, MK et al. “Increased rates of spontaneous sister chromatid exchange in lymphocytes of BRCA2+/- carriers of familial breast cancer clusters.” Cancer Letters 210.1 (2004) 85-94.

  12. References, con’t • Tutt, A. et al. “Mutation in BRCA2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences.” EMBO Journal 20.17 (2001): 4704-4716. • Jonkers, Jos et al. “Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer.” Nature Genetics 29 (2001): 418-425. • Marroni, F. et al. “Penetrances of breast and ovarian cancer in large series of families tested for BRCA1/2 mutations.” European Journal of Human Genetics 12.11 (2004): 901. • http://www.breastcancer.org/mammogram_side_d.html • www.scenta.co.uk/_db/ _images/lab_mouse140.jpg

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