1. BRCA Genes
Dallas Henson

2. BReast CAncer
Women have about a 1 in 7 chance of getting breast cancer in their lifetime.
Most cancer is sporadic, about 5-10% of cases are genetically linked
Women inheriting mutation of BRCA gene have increased chance of disease
Also can lead to ovarian cancer

3. The Numbers Frequency of BRCA Mutations in the U.S. U.S. citizens
Ashkenazi Jews
1 in 40
Women with breast cancer under age 50
Approx. 1 in 13
Women with breast cancer under age 40
1 in 10
Ashkenazi Jews with breast cancer under age 50
Approx. 1 in 8

4. BRCA Genes
BRCA 1 and BRCA 2
Roles they play

5. What are they? BRCA 1 and BRCA 2
Known as breast and ovarian cancer susceptibility genes
Tumor suppressor genes
regulate the cycle of cell division by keeping cells from growing and dividing too rapidly or in an uncontrolled way
inhibit the growth of cells that line the milk ducts in the breast
Involved in many other functions including control of DNA replication and damage repair

6. BRCA 1 Cloned in 1994 (Miki et al) Mapped to chromosome 17q21
5,592kb long
24 exons

7. BRCA1 protein Consists of 1863 amino acids
Expressed in most proliferation cells
Part of large protein complex
3 MDa
BRCT (C-terminal of BRCA) domain
Consists of 2 conserved BRCT repeats~ amino acids long
N-terminal – ring-finger domain

8. BRCA 2 Cloned in 1995 (Wooster et al.) Mapped to chromosome 13q12-13
10,254 kb (3,418 aa)
27 exons

9. BRCA 2 protein 3,418 amino acids 385 kDa Very large exon 11
Encodes peptide motifs for interaction with the RAD51 protein

10. BRCA1 Mutations
Germline mutations within BRCA1 predispose carriers (heterozygotes) to early onset breast
Heterozygous carriers of BRCA1 mutations have an 80% risk of breast cancer
increase risk of ovarian cancer

11. BRCA2 Mutations
Similar statistics for BRCA2 carriers, but later age of onset and lead to other tumors: gastric, colon, pancreatic, prostate, and melanoma
BRCA2 mutations confer higher risk of male breast cancer

12. More Numbers Type of Cancer
General Population That Will Develop Disease
People With BRCA1 Mutation Who Will Develop Disease
People With BRCA2 Mutation Who Will Develop Disease
Breast
12.5%
55 – 85%
33 – 86%
Ovarian
1.43% 
28 – 44%
10 – 30%
Prostate
4 – 6%
12 – 18% 
12 – 18%
Male breast cancer 
Less than 1% 6%
4 – 14%
Pancreatic 
0.6%
not applicable
6 – 7%

13. How does this happen? Tumor Suppressor paradox
Once thought to that loss of BRCA genes resulted from Knudson’s 2-hit model of carcinogenesis

14. Knudson's 2-hit Model of Carcinogenesis CELL PREDISPOSED TO CANCER
Sporadic
         
Normal
Chromosome
           
Inactivation of
one allele
             
both alleles
NORMAL CELL
CELL PREDISPOSED TO CANCER
Hereditary
both

15. How does this happen? Tumor suppressor paradox cont’d
Unlike other tumor suppressors, there have been no disease-dominant mutations detected in sporadic cancers
Now thought to follow Kinzler and Vogelstein’s “caretaker” gene model
Mutations in BRCA genes only predispose for cancer development, but the loss of other genes that cooperate with the loss of BRCA function are necessary for development of cancer

16. Roles of BRCA
BRCA proteins are involved in control of homologous recombination and double-strand break repair in response to DNA damage
Affect proteins such as H2AX, RAD51, and p53

17. Effects of BRCA DNA damage repair
P53 checkpoint loss is associated BRCA gene loss
P53 gene encodes a regulatory protein that activates the expression of genes required for DNA repair
Believed to be due to mutations occurring in BRCT domains

18. Roles of BRCA
After DNA damage, the histone H2AX becomes phosphorylated and forms a foci at the break site
BRCA1 is recruited to the site
H2AX and BRCA1 initiate repair by modifying the local chromatin structure

19. Roles of BRCA Homologous Recombination
BRCA2 is known to interact with RAD51
BRC repeats (8) on BRCA2’s exon 11 interact with RAD51
BRC repeats provide assembly line of RAD 51 monomers and the C-terminus of BRCA2 binds to the ssDNA, displacing RPA
RAD51 filaments can form without BRCA2, but major chromosomal errors occur in BRCA2-deficient cells

20. Roles of BRCA
Investigations of cellular response to Ionizing Radiation (IR)
Used aggregates of repair proteins (IRIFs) to study the signaling mechanism
Found that BCRA1 & 2 associated with RAD51
BRCA 2 more directly controlled RAD51
BRCA 1 regulated and directed both
MRN protein complexes were more abundant in BRCA1-deficient cells

21. In case you were wondering…

23. The End

24.
Powell, S., Kachni, L., (2003). Roles of BCRA1 and BRCA2 in homologous recombination, DNA replication fidelity and cellular response to ionizing radiation. Oncogene, 22,
Welsch, P., King, M., (2001). BCRA1 and BCRA2 and the genetics of breat and ovarian cancer. Hum. Mol. Gen