BRCA GenesDallas Henson

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

The Numbers

Frequency of BRCA Mutations in the U.S.

U.S. citizens  1 in 500

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

BRCA Genes

• BRCA 1 and BRCA 2

• Roles they play

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

BRCA 1

• Cloned in 1994 (Miki et al)

–Mapped to chromosome 17q21

–5,592kb long

–24 exons

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~90-

100 amino acids long

• N-terminal – ring-finger domain

BRCA 2

• Cloned in 1995 (Wooster et al.)

• Mapped to chromosome 13q12-13

• 10,254 kb (3,418 aa)

• 27 exons

BRCA 2 protein

• 3,418 amino acids

• 385 kDa

• Very large exon 11

–Encodes peptide motifs for interaction with the RAD51 protein

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

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

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%

How does this happen?

• Tumor Suppressor paradox– Once thought to that loss of BRCA genes

resulted from Knudson’s 2-hit model of carcinogenesis

Knudson's 2-hit Model of Carcinogenesis

Sporadic

    

     

Normal Chromosome

      

     

Inactivation ofone allele

        

     

Inactivation of both alleles

NORMAL CELL

CELL PREDISPOSED TO CANCER

Hereditary    

      

     

Inactivation of one allele

        

     

Inactivation ofboth

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

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

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

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

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

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

In case you were wondering…

The End

http://www.breastcancer.org

http://www.dnadirect.com/resource/conditions/breast_cancer/GH_Brca_Genes_Cause.jsp

Powell, S., Kachni, L., (2003). Roles of BCRA1 and BRCA2 in homologous recombination, DNA replication fidelity and cellular response to ionizing radiation. Oncogene, 22, 5784-5791.

Welsch, P., King, M., (2001). BCRA1 and BCRA2 and the genetics of breat and ovarian cancer. Hum. Mol. Gen. 10. 705-713.

http://www.mi-cancergenetics.org/articles/brca-risk.html