Transcript BRCA Genes - Texas Tech University

BRCA Genes
Dallas 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~90100 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%
Male breast cancer
Less than 1%
6%
4 – 14%
Pancreatic
0.6%
not applicable
6 – 7%
12 – 18%
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
of
one allele
Inactivation
of
both alleles
NORMAL CELL
CELL PREDISPOSED TO CANCER
Hereditary
Inactivation
of
one allele
Inactivation
of
both
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 doublestrand 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