Breast CA (BRCA1, 2 & HBOC) Flashcards
what does BRCA1 produce? which is responsible for what?
produces breast CA type 1 susceptibility protein - responsible for repairing DNA
where is BRCA1 gene located?
located on q arm of chromosome 17
region 2, band 1 from BP 38, 429, 551 to bp 38, 551, 283
function of BRCA1? what happens if damaged? where does repair happen?
either repairs damaged DNA or destroys cells if not repairable, specifically repairs double-strand breaks
if damaged DNA is not repaired properly and risk of various cancer increases
repair happens in the nucleus, while DNA remains wrapped around a histone, repair mechanism utilizes intact sequence from other sister chromatid as a template
what can cause breaks in double-stranded DNA?
natural radiation or other exposures but also occur during homologous recombination (crossover) during meiosis
how do RAD51 and BRCA1 interact?
in the nucleus, when there is a break in the DNA BRCA1 protein and RAD51 interact during the repair process
where is BRCA2 located?
on the q arm of chromosome 13 at position 13q12.3 and is 84,188 bps long
where does BRCA2 bind?
binds the damaged single strand DNA and directly interacts with recombinase RAD51 to stimulate strand invasion and recombination
theories of why BRCA1/2 mutations put individuals with mutations at such increased risk?
target tissue may have receptors for the pathogen
target tissue may become selectively exposed to an inflammatory process or carcinogen
innate genomic deficit exacerbates the susceptibility to dz in organ targets
women with abn BRCA1/2 gene have what %age risk of developing BrCA by 90 yo? risk of developing ovarian CA?
BrCA risk: 60%
ovarian CA risk: 55% for women w/BRCA1 mutation, 25% for women with BRCA2 mutation
BRCA1 mutation carries have what %age risk to develop BrCA and ovarian CA by 70 yos? risk for males with the BRCA1 mutation?
57-87% risk for BrCA
39-40% risk for ovarian CA
males w/BRCA1 mutation have 1.2% risk by age 70 yo of developing BrCA
where do we see an example of a founder effect??
Ashkenazi jews
3 mutations in BRCA1 have been reported to account for the majority of Ashkenazi Jewish pts w/inherited BRCA1-related breast and/or ovarian CA
carrier frequency of BRCA1 in Ashkenazi Jewish population?
1/40 or 2.6% (compared to 0.2% or 1/500 in non-AJ population)
what BRCA1 mutation has a frequency of 1% and accounts for 16-20% of BrCA cases dx before 50 yo?
BRCA1 185delAG
risk for females with BRCA2 mutation to develop BrCA or ovarian CA by age 70? males risk with BRCA2 mutation for prostate and BrCA?
45-84% for BrCA
11-18% for ovarian CA
males up to 15% prostate CA risk and BrCA risk of 6.8% by 65 and 70 yo respectively
BRCA1/2 mutation carriers are also at an increased risk for what other diseases?
melanoma, pancreatic, GB, bile duct and stomach CA
BRCA1 gene mutations also increase the risk for what GU CAs?
increase risk of ovarian, fallopian tube and prostate CAs
what does the BRCAplus panel measure?
detects mutations in 6 high-risk BrCA susceptibility genes (BRCA1, BRCA2, CDH1, PTEN, STK11 and TP53) by next-generation sequencing of all coding
mutations in CDH1 is associated with what? risk for carriers (men vs women)
gastric cancer, lobular BrCA in female mutation carriers
risk for gastric cancer is 67% to 83% by 80 yo for men and women respectively
risk for lobular BrCA is also elevated with HDGC with estimated lifetime BrCA risk of 39-52%
how do HDGC (gastric CA) pts typically present?
with diffuse-type gastric CA with signet ring cells diffusely infiltrating the wall of the stomach and at a later stage, linitis plastic
germline mutations with PTEN are associated with what?
Cowden syndrome, PTEN hamartoma tumor syndrome, autism spectrum d/os
characteristics of Cowden syndrome?
multiple hamartomas, high risk of developing tumors of thyroid, breast and endometrium
can also include mucocutaneous lesions, thyroid abn, fibrocystic dz, multiple uterine leiomyoma and macrocephaly
over 90% of individuals with CS will express some clinical manifestation by 2nd decade of life
if PTEN mutation, what is the risk for BrCA, thyroid CA and endometrial CA?
BrCA: 50%
thyroid CA: 10%
endometrial CA: 5-10%
STK11 mutations associated with what? risk of developing CA by 70 yo? MC types of CA to develop?
Peutz-Jegher syndrome - AD d/o
57-81% risk of developing CA by 70 yo
MC: GI/colon, BrCA
characteristics of Peutz-Jegher syndrome?
development of GI hamartomatous polyps and melanin hyperpigmentation of the skin and mucous membranes
TP53 mutations associated with? risk of developing CA by 30 yo and lifetime risk of developing CA?
associated with Li-Fraumeni and Li-Fraumeni like syndrome that can affect adults and children
50% risk of developing any associated CA by 30 yo and lifetime risk of CA of 90%
Li-Fraumeni syndrome associated CAs?
sarcomas, BrCA, brain tumors, adrenocortical carcinoma
BRCAplus could be considered for individuals with personal or family hx or what what other 5 RFs?
early onset BrCA or B/L BrCA
2 primary BrCA or clustering of breast and ovarian CA
presence of male BrCA
ovarian CA at any age
at-risk populations such as Ashkenazi Jewish population
BrCA screening recommendations?
breast self-exam training and education at 18 yo
CBE every 6-12 mos, beginning at 25 yo or 5-10 yrs before earliest BrCA dx in the family
annual mammography and breast MRI screening 30-35 yo or 5-10 yrs before earliest BrCA dx in the family
ovarian CA screening?
consider risk-reducing oophorectomy after childbearing years
consider TVUS and CA-125 analysis every 6 mos beginning at 35 yo or 5-10 yrs before earliest ovarian CA dx in the family
people who have 2 mutated copies of BRCA2 gene have what?
fanconi anemia
caused by extremely reduced levels of BRCA protein in cells which allows for accumulation of damaged DNA
what is faconi anemia? majority develop what type of CA by what age? %age of congenital defects seen in FA pts and what are those defects? median age of death in 2000?
genetic dz
1/350,000 births
higher frequency in Ashkenazi Jewish population and Afrikaners in SA
result of genetic defect in a cluster of proteins responsible for DNA repair
majority developing CA (AML) and 90% develop BM failure by 40 yo
60-75% have congenital defects: short stature, abn of skin, arms, head, eyes, KDs, ears, developmental disabilities
75% have some form of an endocrine problem
median age of death was 30 yrs in 2000
what is usually the first sign of FA? what happens over the next 10 years after the first sign?
megaloblastic anemia is usu the 1st detected abn, often w/in the 1st decade of life
w/in next 10 yrs, over 50% of pts presenting with hematological abn will have developed pancytopenia
in FA, does thrombocytopenia usu come before or after neutropenia?
thrombocytopenia usu precedes neutropenia
if no one has been tested for BRCA mutation what happens?
comprehensive BRCA analysis is done
if comprehensive testing shows a mutation what does this mean for your risk?
risk of BrCA is largely unknown
what is done for testing for those of Ashkenazi Jewish descent?
multisite 3 point BRCA analysis - looks for 3 MC mutations in BRCA1/2 genes
what is ordered if a pt has a relative that has already been tested and is known to have a mutation?
single site BRCA test
