BRCA1/2

Question 1

History of BRCA1/2.

Answer 1

1994/1995 Myriad Genetic Laboratories and the University of Utah patent the BRCA1/2 genes
2013 the US Supreme Court rules human genes cannot be patented

Question 2

Describe the genetics of cancers developed through mutations in Tumor Suppressor genes.

Answer 2

autosomal dominant
5-10% of cancers are hereditary
50% of hereditary breast cancers are caused by BRCA1/2 defects (0.125% prevalence in general population; 4-14% of males with breast cancer; 10% of females with ovarian cancer)

Question 3

Describe the two-hit hypothesis for cancer as it relates to sporadic and hereditary cancers.

Answer 3

sporadic: begins with two working genes, one hit makes one non-working copy, second hit to the other copy (loss of heterozygosity) results in tumor growth
hereditary: only one working copy to start with; first hit results in loss of heterozygosity and tumor growth

Question 4

Describe the founder effect in the AJ population as it relates to BRCA mutations.

Answer 4

1 in 40 AJ individuals carry a BRCA1 or 2 mutation

BRCA1/2 account for 95% of all mutations in this population

Question 5

What are the functions of BRCA1/2?

Answer 5

tumor suppression via DNA damage repair of double stranded breaks (also protein ubiquitination [tagging for degradation], cell cycle checkpoint control, transcriptional regulation)

Question 6

What features increase the chance of BRCA1/2 mutations?

Answer 6

multiple cases of early-onset breast cancer (<50 years old)
presence of ovarian/fallopian tube cancer
breast and ovarian cancer in the same woman
bilateral breast cancer
AJ heritage
Male breast cancer
triple negative (BRCA1 only)- ER(-)PR(-)HER2-neu(-)

Question 7

What strategies are available for determining if you should consider BRCA1/2 testing?

Answer 7

medical history paramount (specific type(s) of cancer, with pathology documentation whenever possible, previous GT, environmental/hormonal risk factors)
family history (3-4 generation; documentation of relatives' diagnosis; be aware of limited family structure or paucity of females; identify most informative relative to test first)
NOTE if relative has already tested positive, targeted testing is possible BUT beware of other side of the family
don't forget to test all 3 founder mutations if AJ

Question 8

What are the preferred risk assessment models for breast and ovarian cancer?

Answer 8

to predict risk of breast cancer: Tyrer-Cuzick (IBIS) Model

to predict the chance of harboring a germline mutation in BRCA1/2: BRCAPro

Question 9

What genetic testing is best for BRCA1/2 mutations?

Answer 9

Sanger (direct) sequencing

NextGen sequencing

Question 10

What are the potential outcomes of genetic testing for BRCA1/2 mutations?

Answer 10

definitive results (positive- means there is an alteration which is know to be associated with increased risk for cancer; TRUE NEGATIVE- an alteration which was previously identified in a relative is not found)
indeterminate results (no alteration identified- genes thus look "normal"; VUS is a change that is identified but its significance and contribution to cancer risk is not known)
*in either indeterminate instance the presence of a genetic predisposition to caner cannot be completely eliminated and the risk to develop cancer may remain elevated- consider panel testing

Question 11

What factors influence the penetrance of BRCA1/2?

Answer 11

modifier genes
carcinogens
estrogen (hormonal/reproductive factors)
response to DNA damage (repair enzymes)
*note that individuals with BRCA1/2 mutations are at HIGH risk for second primary breast cancers

Question 12

Describe the ovarian cancer common with BRCA1/2 mutations.

Answer 12

epithelian in origin (rather than stromal or germ cell)
generally higher grade and more frequently bilateral
includes fallopian tube and primary peritoneal cancer
emerging evidence that many “ovarian” cancers may actually begin in the fallopian tube (serous tubal intraepithelial carcinoma lesions likely prcursors to invasive cancer)

Question 13

What is the pathology of ovarian cancer in BRCA1/2 mutations?

Answer 13

excess of serous adenocarcinomas, though endometriod and clear-cell ovarian cancer also seen; not mucinous

Question 14

What is the relationship between prostate cancer in HBOC?

Answer 14

studies indicate that BRCA2 mutations in particular confer greater likelihood of earlier age at diagnosis, higher grade cancer, and poorer prognosis than the GP
not a significant cause of familial prostate cancer

Question 15

What is the relationship between Pancreatic cancer and BRCA2?

Answer 15

familial pancreatic cancer: greater than or equal to two first-degree relative with pancreatic adenocarcinoma
majority have no identifiable genetic cause
in one study o fFPC, 17% tested positive for BRCA2 mutation however BOTH BRCA1/2 mutations confer an increased risk to develop pancreatic cancer

Question 16

How is HBOC managed?

Answer 16

Increased surveillance: earlier starting age (25 years for breast screening), greater frequency (consider atlernating mammogram and MRI every 6 months), more intensive (breast MRI in addition to mammography)
risk reducing: chemoprevention (eg. Tamoxifen for breast cancer; oral contraceptives for ovarian cancer), surgical (risk reducing mastectomy [reduces risk in carriers by >90%], salpingooophorectomy)

Question 17

What can be detected on breast MRI?

Answer 17

smaller, earlier-stage cancers

2x as sensitive as mammography

Question 18

What methods can be used for ovarian cancer surveillance?

Answer 18

CA-125 serum tumor marker + transvaginal ultrasound

Question 19

What risk reduction strategies are available for ovarian cancer?

Answer 19

Oral contraception (reduces risk by 50% in all women including BRCA+)
prophylactic bilateral salpingo-oophorectomy (BSO)- >90% risk reduction

Question 20

What medical treatments are available for BRCA associated cancers?

Answer 20

sensitive to platinum-based chemotherapis

Poly ADP-ribose polymerase (PARP) inhibitors

Question 21

What reproductive considerations should be discussed in patients with BRCA1/2 mutations?

Answer 21

prenatal diagnosis or in vitro fertilization with preimplantation GT (PGT-M)
fanconi anemia risk- BRCA2=FANCD1 (especially important to discuss with patients of reproductive age and inquire about partner’s FHx; make testing available to partner)