Genetic Implications of Breast Cancer

Question 1

What’s the lifetime risk for breast cancer for a woman in the US?

Answer 1

13%

Question 2

5 causes of hereditary breast cancer?

Answer 2

BRCA1
BRCA2
TP53
PTEN
Undiscovered genes

Question 3

What process to BRCA1 and BRCA2 gene products play a role in?

Answer 3

Homologous DNA repair.

Question 4

What makes a DNA test for breast cancer related genes useful?

Answer 4

Defined response to positive result.

Defined response to negative result.

Question 5

What is absolute risk of breast cancer in carriers of BRCA1/BRCA2 mutations?

Answer 5

60-80% risk (vs. 13% in general population)

Question 6

Does BRCA1 mutation increase the risk of breast cancer in men?

Answer 6

Yes - but it’s going from 0.1% incidence to 1-2% incidence. (look into it if you see breast cancer in a man)

Question 7

Outside of reproductive cancers, what specific cancers to BRCA1 and/or BRCA2 mutations increase the risk of?

Answer 7

BRCA1: pancreas
BRCA2: pancreas and melonoma

Question 8

Which BRCA gene increases the risk of prostate cancer in men?

Answer 8

BRCA2

Question 9

Diagnosis of breast cancer before what age would make you suspicious of BRCA1/2 mutation?

Answer 9

• Before age 40
• At least 2 women in same lineage with breast cancer under 50
• Ashkenazi Jewish woman
• Triple negative breast cancer under 50 (neg ER/PR/HER2-neu)

Question 10

Ethnic group noted as having higher rates of carrying BRCA1/2?

Answer 10

Ashkenazi Jews

Question 11

Who is it most informative to test for deleterious mutations?

Answer 11

AFFECTED FAMILY MEMBER (person who actually has the disease)

A negative result in an unaffected individual doesn’t tell you much about their risk.

Question 12

What are “variants of unknown significance”?

What’s one way to figure out their significance?

Answer 12

• Mutations in the tested gene, but unclear whether they cause loss of function.
• Test many family members to see if the specific mutation tracks with cancer incidence
• MUCH more common in African American population

Question 13

5 things you do in response to positive BRCA1/2 test?

Answer 13

Test adult relatives.
Increase surveillance.
Lifestyle changes.
Chemo-prevention.
Prophylactic surgery.

Question 14

What’s the penetrance like in BRCA1/2 mutations?

Answer 14

Not 100%.–> there is significant variability in penetrance

May be modified by other genes and environment.

Question 15

Does Risk Reducing Salpingo-Oophrectomy work to prevent cancer and all-cause mortality?

Answer 15

Yes.
It has the greatest effect when used as secondary prevention - but this isn’t surprising, as these women are higher risk.

Question 16

Do BRCA1/2 related tumors have worse prognoses than sporadic tumors?

Answer 16

Nope. There is no difference in prognosis. Some ovarian tumors in BRCA1/2 carriers may actually respond better to chemo/ have better prognosis (with use of platinum chemo agents)

Question 17

Might the specific kind of chemotherapy that is used be more effective when the patient is a BRCA1/2 carrier?

Answer 17

Yes.
At least in BRCA1-deficient tumors, cisplatin works better because it’s a kind of damage these cells can’t repair.
(taxanes don’t seem to work as well)

Question 18

What is synthetic lethality? What does it take advantage of?

Answer 18

BRCA1/2 normally repairs double-stranded DNA breaks. PARP works in an alternative dsDNA break repair mechanism.
If you inhibit PARP in a BRCA-deficient cell, the repair pathway is knocked out entirely and results in CELL DEATH

Question 19

What nefarious phenomenon has been seen in tumors that become resistant to “synthetic lethality”?

Answer 19

Second mutations that restore BRCA proteins function (normally is knocked out in people who carry the BRCA1/2 mutations), allowing them to overcome PARP inhibitors and platinum agents.

Question 20

What have GWAS revealed about heritability of breast cancer?

Answer 20

• Dominant alleles have been ID’d
• FGFR2 (SNP gene)
• Any1 SNP will raise risk only minimally
• SNP panels may have future application to give overall risk level

Question 21

How are BRCA1 tumors different from BRCA2 tumors? What may this mean for TX?

Answer 21

BRCA1= Triple negative (ER/ PR/ HER2-neu)

BRCA2= ER +

May not have the same sensitivity to the same drugs