Hereditary Breast and Ovarian Cancer

Question 1

Is most of breast/ovarian cancer sporadic or hereditary?

Answer 1

Sporadic

Question 2

How does age of onset differ between sporadic and hereditary cancer?

Answer 2

Sporadic is generally later onset

Question 3

Why is it that a greater proportion of BRCA1 mutations are large dels/dups compared to those in BRCA2?

Answer 3

More Alu repeats in BRCA1

Question 4

What are the chromosomal locations of BRCA1 and 2?

Answer 4

• BRCA1 = chr17

- BRCA2 = chr13

Question 5

What is the carrier frequency of BRCA1 and 2 mutations?

Answer 5

• Approx 1/500 to 1/1,000 in the general Caucasian population
• 1/40 to 1/50 in Ashkenazi Jews

Question 6

Describe how mutations work in BRCA

Answer 6

• Germline loss of one wildtype allele

- Loss of other allele (somatic mutation or loss of heterogeneity)

Question 7

What is the major role of the BRCA1/2 genes?

Answer 7

DNA repair by homologous recombination and integrity of the genome

Question 8

What type of gene are BRCA1 and 2 and how does this implicate them in cancer?

Answer 8

• Both tumour suppressor genes
• Involved in regulation of cell growth and maintenance of cell cycle
• Mutation leads to inability to regulate cell death and uncontrolled growth, which leads to cancer

Question 9

Risk of breast cancer increases with advancing age for BRCA mutations but is the risk higher for BRCA1 or BRCA2 mutation carriers?

Answer 9

BRCA1

Question 10

There is an increased risk of cancers other than breast and ovarian for carriers of BRCA1/2 mutations - what are they?

Answer 10

• BRCA1 and BRCA2: prostate, pancreatic

- BRCA1 only: endometrial, cervical

Question 11

What percentage of BRCA1 breast cancers are triple negative? What does this mean?

Answer 11

• 80% = triple negative

- Absence of oestrogen (ER), progesterone (PR) and HER2 receptors

Question 12

Are a higher or lower number of BRCA2 breast cancers ER positive compared to BRCA1?

Answer 12

Higher number of BRCA2 breast cancers are ER positive

Question 13

What are the criteria for referral for genetic counselling in breast cancer that should alert someone that the cancer may be hereditary?

Answer 13

• Multiple cases of breast/ovarian cancer on same side of family (closely related relatives, more than one generation)
• family member with breast cancer under 35yrs
• family member with both breast and ovarian cancer
• Ashkenazi Jewish heritage (particularly with relatives with breast or ovarian cancer)
• Male breast cancer
• Bilateral breast cancer

Question 14

What syndrome is associated with increased risk of GI cancers, as well as breast and ovarian?

Answer 14

Peutz-Jeghers syndrome (can have pigmented lips)

Question 15

A positive test result in breast cancer genetic testing would mean a deleterious mutation has been identified. What would a negative test depend on and what does this mean?

Answer 15

Depends on whether the mutation is known in the family

• if known then it is a true negative
• if not known then it is uninformative

Question 16

A negative, uninformative result when the familial mutation is unknown in breast cancer genetic testing can be caused by what?

Answer 16

• presence of a deleterious mutation that has not been detected
• Mutation present in other gene
• BRCA1/2 variant of uncertain significance has been identified

Question 17

What is the main method of breast cancer surveillance?

Answer 17

• normal risk pop = mammography age 50-70
• BRCA1/2 mutation carriers = mammography and MRI annually from age 30 (if surveillance required before age 30 = MRI as has higher sensitivity in lower age groups due to increased density of breast)

Question 18

What does surveillance involve in ovarian cancer?

Answer 18

• 6 monthly screening starting at age 30-35
• Involves pelvic exam, transvaginal ultrasound and serum CA-125 levels
• CA-125 levels elevated in 50% of stage 1 ovarian cancers but also elevated in some benign conditions including endometriosis

Question 19

What are the two main treatment options for carriers of BRCA1/2 mutations?

Answer 19

• Chemoprevention

- Prophylactic surgery (bilateral mastectomy/bilateral oophorectomy)

Question 20

Provide some details on chemoprevention for carriers of BRCA1/2 mutations?

Answer 20

• 5 year Tamoxifen shows 60% reduction in breast cancer risk for ER +ve BRCA2 carriers
• Oral contraceptives reduce ovarian cancer risk but may increase breast cancer risk

Question 21

How successful is prophylactic bilateral mastectomy as a treatment option for BRCA1/2 mutation carriers?

Answer 21

Approx 90% reduction in breast cancer risk

Question 22

How successful is prophylactic bilateral oophorectomy as a treatment option for BRCA1/2 mutation carriers?

Answer 22

• up to 95% reduction in ovarian cancer risk
• approx 50% reduction in breast cancer risk
• dependent on it being done pre-menopausal (should be done by age 35)

Question 23

What type of breast cancer is more sensitive to cytotoxics?

Answer 23

• Triple negative
• In comparison to ER positive tumours
• Inferior survival outcomes though overall

Question 24

What are PARP inhibitors and how do they work in breast cancer patients?

Answer 24

• Poly(ADP-ribose) polymerases are multifunctional enzymes that repair single strand breaks
• PARP inhibitors result in accumulation of single strand breaks - during cell division these result in double strand breaks at replication forks
• BRCA-deficient tumours do not have inability to repair these double strand breaks and their build up = toxic

Question 25

Name some hereditary breast cancer syndromes

Answer 25

• Cowden
• Li Fraumeni
• Hereditary diffuse gastric syndrome
• PALB2 gene mutation
• CHEK2 mutation

Question 26

Name an ovarian cancer syndrome

Answer 26

HNPCC (aka lynch syndrome)

Question 27

Mutations in which gene cause Li Fraumeni syndrome?

Answer 27

TP53

Question 28

What gene is involved with Cowden syndrome?

Answer 28

PTEN