Hereditary Breast and Ovarian Cancer Flashcards
Is most of breast/ovarian cancer sporadic or hereditary?
Sporadic
How does age of onset differ between sporadic and hereditary cancer?
Sporadic is generally later onset
Why is it that a greater proportion of BRCA1 mutations are large dels/dups compared to those in BRCA2?
More Alu repeats in BRCA1
What are the chromosomal locations of BRCA1 and 2?
- BRCA1 = chr17
- BRCA2 = chr13
What is the carrier frequency of BRCA1 and 2 mutations?
- Approx 1/500 to 1/1,000 in the general Caucasian population
- 1/40 to 1/50 in Ashkenazi Jews
Describe how mutations work in BRCA
- Germline loss of one wildtype allele
- Loss of other allele (somatic mutation or loss of heterogeneity)
What is the major role of the BRCA1/2 genes?
DNA repair by homologous recombination and integrity of the genome
What type of gene are BRCA1 and 2 and how does this implicate them in cancer?
- 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
Risk of breast cancer increases with advancing age for BRCA mutations but is the risk higher for BRCA1 or BRCA2 mutation carriers?
BRCA1
There is an increased risk of cancers other than breast and ovarian for carriers of BRCA1/2 mutations - what are they?
- BRCA1 and BRCA2: prostate, pancreatic
- BRCA1 only: endometrial, cervical
What percentage of BRCA1 breast cancers are triple negative? What does this mean?
- 80% = triple negative
- Absence of oestrogen (ER), progesterone (PR) and HER2 receptors
Are a higher or lower number of BRCA2 breast cancers ER positive compared to BRCA1?
Higher number of BRCA2 breast cancers are ER positive
What are the criteria for referral for genetic counselling in breast cancer that should alert someone that the cancer may be hereditary?
- 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
What syndrome is associated with increased risk of GI cancers, as well as breast and ovarian?
Peutz-Jeghers syndrome (can have pigmented lips)
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?
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
A negative, uninformative result when the familial mutation is unknown in breast cancer genetic testing can be caused by what?
- presence of a deleterious mutation that has not been detected
- Mutation present in other gene
- BRCA1/2 variant of uncertain significance has been identified
What is the main method of breast cancer surveillance?
- 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)
What does surveillance involve in ovarian cancer?
- 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
What are the two main treatment options for carriers of BRCA1/2 mutations?
- Chemoprevention
- Prophylactic surgery (bilateral mastectomy/bilateral oophorectomy)
Provide some details on chemoprevention for carriers of BRCA1/2 mutations?
- 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
How successful is prophylactic bilateral mastectomy as a treatment option for BRCA1/2 mutation carriers?
Approx 90% reduction in breast cancer risk
How successful is prophylactic bilateral oophorectomy as a treatment option for BRCA1/2 mutation carriers?
- 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)
What type of breast cancer is more sensitive to cytotoxics?
- Triple negative
- In comparison to ER positive tumours
- Inferior survival outcomes though overall
What are PARP inhibitors and how do they work in breast cancer patients?
- 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
Name some hereditary breast cancer syndromes
- Cowden
- Li Fraumeni
- Hereditary diffuse gastric syndrome
- PALB2 gene mutation
- CHEK2 mutation
Name an ovarian cancer syndrome
HNPCC (aka lynch syndrome)
Mutations in which gene cause Li Fraumeni syndrome?
TP53
What gene is involved with Cowden syndrome?
PTEN
