Reproductive Genetics 4 Flashcards
Recognize pedigree patterns consistent with hereditary gynecologic cancer syndromes.
What are the major heritable gynecologic cancer syndromes?
- BRCA1/BRCA2 (hereditary breast and ovarian cancer syndrome)
- Lynch syndrome (Hereditary non-polyposis colorectal carcinoma)
What is the indication for doing genetic testing for hereditary cancer syndromes?
- For carrier, positive status will impact surveillance recommendations
- For non-carriers in families with mutation, avoids unecessary interventions
- Risk-reducing surgery
- Family members may be impacted
- Reproductive decision-making
What are the BRCA1/2 mutations? What do they increase risk for?
- Autosmal dominant, function as tumor suppressor genes
- Heterozygous mutation = substantial increase in risk for early onset breast and/or ovarian cancer
- “2nd hit” in remaining BRCA gene results in tumor formation
What are features that may indicate a BRCA1/2 mutation in a family?
- Multiple cases early-onset breast cancer
- Ovarian cancer, esp. early-onset
- Breast and ovarian cancer in same patient
- Bilateral breast cancer
- Male breast cancer
- Ashkenazi Jewish ancestry
What are the risks in individuals with BRCA1 mutations to develop cancer?
- 85% lifetime risk for breast cancer, increases with age
- 10% of women with breast cancer under 35 are carriers
- 40% lifetime risk of ovarian cancer
What are the risks in individuals with BRCA2 mutations to develop cancer?
- Lifetime breast cancer risk about 60%, up to 80%
- Lifetime ovarian cancer risk 15-20%
- Lifetime male breast cancer risk - 6%
- 100 fold increase compared to general population
What are some methods to reduce risk of ovarian cancer in individuals with a BRCA mutation?
- Birth control pills
- First full-term pregnancy < age 25; number of pregnancies
- Breast-feeding
- BTL/hysterectomy RR 0.33/0.67
- Prophylactic oophorectomy
- Risk of primary peritoneal cancer remains
What is the epidemiology and genetics associated with lynch syndrome?
- Defect in mismatch repair, mutation in one of the following
- MLH1
- MLH2
- MSH6
- PMS2
- Results in microsatellite instability
- Accounts for 1-6% of colorectal cancers and 2-3% of endometrial cancers
- lifetime GI cancer risk is 90%
- lifetime endometrial cancer risk is 60%
- lifetime ovarian cancer risk is 15%
What are the clinical guidelines for diagnosis of Lynch syndrome, and what are the evaluation options for families with suspected mutations?
- Amsterdam II criteria
- At least 3 relatives with HNPCC-associated cancer
- At least 2 successive generations affected
- 1 affected is 1st-degree relative of the other 2
- At least one of the malignancies diagnosed before age 50
- Genetic evaluation
- tumor testing for microsatellite instability
- immunohistochemical testing of tumor
- if positive, proceed to germline mutation testing
What is the surveillance protocol in an individual with Lynch syndrome?
- Colonoscopy every 1-2 years beginning at 25
- Endometrial/ovarian screening every year starting at 25-35
- Prophylactic surgery may be option for patient