Reproductive Genetics 4

Question 1

What are the major heritable gynecologic cancer syndromes?

Answer 1

• BRCA1/BRCA2 (hereditary breast and ovarian cancer syndrome)
• Lynch syndrome (Hereditary non-polyposis colorectal carcinoma)

Question 2

What is the indication for doing genetic testing for hereditary cancer syndromes?

Answer 2

• 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

Question 3

What are the BRCA1/2 mutations? What do they increase risk for?

Answer 3

• 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

Question 4

What are features that may indicate a BRCA1/2 mutation in a family?

Answer 4

• 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

Question 5

What are the risks in individuals with BRCA1 mutations to develop cancer?

Answer 5

• 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

Question 6

What are the risks in individuals with BRCA2 mutations to develop cancer?

Answer 6

• 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

Question 7

What are some methods to reduce risk of ovarian cancer in individuals with a BRCA mutation?

Answer 7

• 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

Question 8

What is the epidemiology and genetics associated with lynch syndrome?

Answer 8

• 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%

Question 9

What are the clinical guidelines for diagnosis of Lynch syndrome, and what are the evaluation options for families with suspected mutations?

Answer 9

• 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

Question 10

What is the surveillance protocol in an individual with Lynch syndrome?

Answer 10

• Colonoscopy every 1-2 years beginning at 25
• Endometrial/ovarian screening every year starting at 25-35
• Prophylactic surgery may be option for patient