1. GYN CANCER RISK AND GENETICS
Meagan Farmer, MS, CGC
Certified Genetic Counselor
Director of Cancer Genetic Counseling
Department of Genetics
University of Alabama at Birmingham

2. No conflicts of interest to report

3. Introduce examples of hereditary conditions associated with GYN cancer
LEARNING OBJECTIVES
Differentiate between sporadic, familial, and hereditary cancer and review genetics basics
Introduce examples of hereditary conditions associated with GYN cancer
Discuss pros and cons of multigene panels
Explore the role of cancer genetic counselors

4. cancer categories

5. CANCER CATEGORIES
Traditionally, 5-10% of cancers estimated to be due to hereditary (single gene) cause.

6. CANCER CATEGORIES- OVARIAN CANCER
Today, 10-25% of invasive ovarian cancers estimated to be due to hereditary (single gene) cause.

7. Few family members with cancer Later age of onset Chance
Sporadic Cancer
Few family members with cancer
Later age of onset
Chance
Environmental factors
Ov ca dx 71

8. Typically later ages of onset Shared genes and environment
Familial Cancer
> 1 individual on the same side of the family with same type of cancer
Typically later ages of onset
Shared genes and environment
Ut ca dx 71
Ut ca dx 63

9. HEREDITARY CANCER RED FLAGS
Cancer at early ages
Multiple primary cancers in one person
Multiple cases of same or related cancers on the same side of the family
Rare cancers
Ethnic Background

10. Cancer genetics basics

11. GENETICS 101

12. TUMOR SUPPRESSOR GENES
PROTECTION AGAINST TUMOR DEVELOPMENT
Tumor Suppressor/ Repair Gene(s)   
            
         
Tumor Suppressor/ Repair Gene(s) w/ pathogenic variant (harmful difference)
XXX
DECREASED PROTECTION AGAINST TUMOR DEVELOPMENT

13. XXX AUTOSOMAL DOMINANT 2 copies of each gene- one from each parent
Pathogenic variant in one copy is enough to cause the condition
50% chance to pass copy with pathogenic variant in each pregnancy (sons and daughters)
XXX

14. AUTOSOMAL DOMINANT V

15. TEST RESULTS
Pathogenic variant (aka mutation)
Likely pathogenic variant
Variant of Uncertain Significance (VUS)
Variant, Favor polymorphism (likely benign)
Negative
True negative
Uninformative negative

16. BRCA-RELATED Hereditary breast and ovarian cancer (hboc)

17. BRCA RED FLAGS Cancer at early ages Multiple cancers in one person
Breast cancer < 50
Multiple cancers in one person
Bilateral breast cancer
Multiple cases of same or related cancers in a family
Breast cancer in combination with ovarian ca, pancreatic ca, prostate ca, melanoma
Rare cancers
Male Breast Cancer
Triple negative breast cancer
Ethnic Background
Ashkenazi Jewish ancestry and HBOC

18. TUMOR SUPPRESSOR GENES
BRCA1/BRCA2
PROTECTION AGAINST TUMOR DEVELOPMENT   
            
         
BRCA1/ BRCA2 w/ pathogenic variant.
XXX
DECREASED PROTECTION AGAINST TUMOR DEVELOPMENT

19. Cancer BRCA1 BRCA2 Gen. Pop.
HBOC CANCER RISKS
Cancer
BRCA1
BRCA2
Gen. Pop.
Breast
46-63%
38-53%
12%
Ovarian
34-44%
12-20%
1-2%
Prostate
increased
20-30%
16%
Male Breast 7%
0.1%
Pancreatic
3-4%
2-5%
0.9%
Melanoma
not increased 2%
(Graeser et al, 2009) (Chen and Parmigiani, 2007) (Liede, Karlan, and Narod, 2004) (Consortum TB, 1999)

20. BRCA MANAGEMENT-FEMALES
Cancer
Screening/Risk-reducing Measure
Breast
Screening:
Annual clinical breast exam (18 yo)
Semiannual clinical breast exam (25 yo)
Annual breast MRI (25 yo)
Annual mammogram (30 yo)
Risk-Reducing:
Medications (ex: Tamoxifen)
Preventive mastectomies with or without reconstruction
Ovarian
Screening?
Oral contraceptive pills
Bilateral salpingo-oophorectomy (ovary and fallopian tube removal) (35-45 yo)
Melanoma
Annual skin and eye exams

21. BRCA-RELATED HBOC 2 2 BRCA2+ BRCA2+ d. 80s d. 60s Ovarian Ca d. 77
Br 40s 65 68
d. 67
d. 20s 75 73 75
d.67 69 70 2 51
Br Ca 50
d. 55
Br 46 48
Br 46
d.48 . 39
BRCA2+
BRCA2+ 2 32 24 23

22. LYNCH RED FLAGS Cancer at early ages Multiple cancers in one person
Colon or uterine ca < 50
Multiple cancers in one person
Colon ca x 2 in same person
Multiple cases of same or related cancers in a family
Colon, uterine, ovarian, other GI, urinary tract ca
Rare cancers
Sebaceous cancer

23. LYNCH GENES: MLH1, MSH2, MSH6, PMS2, and EPCAM
Repair of errors in genetic information, Protection against tumor development
Lynch Gene   
            
         
Faulty repair system, Decreased protection against tumor development
Lynch Gene w/ pathog. variant
XXX

24. d. 65
CRC dx 48
CRC dx 51
Endo ca dx 52
MLH1-
MLH1+
MLH1+
MLH1-
MLH1+

25. LYNCH SYNDROME Cancer MLH1/MSH2 Risk MSH6 Risk PMS2 Risk Colon 40-80%
Lynch-associated genes: MLH1, MSH2, MSH6, PMS2, and EPCAM
Cancer
MLH1/MSH2 Risk
MSH6 Risk
PMS2 Risk
Colon
40-80%
10-22%
15-20%
Endometrial
25-60%
16-26%
15%
Stomach
1-13%
< 3%  *
Ovary
4-24%
1-11%
Hepatobil. tract
1-4%
Not reported
Urin. tract
<1%
Small bowel
3-6%
CNS
1-3%
Sebac. Neop.
1-9%
Pancreas
1-6%
* Combined risk 6%
(NCCN Colorectal )

26. LYNCH SYNDROME MEDICAL MNGT
Colorectal Cancer
Non-Surgical/Surveillance
Colonoscopy every 1-2 yrs beginning at age 25 or 2-5 yrs before earliest CRC dx in family
Surgical
Consider colon resection or colectomy upon CRC dx
Gynecologic Cancer
Non-Surgical
Speak with GYN about symptoms of endometrial cancer
Discuss pros and cons of GYN cancer screening
OC Pills for ovarian cancer risk reduction
Consider prophylactic hysterectomy
*Customize remaining mngt plan based on family
history, etc.

27. MULTI-GENE panels

28. Breast/Ovarian High Risk Genes Moderate Risk Genes Newer Genes
BRCA1/BRCA2
(HBOC: breast, ovary, prostate, pancreatic)
ATM
(breast, colon, pancreatic)
BARD1
(breast, ovary)
CDH1
(HDGC: breast, gastric, colon)
CHEK2
(breast, colon, prostate)
FANCC
(breast, pancreatic)
PTEN
(Cowden: breast, thyroid, endometrial)
BRIP1
(ovary, breast)
NBN
(breast, melanoma, NH-lymphoma, colon)
TP53
(LFS: breast, ovary, sarcoma, brain)
RAD51C
XRCC2
MLH1/MSH2/MSH6/PMS2/
EPCAM
(Lynch: colon, endometrial, ovary, etc.)
RAD51D
PALB2
(breast, ovary, pancreatic)
GeneDX

29. GYN Cancer High Risk Genes Moderate Risk Genes Newer Genes BRCA1/BRCA2
(HBOC: breast, ovary, prostate, pancreatic)
CHEK2
(breast, colon, prostate, ovary)
BARD1
(breast, ovary)
MLH1/MSH2/MSH6/PMS2/
EPCAM
(Lynch: colon, endometrial, ovary, etc.)
BRIP1
(ovary, breast)
POLD1
(colon, endometrial)
PTEN
(Cowden: breast, thyroid, endometrial)
RAD51C
TP53
(LFS: breast, ovary, sarcoma, brain)
RAD51D
STK11
(PJS: colon, breast, pancreatic, gastric, etc.)
PALB2
(breast, ovary, pancreatic)
GeneDX

30. Comprehensive High Risk Genes Moderate Risk Genes Newer Genes BRCA1/2
(HBOC: breast, ovary, prostate, pancreatic)
ATM
(breast, colon, pancreatic)
AXIN2
(breast, colon)
MLH1/MSH2/MSH6/PMS2/EPCAM
(Lynch: colon, endometrial, ovary, etc.)
CHEK2
(breast, colon, prostate, ovary)
BARD1
(breast, ovary)
APC/MUTYH
(FAP/MAP: colon, gastric, breast, etc.)
BRIP1
(ovary, breast)
CDK4
(breast, pancreatic, skin)
SMAD4/BMPR1A
(JPS: colon, gastric, pancreatic)
RAD51C
FANCC
(breast, pancreatic)
CDH1
(HDGC: breast, gastric, colon)
RAD51D
NBN
(breast, melanoma, NH-lymphoma, colon)
PTEN
(Cowden: breast, thyroid, endometrial)
XRCC2
STK11
(PJS: colon, breast, pancreatic, gastric, etc.)
POLD1
(colon, endometrial)
TP53
(LFS: breast, ovary, sarcoma, brain)
POLE
(colon)
CDKN2A
(FAMMM: melanoma, pancreatic)
GREM1 (SCG5)
VHL
(VHL: neuroendocrine, renal)
PALB2
(breast, ovary, pancreatic)
GeneDX

31. MULTIGENE PANELS BENEFITS CHALLENGES
More cost-effective and efficient if considering multiple syndromes. Insurance may only allow one genetic test per lifetime.
More expensive than single gene testing
May identify rarer genetic causes of cancer in an individual/family
May identify mutation in gene for which there is limited info/guidance
Tumor Spectrum
Cancer risk estimates
Management recommendations
May identify genetic causes in “non-textbook” cases of well known cancer syndromes
Inconclusive test results more likely

32. GENETIC COUNSELING

33. GENETIC COUNSELING DEFINITION
Genetic counseling is the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. This process integrates the following:
Interpretation of family and medical histories
Education about inheritance, testing, management, prevention, resources and research
Counseling to promote informed choices
(NSGC, 2006)

34. WHEN TO CONSIDER TESTING
American Society of Clinical Oncology: “Genetic counseling and testing should be offered if…”
An individual has personal or family history features suggestive of cancer predisposition
The test can be adequately interpreted
The test will influence medical management
(ASCO, 2003)

35. GENETIC COUNSELING GOALS
Contracting
Risk assessment
Education
Informed consent
Results
Medical Management Recommendations
Support

36. Motivations-Patients often want to gain a better understanding of:
CONTRACTING
Motivations-Patients often want to gain a better understanding of:
Personal cancer risks
Options and considerations for participation in genetic testing or research
Screening and cancer prevention
Implications/recommendations for family members
What can we offer?

37. Methods Challenges Medical and family history analysis Risk models
RISK ASSESSMENT
Methods
Medical and family history analysis
Risk models
Challenges
Limited information
Family structure
Variability
d.80
d. 25 67 64
d.48 47
d. 32

38. PT CONCERNS REGARDING TESTING
Cost
Timing/Impact on treatment
Childbearing considerations
Age at hysterectomy/ovary removal
Risk to current/future children
Quality of life
Perceived cancer risk
Body image; self-esteem
Surgery impact on quality of life
Management of surgical menopause
Discrimination

39. Testing Options Informed Consent Test Interpretation
Benefits
Limitations
Possible outcomes
Risks
Test Interpretation
Result Explanation

40. Recommendations for patient and family
MANAGEMENT
Recommendations for patient and family
NCCN guidelines if exist
Use studies and customize to medical/family history otherwise
Take limitations into account (insurance coverage, location, etc.)

41. Facilitate decision-making
SUPPORT
Facilitate decision-making
Discuss how each test option and potential results might impact patient
Identify what is most important to patient
Listen to concerns and help them come to a decision
Psychosocial counseling
Provide support/resources

42. TAKE HOME MESSAGE
5-10% of cancer in general is due to underlying hereditary cause
10-20% of invasive ovarian cancer is due to hereditary cause
20%+ of cancers are due to combination of genetic and environmental factors. Increased surveillance may still be appropriate!
A GC can review medical and family histories to determine:
whether testing is appropriate
who the best person is to test in a family
what testing is indicated
how test results and family history may affect medical management for patient and family

43. GYN CANCER RISK AND GENETICS
Meagan Farmer, MS, CGC
Certified Genetic Counselor
Director of Cancer Genetic Counseling
Department of Genetics
University of Alabama at Birmingham