2. Overview of Cancer Genetics
The Role of Cancer Genetics in Precision Medicine
April 17, 2018 / May 1, 2018
Vanessa Manso / Matthew Share, MS
Licensed / Certified Genetic Counselor
William G. Rohrer Cancer Genetics Program

3. Objectives
Identify the best practices for referring patients for genetic counseling
Discuss the key components of genetic assessment and testing
Describe current approaches to genetic testing for hereditary cancer syndromes
Identify potential benefits and limitations of the multigene panel testing approach for hereditary cancer
Discuss the implications, risks, and benefits of genetic testing for the individual and their family
Recognize key features of major genetic syndromes

4. Most Cancers are Sporadic
Environmental exposures / random chance
Familial (~20%)
Shared environmental exposures
Similar genetic background
Hereditary (~10%)
Inherited genetic mutation  increased risk
Image from

5. Family History Features Suggestive of Hereditary Cancer Syndromes
Cancer in 2+ relatives
Multiple generations
Same side of the family
Younger cancer diagnosis
Multiple primary cancers
Includes bilateral
Less common cancer types
Ovarian cancer
Breast cancer in a man
Paraganglioma
Medullary thyroid cancer
Absence of typical environmental risk factors
Cancer with certain pathologic characteristics
“Triple negative” breast cancer
Cancer cells with genetic instability or abnormal staining
Ancestry w/ higher incidence of mutations in hereditary cancer syndrome genes
Ashkenazi Jewish ancestry & BRCA1, BRCA2
Blood relative(s) with a known mutation

6. Sporadic Familial Hereditary Bilateral Breast @71 Breast @41 & 52

7. Key Components of Genetic Assessment and Testing
Medical & family history obtained / assessed
Education regarding hereditary cancer
Informed consent: explain clinical and familial implications of genetic testing and other diagnostic studies
Healthy tissue sample (blood, saliva, cheek cells) obtained if proceeding with testing

8. Genetic Testing Practices
Syndrome- or gene-specific testing (1990’s-present)
Typically single gene or single syndrome testing
i.e. BRCA1 / BRCA2; Lynch syndrome; CDH1; etc.
Single-site testing for a known mutation
Multi-gene testing (“panel testing”; 2013-present)
Variable number of genes tested
Pan-cancer versus targeted cancer gene panels
Panel based on level of known cancer risk
High / moderate / “increased” risk levels

9. The Majority of Breast Cancers Do Not Have an Identifiable Germline Mutation

10. The Majority of Ovarian Cancers Do Not Have an Identifiable Germline Mutation

11. When to Refer for Further Genetic Risk Evaluation: Breast & Ovarian
Breast cancer diagnosed ≤ 50 years
Ashkenazi Jewish ancestry and breast/ovarian (or pancreatic) cancer
Triple negative breast cancer ≤ 60
Multiple primary cancers
Breast cancer in a male
Ovarian cancer at any age
Family history and/or known familial mutation
NCCN version “Genetic/Familial High Risk Assessment: Breast and Ovarian”;

12. http://www. breastlink

13. Hereditary Breast Cancer Genes
High Risk
Moderate Risk
Increased Risk
BRCA1
ATM
BARD1
BRCA2
CHEK2
BRIP1
CDH1
PALB2
NBN
PTEN
RAD50
STK11
RAD51C
TP53
RAD51D
others…
Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, EPCAM)
**possible increased risk of breast cancer for carriers**

14. The Majority of Colorectal Cancers Do Not Have an Identifiable Germline Mutation

15. When to Refer for Further Genetic Risk Evaluation: Colorectal Cancer (CRC)
CRC diagnosed ≤ 50
Amsterdam and Bethesda Criteria
Lynch screen: IHC/MSI
Lifetime polyp count
Family history
Known familial mutation
NCCN version “Genetic/Familial High Risk Assessment: Colorectal”;

16. Hereditary CRC Syndromes
Lynch syndrome (Hereditary nonpolyposis colorectal cancer)- MLH1, MSH2, MSH6, PMS2, EPCAM
Colon, uterine, stomach, other cancer risks
Familial adenomatous polyposis (FAP)- APC
Colon polyps (100+)
Extracolonic findings: CHRPE, extra teeth, desmoids
MUTYH-associated polyposis (MAP)- MUTYH
Colon polyps (0-100), duodenal cancer, duodenal polyps
NCCN version “Genetic/Familial High Risk Assessment: Colorectal”;

17. Hereditary Gastric Cancer Syndromes
Hereditary diffuse gastric cancer: CDH1 (possibly CTNNA1)
Gastric cancer (up to 70-80%); lobular breast cancer (40-50%)
Gastric cancer: Lynch syndrome, Juvenile polyposis syndrome (BMPR1A, SMAD4), Peutz-Jeghers syndrome (STK11), APC
Gastrointestinal stromal tumor (GIST): KIT, NF1, PDGFRA, SDHA/B/C/D
NCCN version “Gastric Cancer”;

18. Potential Benefits of Multi-Gene Testing (versus traditional sequential gene testing)
Higher mutation detection rate especially for patients who do not meet specific personal or family history criteria
Lower likelihood of “uninformative” negative results
Often more cost- and time-efficient
May find a mutation in more than one gene
NCCN version “Genetic/Familial High Risk Assessment: Breast and Ovarian”;

19. Considerations of Multi-Gene Testing
Which test (# genes?) or laboratory to choose?
Increased risk for variant result
Faster / cheaper ≠ better
Limited data re: cancer risks associated with some genes
Potential lack of clear medical management guidelines for mutation carriers
Challenges in making medical management recommendations if a patient carries mutations in multiple genes
Potential added TAT for larger panels
NCCN version “Genetic/Familial High Risk Assessment: Breast and Ovarian”;

20. Possible Results of Genetic Testing
Positive
“Mutation”
“Pathogenic variant”
“Deleterious variant”
“Likely pathogenic/deleterious variant”
Negative
Variant of uncertain/unknown significance

21. Pathogenic mutation
Slide for professional use from Myriad Genetic Laboratories
Use of this image does not imply endorsement.

22. Positive Test Result Cancer risk(s) increased due to pathogenic hereditary gene mutation
Cancer treatment decisions (if applicable)
Result may influence surgical decisions, chemotherapy options, clinical trial eligibility
Cancer screening and risk reduction options
Additional imaging? More frequent clinical exams?
Surgery? Chemoprevention? Lifestyle changes?
Information for the family
A “diagnosis” for the family
Testing of relatives with / without cancer for the known mutation
May or may not influence clinical care and management

23. Negative/Uncertain Test Result Cancer risk(s) may still be increased based on personal risk factors and/or family history
Cancer treatment decisions (if applicable)
Not impacted by result
Cancer screening and risk reduction options
Based on personal and family history
Information for the family
A negative/variant result does not eliminate the possibility of hereditary cancer in the family
Other family members may still wish to consider genetic testing

24. What is a Variant of Uncertain Significance?
Alteration in a gene with limited and/or conflicting evidence regarding pathogenicity
Classification system
AA biochemical similarities
Presence/absence in healthy individuals
Presence in individuals with X-related cancers
Prediction algorithms: PolyPhen and SIFT
Internal data
*Occasional variant classification studies through laboratory*

25. Emerging Evidence Testing
Single nucleotide polymorphisms (SNP)
Small single-base changes in the genetic code that collectively may increase cancer risk
Polygenic risk score combined with risk models to calculate new risk estimate
Considerations:
How to use results clinically is not yet clear
Labs will not re calculate score as information changes
Some opt out, others opt in, rapidly evolving field

26. Tumor vs. Germline Testing
One is not a substitute for the other!
Tumor genetic testing may detect a mutation that is also in the germline
A tumor “mutation” might be considered a germline “variant of uncertain significance”
May do germline testing to follow up on a mutation found via tumor testing
dependent on the gene and the personal / family history
targeted to the mutation or to include full gene analysis +/- other genes

27. Slide for professional use from Myriad Genetic Laboratories
Use of this image does not imply endorsement.

28. DTC testing- 23andMe

29. DTC testing- 23andMe No physician order necessary
Consumers “opt-in” to receive this part of result
Not relevant result for general population (non-AJ)
Not full BRCA1/BRCA2 analysis
No other hereditary breast cancer genes studied
Positive* result
Negative result - concerns
may lead to false sense of security re: cancer risk
may deter individuals from seeking clinical genetic evaluation

30. Summary Several reasons for a patient to be referred to genetics
Personal diagnosis, family history, screening tests, less common cancer types
The scope of testing can vary
Genetic testing is negative more often than not
Identification of a genetic syndrome / mutation can have major impact on patients and families

31. Case #1 Prostate @ 43 Breast @ 72
BRCA2: breast (male and female), ovarian, prostate, pancreatic, melanoma 43 45 38 40
Single site testing:
BRCA2-
Single site testing:
BRCA2+
Single site testing:
BRCA2+
Breast @ 42
9-gene breast cancer panel: BRCA2+ 20 18
Single site testing:
BRCA2+
Single site testing:
BRCA2-
Ancestry: Maternal- SE Asian, Paternal- Irish, non-Jewish

32. Case #2 Prostate @ 72 Colon @49 Ovarian @60
MLH1: colon, uterine, gastric, ovarian, pancreatic, etc. 62 59 58 57 52
& 58
Single site testing:
MLH1+
Genetic testing 2014
9 gene gyn cancer panel: MLH1+ 34 28 6
Single site testing:
MLH1+
Single site testing:
MLH1-
Ancestry: African, non-Jewish 32

33. Case #3 63
CDH1: diffuse gastric cancer, lobular breast cancer, signet ring colon cancer
Lobular 51 23 31 20
Single site testing:
CDH1+
Signet ring features
Single site testing:
CDH1+
Genetic Testing: CDH1+ P
Ancestry: Maternal & Paternal- Irish, Non-Jewish

34. Cancer Genetics Program Practice Locations
2 Cooper Plaza, Camden
900 Centennial Blvd, Voorhees
100 Salem Drive, Willingboro
Locations for Inspira patients: Vineland, Mickleton, Mullica Hill

35. Cancer Genetics Program Team
Oncologists
Generosa Grana, MD (Program Director)
Christina Brus, MD
Alexandre Hageboutros, MD
A. Kamel Abou Hussein, MD
Pallav Mehta, MD
Jamin Morrison, MD
Kumar Rajagopalan, MD
Kanu Sharan, MD
Robert Somer, MD
Christian Squillante, MD
Preeti Sudheendra, MD
Advanced Practice Nurses (APNs)
Jennifer Bonafiglia, APN-C
Phyllis Duda, APN-C
Kristi Kennedy, APN-C
Helen Nichter, APN-C
Evelyn Robles-Rodriguez, APN-C
Genetic Counselors Brooke Levin, MS, LCGC Vanessa Manso, MS, LCGC Kristin Mattie, MS, LCGC Matthew Share, MS, LCGC Jennie Stone, MS, LCGC Program Staff Manager Evelyn Robles-Rodriguez, RN, MSN, APN, AOCN Administrative Coordinator Brandi Ford, CCMA, AAS (Camden) Medical Assistant Myra Salcedo, RMA (Camden)

36. Cancer Genetics Program Genetic Counselors
L to R: Kristin Mattie, Vanessa Manso, Matthew Share, Jennie Stone, Brooke Levin