1. Genetics: For this Generation and the Next
Andrea Forman, MS, LCGC
Fox Chase Cancer Center
Risk Assessment Program
Department of Clinical Genetics

2. Common Diseases Cancer Heart disease Diabetes Hypertension Stroke
Alzheimer's
Arthritis
Osteoporosis
Here are several common disease here in the US.
For almost every disease, if you ask a doctor what the main risk factors are, you tend to get very similar answers

3. Common Risk Factors Age Family history Ethnicity Lifestyle Diet
Alcohol
Smoking
THESE (CLICK) we have some control over. These same factors appear in study after study and lecture after lecture by your doctor. Believe it or not, an overall healthy lifestyle will lead to a healthier life although it still doesn’t guarantee that disease will never happen. Regular exercise, diets based on fruits and vegetables and lean proteins, limited alcohol use and no smoking. We all know this and we do our best to various degrees of success. CLICK
But why are these things so important? Because over time these things start to damage those happy, healthy cells we were born with. And when a cell becomes too damaged, it usually dies. A few dead cells out of billions is not so bad, but this accumulates over time and can begin to manifest as heart, bone, or lung disease or other issues.
But what about THESE risk factors? (CLICK) We don’t have much control over growing older or what our family history looks like. How do these influence disease?

4. Top 5 Reasons to Know Your Family History
5. Family recipes should be kept secret — family medical history should not.
4. Knowing your risk might save your life.
3. It’s free and you don’t have to leave home.
2. It’s a priceless gift to leave to your children.
1. Because every family has a story, but not every family has YOUR story.
This is my extended family starting with my 90 year old great grandmother there in the middle.
5. Family recipes should be kept secret — family medical history should not.
4. Knowing your risk might save your life.
3. It’s free and you don’t have to leave home.
2. It’s a priceless gift to leave to your children.
1. Because every family has a story, but not every family has YOUR story.

5. Genetic information is key
Genetics can help us identify the people who have risks for disease that go far above the general risks we all have based on our lifestyle and health choices we make.
Who are the people who will get heart disease no matter how many veggies they eat and marathons they run?
Who are the people who have such a risk for cancer that they should take extra steps to detect or prevent this disease?
This is where genetics and genetic testing plays a role in healthcare. 5

6. We have been learning about genetic influence on life and disease for a long time and it has fascinated both scientists and the general public

7. What is a Gene?
You might have suspected there would be a biology lesson in today’s lecture. Now, some of you in the audience today have some scientific or medical background, so this may be very familiar to you. But for some of us, we haven’t had any biology or genetics education since school, if ever. So bear with me for a little overview here.
Our body is made up of billions of cells. Skin cells, heart cells, eye cells. Within the center of every cell are structures called chromosomes. CLICK
Chromosomes are made up of very, very long strands of DNA. CLICK Think of DNA like a book of recipes.
Sections of this DNA make up individual genes. CLICK We have about 20 thousand genes, or recipes, within every cell of our body. CLICK
The cell is able to read the recipes of our genes and build proteins that we need to function.
Genes determine our eye color and hair color, but they also control how cells live and die. The proteins that genes make, work with each other and they also interact with environmental influences.

8. DAD
MOM
You end up with 23 pairs of chromosomes holding all of our genetic material.
CLICK You get one of each pair from mom and one of each pair from dad.
This one cell starts to divide and divide and divide until you end up with…

9. The sweetest little snoogaboo you’ve ever laid eyes upon.
How many of you have grandchildren cuter than this baby?
I had a feeling a lot of you might. 
Now, from the day we are born, our genes are as good as they get. However, no one is genetically perfect

10. We start off at our genetic best from day one, and then the aging begins. Time passes. And over time, we start to accumulate damage. This damage can lead to disease.

11. Personal Cancer Risk Family History Lifestyle Environ-ment Aging
Genetics
Aging
Chance
When we look at cancer specifically, we see many of those same risk factors we talked about before. Age, lifestyle, and to some extent, genetics

12. Percentage of cancers that are due to inherited genetic risk
Cancer and Genetics
Percentage of cancers that are due to inherited genetic risk
i.e. 1 out of 10

13. Family history was the first genetic test
Fortune Cookie Tip #1
Family history was the first genetic test

14. Clues: Genetic Risk for Cancer
YOUNG
Breast <45, Colon <50
RARE
Examples include Ovarian, Male Breast, Pancreatic
MULTIPLE
Two or more different cancers in the same person
FAMILY
Two or more family members with the same or related types of cancer.
Breast/Ovary. Breast/Thyroid/Uterine. Breast/Sarcoma/Brain

15. Sporadic Family History
Young? No
Rare? No
Multiple occurrences? No
Colon, 72
Risk for cancer is AVERAGE

16. Familial Family History
Lung, 65
coal miner
Stomach, 55
H. pylori
Lung, 58
smoker
Prostate, 75
Basal Cell
sun exposure
Young? No
Rare? No
Multiple? Yes
Environmental influences? Yes
Liver, 50
alcohol abuse
Risk for cancer is MODERATE
Cervix
HPV, smoker

17. Hereditary Family History
Breast, 55
Prostate, 59
Breast, 50
Young? Yes
Rare? Yes, ovarian
Multiple? No
Family? Yes
Who passed this theoretical mutation on to our young patient? DAD!
Breast, 34
Ovarian, 44
Risk for cancer is HIGH

18. Don’t forget to look at both sides of the family!
Fortune Cookie Tip #2
Don’t forget to look at both sides of the family!

19. Why would I want to know? Possible risk of another, new cancer
Risks to your children
Risks to other family members
Screening and prevention are often available and may save a life

20. We're trying to predict the future so we can maybe change the future

21. * This family of 5 sisters came to see me after one sister was diagnosed with breast cancer at the age of 34. She has always felt that she was destined to get cancer after her mother had breast cancer three times. Her personal and family history of cancer had several features suggestive of an inherited cancer syndrome. Breast cancers diagnosed in multiple family members over multiple generations. Several cases of BC dx under 50. And people who had BC more than once.
* This family meets those genetic criteria. Who should we test first?

22. Family history of breast cancer? Who is the best person to test?
Red apple tree growing red apples
New yellow apple
Red apple tree growing one yellow apple
Courtesy of Kallie Weinan, MS, CGC

23. Fortune Cookie Tip #3
When searching for something rare, start the search with the most likely target.

24. Does not want testing BRCA1 - BRCA1 - BRCA1 + BRCA1 +
- She underwent genetic testing and tested positive for a BRCA1 mutation CLICK
You’ll notice that she is one of 5 girls. We know that CA had to inherit this mutation from one of her parents, and given the cancer history in mom we assume it was through her. Her mother was diagnosed with pancreatic cancer and has since passed away without being tested. But this means that CA’s four sisters have a 50% risk of having the same mutation. WE discussed how important it was to get them tested because if they have that mutation, they need to start a high risk screening regimen to help detect cancer if it happens or even prevent it from happening with surgical interventions.
Would you want to know?
3 sisters were tested. Two sisters tested negative If we had started testing with them, would we have found this mutation? Would we have kept testing everyone? One sister tested positive and is doing high risk screening. The fourth sister is not ready yet.
Does not want testing
BRCA1 -
BRCA1 -
BRCA1 +
BRCA1 +

25. Cancer Risks with HBOC

26. What Can You Do? Increased screening Prevention Start Earlier
25yo for breast screening
More Often
Alternating imaging every 6 months
More Aggressive
Mammogram +
Breast MRI
Medication
Tamoxifen (breast cancer risk)
Birth control pills (ovarian cancer risk)
Surgery
Risk reducing mastectomy
Salpingo-oophorectomy (removal of ovaries and fallopian tubes)

27. Guess what?

28. You won’t be seeing many tests for just BRCA1/2 anymore

30. Busy slide, but essential the way we do DNA testing has changed
Busy slide, but essential the way we do DNA testing has changed. It is now cheaper and faster

31. Multi-Gene (NGS) Panels
Genetic tests to look at dozens of genes related to cancer
Similar cost and turn around time as gene specific testing
Higher risk of uncertain results

32. NGS Panels- Breast Walsh et. al. 2013 (ASHG Platform Presentation)
800 families with negative BRCA1/2 testing
206 tested positive with NGS BROCA panel (26%)
Of the 26% with a new positive results
39% (80/206) had BRCA1/2 mutations
37% carried mutations in CHEK2, PALB2, or TP53
20% carried mutations in 10 less characterized genes
ASHG Platform presentation 10/2013
More than 25% of breast cancer families with wild-type results from commercial genetic testing of BRCA1 and BRCA2 are resolved by
BROCA sequencing of all known breast cancer genes. T. Walsh1, S. Casadei1, M. K. Lee1, A. M. Thornton1, G. Bernier1, C. Spurrell1, J. Mandell1, T. Lajus2, E. Swisher1, M.-C. King1 
  A challenge to the present practice of genetic testing for inherited risk of breast cancer is how to explain the illness in breast cancer patients with severe family history, but negative (wild-type) results from commercial testing for BRCA1 and BRCA2. To address this problem, we applied BROCA, a targeted capture sequencing approach, to identify all single base pair substitutions, insertion-deletions, and copy number variants in all known breast cancer genes. Our subjects were all living affected persons in 800 families with at least three cases of breast and/or ovarian cancer. Probands of all families had received wild-type results of commercial genetic testing of BRCA1 and BRCA2. Of the 800 families, 206 (26%) were resolved by BROCA. The 206 resolved families harbored 166 different damaging germline mutations in 21 different genes. Of the resolved families, 39% (80/206) carried mutations in BRCA1 or BRCA2 that were not detected by commercial sequencing of the proband, either because the patient did not have comprehensive commercial large rearrangement testing in addition to commercial Sanger sequencing; or the proband was wild-type for BRCA1 and BRCA2, but other cases in the family carried a BRCA1 or BRCA2 mutation; or the family carried a BRCA1 or BRCA2 mutation not reported by commercial testing (e.g. mutation of a splice enhancer, a small damaging in-frame indel, or a missense with good experimental evidence of damaging effect.) Of the resolved families, 37% (77/206) carried mutations in other breast cancer genes whose role in inherited predisposition is well characterized: 39 in CHEK2, 28 in PALB2, and 10 in TP53. Finally, of the resolved families, 20% (41/206) carried mutations in breast cancer genes that have been published but whose role in inherited predisposition has been less fully characterized: 15 in ATM, 4 in BARD1, 5 in BRIP1, 1 in CDH1, 2 in ABRAXAS, 2 in NBN, 3 in RAD51C, 5 in RAD51D, 1 in STK11, 1 in XRCC2. Our results indicate that families severely affected by breast cancer but with wild-type results from commercial genetic testing are well served by complete genomic sequencing of all known breast cancer genes. As such comprehensive testing becomes more widespread, it will be important to determine more precisely the risks associated with damaging mutations in each of these genes so as to incorporate them most effectively into clinical care.

33. Labs offering NGS panels
Labs offering BRCA1/2
Labs offering NGS panels
Different NGS tests that include BRCA1/2
Genetic counselors pulling their hair out
Costs vary between labs from over $4000 to as low as $250 out of pocket.

34. Ms. Smith 46 year old woman with a newly diagnosed left breast cancer
ER/PR+ invasive ductal carcinoma
Referred to Risk Assessment as patient wants risk estimate to help her make a decision about bilateral mastectomy
She began by saying “If my risk of a second BC is >50%, I will do RRBM.” While waiting for results, she expressed that she would do the surgery if her risk was >30%. Very numbers oriented.

35. NGS Test Result Positive for a gene mutation CHEK2
Variants of Uncertain Significance
BRCA 2
STK11

36. Sometimes, in our quest for answers, we end up with more questions
Fortune Cookie Tip #4
Sometimes, in our quest for answers, we end up with more questions

37. Moderate Risk Genes Cancer risks may not be very high
How high does risk need to be before we pursue surgery or medications?
Cancer risks may be unclear
How do we make medical decisions when we don’t know the risks?
We’re still learning
The recommendations you get today may be different in 5 years

38. NGS Test Result Positive for a gene mutation CHEK2
Variants of Uncertain Significance
BRCA 2
STK11

39. N=398

41. Rates of Uncertain Variants
Thanks to the collaborative effort of providers and Myriad Reclassification team, the variant rate continues to decrease, as shown here.
This data was published in March 2012 as part of a poster presented at the ACMG meeting.
Eggington et. al. Current Variant of Uncertain Significance Rates in BRCA1/2 and
Lynch Syndrome Testing (MLH1, MSH2, MSH6, PMS2, EPCAM),
Eggington et. al. Current Variant of Uncertain Significance Rates in BRCA1/2 and Lynch Syndrome Testing (MLH1, MSH2, MSH6, PMS2, EPCAM), March 2012, ACMG Poster Presentation. 41

42. Isn’t it just a blood test?
Positive results with limited information
Inconclusive results
Results that don’t “fit”
Worry/anxiety

43. Consider This… RISKS BENEFITS LIMITATIONS Anxiety/ distress Privacy
Appropriate follow-up?
Clarification of risk
Guidance for medical management
Information for family
Unclear results
Limited data
Limited usefulness
Changes in technology

45. What can you do?
Know your family history
Educate your family about its history
Talk to your doctor or a genetic counselor

46. What is a Genetic Counselor?

47. I take complicated genetic information, and translate it into understandable information for patients who may have little or no science background. I am a bridge between information overload and comprehension, in the process helping them make decisions for themselves and their families about genetic testing
Now, we are not MD’s. Specialize in genetics, psychosocial skills, ethics, and the ability to combine this all to help people understand the varied implications of genetic contributions.
I am a translator

48. NSGC:

50. Department of Clinical Genetics, Fox Chase Cancer Center
Questions?
Andrea Forman, MS, LCGC
Genetic Counselor
Department of Clinical Genetics, Fox Chase Cancer Center