Genetic counselor, Heather Herrmann, will dive in to the topic of Lynch Syndrome & CRC. Heather has enjoyed working in both pediatric genetics and cancer genetics throughout her career. She has focused the last eight years in the area of hereditary cancer syndromes and hereditary cancer risk assessment.

1. Our webinar will begin shortly.
WELCOME!

2. • Speaker(s):Heather Herrmann, MS, LCGC
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3. Disclaimer
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Cancer are for general informational purposes only. The
information and services are not intended to be substitutes
for professional medical advice, diagnoses or treatment.
If you are ill, or suspect that you are ill, see a doctor
immediately. In an emergency, call 911 or go to the nearest
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4. Brought to you by the
One Million Strong Collection:
One Million Strong Showcase panelist and genetic counselor, Heather
Herrmann, will dive in to the topic of Lynch Syndrome to set the stage for our
conversation in Nashville about Colorectal Cancer under 50.
Join us in Nashville, TN on April 1st

5. Speaker:
Heather Herrmann, MS, LCGC is a licensed genetic
counselor in Nashville, Tennessee. Heather obtained
a Bachelor of Science degree from Vanderbilt
University in 1995 with a major in Biology and a minor
in Chemistry. She obtained a Master of Science
degree in Genetic Counseling from the University of
Pittsburgh in 2000. Heather has enjoyed working in
both pediatric genetics and cancer genetics throughout
her career. She has focused the last eight years in the
area of hereditary cancer syndromes and hereditary
cancer risk assessment. She currently works at Saint
Thomas Health Cancer Care – Genetics where she
provides genetic counseling and risk assessment for
individuals with a personal and/or family history of
cancer.

6. Lynch Syndrome and Colorectal
Cancer Genetics
March 23, 2016
Heather Herrmann, MS, LCGC
Saint Thomas Health
Cancer Care-Genetics

7. Disclosures
• No disclosures to share.

8. Objectives:
• To Define Cancer Risk Assessment
• To Describe Management Modifications
• To Outline the Process of Genetic Testing for
Hereditary Colorectal Cancer conditions

9. The Facts
• ~137,000 men and women per year diagnosed with
colorectal cancer
• 5-year survival rate for early stage colorectal cancer
is >90%
• 4 out of 10 cancers are
found at an early stage
• Polyps are the precursor
to colorectal cancer
• Only ½ of the people
that are due for colon
screening pursue screening!
Cancer.org
Even Polyps Have Dreams
Dailymedicalexaminer.com

10. Who is at risk?
Colon Cancer
Average / Sporadic Risk
Increased / Familial Risk
High / Hereditary Risk

11. High
Risk
Increased
Risk
Average Risk
• High Risk
o Diagnosed or undiagnosed gene
mutation
o Untested, but have a 1stdegree relative
with diagnosed gene mutation
• Increased Risk
o 1st Degree relative with colon cancer
or otherwise strong family history
o Personal History of colon cancer, colon
polyps or other significant risk factors
• Average Risk
o No 1st degree relative with colon cancer
and no otherwise strong family history
o No personal history colon polyps, cancer
or other significant risk factors

12. Hereditary v familial v sporadic risk
0%
20%
40%
60%
80%
100%
120%
SPORADIC FAMILIAL HEREDITARY
RISK
SPORADIC
FAMILIAL
HEREDITARY

13. What are the risks for hereditary
colorectal cancer?
0
20
40
60
80
100
120

14. 0
10
20
30
40
50
60
70
80
90
APC MLH1,
MSH2,
EPCAM
MSH6 PMS2 BMPR1,
SMAD4
STK11 MUTYH
biallelic
PTEN TP53,
CDH1,
OTHERS
Endometrial
Ovarian
Gastric
Breast
Pancreatic, Melanoma, Prostate and Other cancers
What are the other cancer risks
due to these genes?

15. Does Risk Assessment Make a
Difference?
5 year survival rates for early stage colorectal cancer > 90%
Over 60% of deaths from colon cancer could be avoided by
screening
Studies show that individuals who know their risk are more likely
to seek surveillance. 73% of patients known to have Lynch
syndrome had a colonoscopy within 12 months after testing.
-Halbert et al. 2004

16. Colorectal Cancer Risk Assessment
Allows for personalized management
Should be directed through consultation with a health
care provider
Guidelines for management may include:
– Increased screening
– Medications
– Surgeries to remove the organ before cancer
develops

17. Colorectal Cancer Risk Assessment
Red Flags
• Personal history
– Cancer history
• Tumor test results
– Polyp history
– Inflammatory Bowel disease
– Other risk factors
• Family history
– Cancer history
– Ancestry
– Other medical or social history
• Genetic test results
– Somatic
– Germline

18. Red Flags for Personal History
• Colorectal cancer BEFORE AGE 50
• ≥ 2 Lynch syndrome cancers including colorectal diagnosed at
any age
• Abnormal tumor testing by MSI or IHC
• Specific colorectal tumor features < age 60
• Endometrial cancer before age 50 (Red Flag for Lynch syndrome)
• MMRPro, PREMM 1,2,6, or MMRpredict score of ≥ 5% risk of
Lynch syndrome
• ≥ 10 colon polyps
• Inflammatory Bowel Disorders
• Features beyond the colon including: Desmoid tumors, papillary
thyroid cancer, hepatoblastoma and others

19. Tumor testing
• Microsatellite Instability (MSI)
• Immunohistochemistry (IHC)
• BRAF testing ***
• Screening tests for abnormal gene
function
• Automatically ordered on all
colon cancers at SOME hospitals
• If abnormal, further testing is
indicated to identify hereditary
cancer.
• STILL NEED GENETIC TESTING
if tumor testing is positive OR
if negative but meet other Red
Flags for testing.
Openi.nlm.nih.gov

20. Red flags for Family history alone
(No personal history of cancer)
• Family history of a known genetic mutation
• First or second degree relative meeting any of
the previous personal Red Flags
• ≥ 2 first- or second-degree relatives with Lynch
syndrome cancers at any age
• 3 first-, second- or third-degree relatives
diagnosed with colorectal or other Lynch
syndrome associated cancers at any age

21. Degree of relation
• First Degree
– Mother
– Father
– Siblings
– Children
• Third Degree
– Great-grandparents
– Great-aunts and
Great-uncles
– Cousins
• Second Degree
– Grandparents
– Aunt and Uncles
– Grandchildren
– Nieces & Nephews
– Great-grandchildren
– Great-nieces & great-
nephews

22. Genetic Tests
• Germline tests -Most often inherited
from a parent
– Single Site test
– Single or multi-gene tests
– Panel test results
• Somatic tests– Acquired
gene mutation found via
tumor tests, may be used in
cancer treatment decisions

23. Germline testing
Single Site
Single Gene

24. Germline Genetic Tests
– Single Site test
• Evaluates the specific site on the specific gene
• When a gene mutation is known in the family; the known
mutation / result must be available for single site testing
– Single or multi-gene tests
• Many locations along one or many genes are evaluated to
see if there is an alteration or mutation
• When clinical features indicate that a certain gene(s) may
hold a mutation
– Panel test results
• Many genes evaluated in one single test
• When multiple genes may be considered for testing

25. Mutations in Specific Genes are
Responsible for Hereditary Risk of Cancer
MUTYH
MSH2
MSH6
PMS2
MLH1
APC
EPCAM
TP53
PTEN
CDH1
STK11
BMPR1A
SMAD4

26. Genes Colon Breast Ovarian Uterine Pancreatic Prostate Melanoma Other
Cancer
Lynch- MLH1,
MSH2, MSH6,
PMS2, EPCAM
Colon Ovarian Uterine Pancreatic OC
APC Colon Pancreatic OC
MUTYH Biallelic Colon OC
MUTYH
Monoallelic
Colon
TP53 Colon Breast Ovarian Uterine Pancreatic Prostate Melanoma OC
PTEN Colon Uterine Melanoma
STK11 Colon Uterine Pancreatic OC
CDH1 Colon Ovarian
BMPR1A Colon Breast Ovarian Pancreatic OC
SMAD4 Colon Breast Ovarian Pancreatic OC
AXN2 Colon
POLD1 Colon
POLE Colon
SCG5/GREM1 Colon

27. Genetic Test Results
• Positive / Clinically Significant
– Increased cancer risks
• Negative / No known mutation
– May have ruled out hereditary cancer risk
– Management based on personal and family
history
• Variant of Unknown Significance / Variant of
Uncertain Significance

28. Variant of Uncertain Significance
Variant of Unknown Significance
VUS
A Variant is any sequence variation that is different from the normal.
A VUS is a Variant that May or MAY NOT be causing cancer in the
person or family
Additional information will be needed to determine whether or not
the change is clinically significant
Information assessed by some laboratories constantly
VUS determinations may take days, months, years
No clinical action should be taken on the basis of a VUS
PERSONAL AND FAMILY HISTORY SHOULD DRIVE MEDICAL
MANAGEMENT

29. FAMILY TESTING

30. Who orders genetic testing?
• Knowledgeable provider
• MD, GC, NP, PA, or other
• Genetic counselor or APNG
– Genetic counselors are certified, licensed in some
states
• Telephone genetic counseling services
• NSGC.org – FIND A GENETIC
• COUNSELOR

31. Process for genetic testing
• Gather your history = can be done today!
– Family history gathering – Surgeon General’s
“My Family Health Portrait”
https://familyhistory.hhs.gov/FHH/html/index.html#
– Maternal and paternal history are important
– Types of cancer, age of diagnosis, current age or age of death
• Share your history / talk to your doctor
• Find a provider for risk assessment / genetic counseling
– May need a referral
• Provide a blood or saliva sample to be sent to the
laboratory for testing
• Review results with your provider

32. Genetic Counseling
Consultation may include:
• Review of personal medical history
• Review of family history
• Risk assessment
• Discussion of genetics
• Informed consent discussion for genetic testing
• Coordination of genetic testing
• Result interpretation
• Resource identification
• Family testing coordination

33. Genetic Testing
Many labs, many tests
How do providers decide what to order?
– Clinical assessment of history and likelihood of inherited genes
– ACMG Guidelines (what is the placement of these)
What to look for in a lab or lab result?
– Reputable quality
– Analytical Standards
• Test Validation
• Variant Classification
– Reporting Standards
– Genetic counselor on staff
“ASCO believes that the tests used to detect those abnormalities must be of
the highest quality and thoroughly validated before being offered to doctors
and patients,” ASCO President Peter Paul Yu, MD, FACP, FASCO, wrote. “Our
patients depend on high quality tests as much as they depend on carefully
studied, safe and effective drugs to achieve the best possible outcomes.”

34. How to utilize your lab result for
improved health
• If Positive:
– Gene related cancer risks may exist
– Management is based on guidelines for high cancer risk
– Family members test for risk assessment:
If positive = gene associated cancer risks
If negative = cancer risks may be back to average; assess for
remaining history not attributed to mutation
• If negative:
– Management is based on personal and family history
• If VUS:
– Management is based on personal and family history

35. REPRODUCTIVEOPTIONS & CONSIDERATIONS
• Prenatal diagnosis
– Testing for Adult onset conditions at age of adult onset
• Assisted Reproduction
• Preimplantation diagnosis = PGD
• CCMRD = Constitutional Mismatch Repair Deficiency
A condition that is possible if two parents carry a
mutation in the same mismatch repair gene

36. High Risk / Hereditary Risk medical management:
NCCN guidelines and personalized management
Patients with Lynch syndrome (MLH1, MSH2, MSH6, EPCAM, PMS2 mutations)
Colonoscopy is indicated every 1-2 years…..
NOT every 5 or 10 years.
Colonoscopy begins at age 20-25 with MLH1, MSH2, EPCAM, or 25-30 with MSH6 or
PMS2 or 2-5 years younger than the earliest person in the family with colon
cancer…
NOT to begin at average screening age.
Aspirin may decrease risk but not currently a recommendation for standard use
Additional cancer risks should be managed:
Endometrial: hysterectomy considered after childbearing complete
evaluation of abnormal uterine bleeding
screening by endometrial biopsy and transvaginal ultrasound possible
Ovarian: bilateral removal of the ovaries after childbearing complete
screening by transvaginal ultrasound and / or CA-125 possible
Gastric and small bowel: endoscopic ultrasound considered every 3-5 years from age 30-35
Renal / transitional cell cancers: Urinalysis from 25-30 years old
Brain: Annual physical / neurologic exam from 25-30 y
Breast cancer: Average-risk breast cancer screening

37. High Risk / Hereditary Risk medical management:
NCCN guidelines and personalized management
Patients with FAP (APC mutations)
Proctocolectomy or colectomy with surveillance based on treatment:
If colectomy with IRA, rectal endoscopy every 6-12 months, depending on polyps
If TPC with ileal pouch-anal anastomosis or ileostomy, endoscopic evaluation
every 1-3 years based on polyps and up to every 6 months based on findings
Additional cancer risks should be managed:
Upper endoscopy from age 20-25 or earlier if colectomy before age 20
Annual thyroid exam from late teenage years, consider annual thyroid ultrasound
Annual physical / neurologic exam and annual abdominal palpation.
If family history of desmoids, consider abdominal MRI or CT 1-3 years after
colectomy and then every 5-10 years with abdominal symptoms prompting
immediate abdominal imaging.
Consider small bowel CT or MRI for desmoids
Consider helpatoblastoma screening via clinical trial or based on other high risk
recommendations.
* If AFAP (APC mutations) and small burden of polyps, colonoscopy and
polypectomy every 1-2 years with surgical intervention as polyp burden warrants

38. High Risk / Hereditary Risk medical management:
NCCN guidelines and personalized management
Patients with MAP (two MUTYH mutations - biallelic)
Colonoscopy from age 25-30 and every 2-3 years if
negative.
If small burden of polyps, colonoscopy and polypectomy
every 1-2 years with surgical intervention as polyp burden
warrants
Additional cancer risks:
Consider upper endoscopy and side viewing
duodenoscopy from 30-35.

39. High Risk / Hereditary Risk medical management:
NCCN guidelines and personalized management
Patients with Peutz-Jeghers syndrome (STK11 mutations)
Colonoscopy every 2-3 years from late teens
Additional cancer risk management:
Breast mammogram and breast MRI annually from age 25
Upper endoscopy every 2-3 years from late teens
Small bowel CT or MRI enterography at age 8-10 with follow-up
based on findings until age 18 and then every 2-3 years or
individualized
MRCP or endoscopic ultrasound of the pancreas every 1-2 years
from age 30-35
Pelvic exam and Pap smear and consider transvaginal ultrasound
annually from age 18-20
Annual testicular exam and observation from age 10
Education about lung cancer symptoms and smoking cessation if
applicable

40. High Risk / Hereditary Risk medical management:
NCCN guidelines and personalized management
For patients with Juvenile Polyposis syndrome
(SMAD4 and BMPR1A mutations)
Colonoscopy annually found from age 15and every
2-3 years if polyps are not
Additional cancer risks should be managed:
Upper endoscopy annually from age 15 and every
2-3 years if polyps are found
If SMAD4 mutation exists, screen for HHT within
the first 6 months of life

41. Increased Risk / Familial Risk medical
management: NCCN guidelines and
personalized management
At age 40 OR 10 years before the earliest diagnosis of Colorectal
cancer if:
1 first-degree relative with CRC before age 60 OR
2 first-degree relatives with CRC at any age
At age 50 if:
First-degree relative with CRC at age 60 y or older OR
1 second-degree relative with CRC before age 50
At age 50 or at age of onset of adenoma in relative, whichever is
first if:
First-degree relative with confirmed advanced
adenoma(s)
nccn.org

42. Risk-reducing opportunities
– Don’t smoke
– If you do smoke, stop
– Increase your physical activity
– Maintain a healthy body weight
– Avoid overall body fat, especially fat around your
waist
– Reduce how much red meat and processed meats
you eat
– Use alcohol in moderation
FightColorectalCancer.org

43. In Summary:
• Learn YOUR risk for colon cancer and other
potential cancers
• Manage that risk effectively!

44. Thank you!

45. Question & Answer: