Nov 2017 #CRCWebinar :: Genetic Testing & You
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Transcript of Nov 2017 #CRCWebinar :: Genetic Testing & You
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Genetic Testing & YOU!
Our webinar will begin shortly.
WELCOME!
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• Speaker: Heather Hampel
• Archived Webinars: FightColorectalCancer.org/Webinars
• AFTER THE WEBINAR: Expect an email with links to the material & a survey. If you fill it out, we’ll send you an “I booty” bracelet.
• Ask a question in the panel on the RIGHT SIDE of your screen
• Follow along via Twitter – use the hashtag #CRCWebinar
Today’s Webinar:
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Resources:
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Disclaimer:
The information and services provided by Fight Colorectal 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 emergency room.
Fight Colorectal Cancer never recommends or endorses any specific physicians, products or treatments for any condition.
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Speaker:Heather Hampel has been a cancer genetic counselor since 1995 and is a faculty member in the Division of Human Genetics. Her clinical duties include providing comprehensive cancer genetic consultations to individuals and families with a history of cancer. Cancer Genetic consultation requires tremendous documentation of cancers in the family, risk assessment, screening recommendations, and incorporation of genetic testing as necessary. Her research interests include screening all colorectal and endometrial cancer patients for Lynch syndrome, the American Founder Mutation (exon 1-6 deletion in MSH2) as a cause of Lynch syndrome, and the etiology of MSI-negative familial colorectal cancers.
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Genetic Testing and You!
Heather Hampel, MS, LGCGenetic CounselorAssociate Director, Division of Human GeneticsProfessor, Department of Internal Medicine
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The Right Person How to know if you need to pursue genetic counseling and
genetic testing
The Right Test A review of the most common causes of inherited colorectal
cancer Multigene panel testing pros and cons
The Right Time The importance of pre-test genetic counseling
Agenda
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Causes of Colorectal Cancer - Sporadic
FamilialSporadicRisk Factors for Sporadic Colon
Cancer• Increasing age• Smoking• Excessive alcohol• Obesity• Fatty diet• Precancerous colon polyps (adenomas)• Others??
30%
60%
General population lifetime risk for colon cancer = 5.5%
10%
Hereditary
Cancer is common Most cancer is NOT inherited!
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Causes of Colorectal Cancer - FamilialFamilial
Sporadic
Familial Colon Cancer• Environmental/lifestyle
risk factors• Minor genetic changes• Some Family history
30%
60%
Risk for colon cancer if close relative had CRC <50 y of age = 18.2%
Risk for colon cancer if close relative had CRC 50-59 y of age = 13.9%
Risk for colon cancer if close relative had CRC >60 y of age = 10.9%*Close relative = parent, brother, sister, or child
10%
Hereditary
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Causes of Colorectal Cancer - Hereditary
Sporadic
Hereditary Colon Cancer• Single gene mutation
passed down through the family
• Significantly increased cancer risks
• Lynch syndrome is the most common cause of hereditary colon cancer
• Adenomatous Polyposis syndromes are second most common cause
• Hamartomatous Polyposis syndromes are rare
30%
60%
10%
Hereditary
Familial
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Family History is the Key!
• Accurate risk assessment
• Identification of higher risk families
• Appropriate medical follow-up
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On November 8, 2004, Surgeon General Richard H. Carmona launched a national initiative to encourage all American families to learn more about their family health history
My Family Health Portrait: https://familyhistory.hhs.gov/
Thanksgiving is National Family History Day Family gatherings offer an excellent opportunity to talk with your
relatives about their medical histories, record it, and then use the information to improve your health
Family Reunions, Holidays, and others
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U.S. Surgeon General’s Family History Initiative
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Family HealthLinkhttps://familyhealthlink.osumc.edu
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Over 1.2 million individuals in the U.S. have Lynch SyndromeInherited condition that causes high risks for colorectal cancer, endometrial cancerand other cancersPreventable cancers with early and more frequent screening95% of affected individualsdo not know they haveLynch Syndrome
Lynch Syndrome
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Cancer Risks Associated with Lynch Syndrome
Cancer General Population Risk
Cancer Risk Mean Age at Diagnosis
Colorectal 5.5% 15-82% 44-61 years
Endometrial 2.7% 10-60% 48-62 years
Gastric <1% 1-13% 56 years
Ovarian 1.6% 2-12% 42.5 years
Small intestine <1% 3-6% 49 years
Hepatobiliary <1% 1-4% 3 years
Urinary tract <1% 1-4% ≈ 55 years
Brain/CNS <1% 1-3% ≈ 50 years
Sebaceous <1% 1-9% ?
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Lynch Syndrome Genes are Repair Genes
MLH1
PMS2
MSH2 MSH6
EPCAM
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Sporadic Inherited
• Later age at onset (60s or 70s)• Little or no family history of cancer• Single or unilateral tumors
• Early age at onset (<50)• Multiple generations with
cancer• Clustering of certain cancers (e.g. colon and uterine cancers)• Individuals with more than one cancer
Normal gene
Somatic mutation
Somatic mutation
Germline mutation
Somatic mutation
Colon cancer, 75
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Autosomal Dominant Inheritance
The presence of one gene mutation causes an increased risk for cancer
An individual with a mutation has a 50% chance to pass it on to each of their children
Men and women equally likely to have the gene mutation and to pass it on
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Tumor screening Tumors caused by Lynch syndrome usually have specific features Can tell us if someone is more or less likely to have Lynch syndrome Automatically performed on all colon and endometrial tumors at OSUMC
Genetic testing Blood or saliva test Diagnostic
How do we test for Lynch Syndrome?
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Tumor Screening for Lynch Syndrome
Microsatellite Instability (MSI) testing Microsatellites are stretches of DNA with a repetitive sequence
of nucleotides (e.g., AAAAA or CGCGCGCG) that are particularly susceptible to acquiring errors when mismatch repair gene function is impaired
Cancers arising in cells with defective mismatch repair gene function exhibit an inconsistent number of microsatellite nucleotide repeats when compared to normal tissue, a finding referred to as "microsatellite instability.“
77-89% of Lynch related tumors and 10-15% of sporadic tumors show microsatellite instability
Immune therapy recently shown very effective in treating patients whose tumors have microsatellite instability
Le DT et al. N Engl J Med. 2015;372(26):2509-20.
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Immunohistochemistry (IHC) testing Looks for the presence of the
proteins made by each gene in the tumor tissue
If a protein is absent in the tumor tissue it may be due to an inherited mutation in the gene that caused that protein not to be made correctly
83% of Lynch related tumors and 20% of sporadic tumors have at least one of these proteins absent
Tumor Screening for Lynch Syndrome
MLH1 MSH2
MSH6 PMS2
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If MSI or IHC test is positive: There is a 20-25% chance an individual has Lynch
syndrome There is a 75-80% chance an individual does NOT have
Lynch syndrome Follow-up tests can help sort this out
BRAF mutations are almost never found in the tumors of someone with Lynch syndrome.
MLH1 promoter methylation is a common acquired way of shutting down the MLH1 gene (more common in older patients and females)
Either or both of these tests are often performed and patients are only referred to Genetics if the test(s) are negative
Genetic testing can be offered to patients in follow-up to or instead of Tumor Screening (e.g. unaffected individuals or individuals whose tumors are not available)
Tumor Screening for Lynch Syndrome
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Familial Adenomatous Polyposis (FAP) APC gene mutations 30% of individuals with FAP have
de novo mutations and no family history
30 – 1000s of adenomatous polyps
100% risk for colorectal cancer if untreated
Also increases risk for duodenal cancer, thyroid cancer, medullary brain tumors, & hepatoblastoma in children
Many patients have desmoid tumors, osteomas, and CHRPES
Adenomatous Polyposis Syndromes
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MUTYH-Associated Polyposis (MAP) Two MUTYH gene mutations Recessive inheritance pattern so
there may not be any family history
0 – 1000s of adenomatous polyps Colorectal cancer risk high if
untreated A lot of overlap with FAP Patients can have desmoid
tumors, osteomas, and CHRPES
Adenomatous Polyposis Syndromes
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Polymerase Proofreading-Associated Polyposis POLE and POLD1 gene mutations Recently described in polyposis families with no APC or
MUTYH mutations so still learning 0 – 1000s of adenomatous polyps Increased risk for colorectal cancer Increased risks for endometrial and brain cancers possible
Polyposis and Oligodontia AXIN2 gene mutations Polyposis and missing teeth (never developed) Reported in one family in Finland
Adenomatous Polyposis Syndromes
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Hamartomatous Polyposis Syndromes
Peutz-Jeghers syndrome STK11 gene mutations Peutz-Jeghers syndrome Increased risks for colorectal, cervical, pancreatic,
Cowden syndrome PTEN gene mutations Mixed polyp types in the colon Increased risks for breast, thyroid, endometrial, and
colorectal cancers Juvenile polyposis
SMAD4 and BMPR1A gene mutations Increased risks for colorectal
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Indications for Referral - Colon
Colorectal cancer < age 50 Endometrial cancer < age 50 3 family members with a Lynch-associated cancer 2 or more Lynch-associated cancers in a single family
member Immunohistochemistry (IHC) for mismatch repair proteins
(MLH1, MSH2, MSH6, PMS2) demonstrating absence of one or more proteins in tumor
Microsatellite instability (MSI) in tumor Gene mutation already identified in family 10 or more colorectal polyps, especially of the same type
(all adenomas, Peutz-Jegher polyps, Juvenile polyps, or hamartomatous polyps)
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Test an Affected Family Member First Individuals in the family who have had cancer or many
polyps are the MOST LIKELY to have a gene mutation if there is one in the family
First test is most expensive because you have to look through ALL CANDIDATE GENES when trying to identify a mutation in a family After the family’s mutation is found, other relatives can be
tested just for that SINGLE GENE MUTATION which costs less ($50-200)
Improves result interpretation If an unaffected family member is tested first and does not
have a mutation, we do not know if they are a “true negative” and not at any increased risk OR if the family just does not have an identifiable mutation so they may still be at increased risk
Not always possible
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New technology called next-generation sequencing has allowed us to: Test multiple genes at the same time
Tests are available with 2 - >100 cancer genes included Sometimes families have mutations in unexpected genes
Lower the cost of genetic testing Most insurers cover testing for patients with a positive family
history Most labs have Patient Assistance Programs for patients
who are uninsured or underinsured (including Medicaid patients)
Medicare covers testing for patients who meet certain family history criteria
Patient pay prices as low as $249 - $475 Improve mutation detection
Can detect mutations and large deletions Patients tested many years ago may want to repeat testing
Genetic Testing Has Improved Dramatically
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Higher rate of Ambiguous Results called Variants of Uncertain Significance or VUS
Common: The VUS rate for gene panels are 20-40% Normal: We will likely find a one or more variations in one
or more of the genes on this test for which the clinical ramifications are unknown
Probably nothing: 90-95% of VUS results are eventually found to be benign
Will not change management: You will be followed based on your family history and NOT the VUS until/unless it is proven to be pathogenic
Keep contact information up-to-date: Most labs keep an eye on their VUS results and will issue a new report if it is reclassified. Your genetic counselor will recontact you to let you know this new information.
Drawbacks of Multi-Gene Panel Testing
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25-gene Myriad panel on 1260 individuals with suspected Lynch syndrome 9.0% Lynch 5.6% Other
Yurgelun M et al. Gastroenterology 2015;124:604-613.
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Multigene colon panel from Ambry
Cragun D et al. Clin Gen. 2014;86:510-520.
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Statewide initiative began 1/1/2013 Identify those with
hereditary risk Increase colonoscopy
compliance among relatives
Establish research infrastructure and biorepository for future research
50 collaborating hospitals Supported by
Pelotonia!
Ohio Colorectal Cancer Prevention Initiative (OCCPI)
Ohio
Columbus
Cleveland
Cincinnati
Toledo
Dayton
Akron
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Results
Defective Mismatch Repair385 (15.3%)
Proficient Mismatch Repair2125 (84.7%)
Defective Mismatch Repair With MLH1 Methylation
243* (63.1%)*2 with germline methylation
Defective Mismatch Repair Without MLH1 Methylation
142 (36.8% of dMMR)
Eligible for Genetic Testing924
Unexplained46
Universal Screening forLynch Syndrome1Statewide 2012-2017
DONE
Lynch Syndrome = 90Other = 10
96 patients* (3.8%)
Double somatic MMRMutations=43
MSI and/or IHC testing
MLH1 promoter methylation
Coloseq
Coloseq Tumor
MyRisk
+ -
- +
- +
Eligible for Genetic Testing142
+ -
Genetic CounselingCascade Test Family
some patients have > 1 gene mutation
+
+
CRC Patients with Testing Complete2510
-
-
* some patients fit into >1 category
Clinical Criteria1. Dx <502. First Degree Relative with
CRC or EC3. >1 CRC or EC
Lynch Syndrome = 4Other = 64
65 patients* (2.6%)
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MLH1 (13)
MSH2 (17)
MSH6 (2)PMS2 (6)APC (6)
SMAD4 (1)
Biallelic MUTYH
(4)
BRCA1 (2)
APC I1307K
(4)
ATM (4)
BRCA1 (2)
BRCA2 (4)
CDKN2A(1) CHEK2 (1) PALB2 (1)
Cancer Gene Panel Testing in Young CRC patients
1 out of 6 (16%) have at least one hereditary cancer syndrome
1 out of 12 (8.4%) have Lynch syndrome
1 out of 135 (7.6%) have another hereditary cancer syndrome
Pearlman R, et al. JAMA Oncology; 2016 In press.
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What happens in a Genetic Counseling Appointment
• Medical history• Family history - One of our most useful tools!• Targeted physical examination• Risk Assessment• Education• Genetic Testing• Screening/management recommendations in collaboration
with referring physician • Option to participate in genetics-related research studies
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Pre-test Genetic Counseling for Panels: Informed Consent
1. Information on specific genes being tested, including impact on medical care
10. Confidentiality issues
2. Implications of positive & negative results 11. Possible use of samples in future research
3. Possibility that test will not be informative 12. Options and limitation of medical surveillance & prevention strategies after testing
4. Options for risk estimation without testing 13. Importance of sharing test results with at-risk relatives
5. Risk of passing a genetic variant to children 14. Plans for follow-up after testing
6. Technical accuracy of the test *15. Some of the genes included on panels have not been well studied or only contribute modestly to cancer risk
7. Fees involved in testing & counseling *16. Higher likelihood of finding a VUS.
8. Psychological implications of test results *17. Some results will not affect medical management
9. Risks & protections against genetic discrimination
* Issues special for NGS cancer panel testing
ASCO. J Clin Oncol. 2003;21:2397-406.Heather Hampel
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Reproductive Options• Options are available for individuals who do not want to pass
the disorder on to their children• Recurrence Risk for Recessive Disorders such as MUTYH-
Associated Polyposis, Biallelic Mismatch Repair Deficiency • The odds of marrying another carrier and having an affected
child are generally low:• MUTYH carrier frequency 1:50-100• Lynch syndrome population frequency 1:280
Pre-test Genetic Counseling for Panels: Special Issues
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Genetic Discrimination
Genetic Information Non-discrimination Act (GINA) Federal Law signed on May 21, 2008 Prevents health insurers from denying coverage, adjusting
premiums, or otherwise discriminating on the basis of genetic information
Group and self-insured policies Family history is considered genetic information Insurers may not request that an individual undergo a genetic
test Employers cannot use genetic information to make hiring, firing,
compensation, or promotion decisions Sharply limits a health insurer's or employer's right to request,
require, or purchase someone's genetic information.
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Implications for the Entire Family
• Consider the impact of testing on all family members.
• Ultimately, testing is the individual’s choice.
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Take Home Messages:Turning Information into ACTION
1. Even though you cannot change your family history, knowing your family history can help you reduce your risk of developing diseases
2. People with a family history of certain diseases have the most to gain from screening tests and lifestyle changes
3. Together with your doctor, look for the red flags that might indicate the need for a prevention plan, preventive screenings, genetic counseling and potentially, genetic testing
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Refer to an cancer genetic counselor in your institution or city Find a Local Counselor from the NSGC
http://nsgc.org/p/cm/ld/fid=164 Find a Local Cancer Genetics expert from the NCI
http://www.cancer.gov/cancertopics/genetics/directory If there is not a counselor nearby, contact a large academic
center in your state. The counselors there may have an outreach clinic or perform telemedicine cancer genetics for patients at your location
Telephone Genetic Counseling services are available Informed DNA: www.informeddna.com/for-patients 800-975-4819
How to Find a Cancer Genetic Counselor Near You
Heather Hampel
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Question & Answer:
SNAP A #STRONGARMSELFIEBayer HealthCare will donate $1 for every photo posted (up to $25,000).Flex a “strong arm” & post it to Twitter or Instagram! (Use the hashtag!)
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THANK YOU!