1. Universal Screening for Lynch Syndrome
Cecelia Bellcross, PhD, MS, CGC
Emory University School of Medicine
Department of Human Genetics

2. Genetics of CRC
Sporadic (65%–85%)
Familial (10%–30%)
Rare CRC syndromes (<0.1%)
Lynch syndrome (aka Hereditary nonpolyposis colorectal cancer -HNPCC) (3%)
MYH associated polyposis (MAP) (1%)
Familial adenomatous polyposis (FAP) (1%)

3. Clinical Features of Lynch/HNPCC
Early but variable age at CRC diagnosis (~45 years)
Tumor site in proximal colon predominates
Metachronous/synchronous CRCs
Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile duct, pancreatic, sebaceous skin tumors; brain tumors

4. A Classic HNPCC/Lynch Family
CRC
dx 50s
CRC
dx 45
CRC
dx 61
CRC
dx 75
Ovarian Ca, dx 64
CRC
dx 48
CRC
dx 52
Endometrial Ca, dx 59 45
CRC
dx 42

5. Other Features of Lynch Syndrome
Autosomal dominant inheritance
Genes belong to DNA mismatch repair (MMR) family
Genetic heterogeneity (MLH1, MSH2, MSH6, PMS2)
CRC lifetime risk 30-80%
Endometrial cancer lifetime risk 30-60%

6. CRC RISK
*Barrow, Clin Genet 2008

7. Extra-colonic/Extra Endometrial
Lifetime Cumulative Incidence to age 70 yo:
Urologic tract (8.4% overall)
MLH1: female =1.1%, Male = 3.7%
MSH2: female =11.9%, Male = 27.8%
Ovary = 6.7%
Gastric = 5.8%
Small Bowel = 4.3%
Biliary/Pancreatic = 4.1%
Watson, Int. J. Cancer, 2008

8. Surveillance/ Prevention
Surveillance/Prevention Options for Lynch syndrome (Lindor JAMA, 2006;296:1507)
Cancer Site
Surveillance/ Prevention
Frequency
Begin Age:
Colon Rectum
Colonoscopy
Every 1-2 years
20-25 (30)
(Colectomy)
Uterus
Transvaginal Ultrasound / Endometrial Biopsy
Every year
30-35
Hysterectomy
30+
Ovary
Transvaginal Ultrasound / CA-125
Oral contraceptives
> 5 years
Oophorectomy
Stomach Small Bowel
Upper Endoscopy
Every 2 years
Pancreas Biliary
Liver function tests & Abdominal Ultrasound
Urinary Tract
Urinalysis cytology
Renal Ultrasound
Skin Lesions
Dermatology Exam
20-25

9. Impact of Screening Percent
Jarvinen, Gastroent, 2000
Jarvinen, JCO, 2009: 242 mutation +, 367 mutation - : >95% screening compliance, no difference in cancer or all cause mortality rates

10. Failure to meet these criteria does not
Amsterdam II Criteria
3 or more relatives with verified HNPCC associated tumor (CRC, endometrial, ovarian, gastric, small bowel, urinary tract) in family
One case a first-degree relative of the other two
Two or more generations involved
One or more cancer diagnosed by age 50
FAP excluded
Failure to meet these criteria does not
exclude HNPCC

11. Revised Bethesda Guidelines:
CRC < age 50
Patient with 2 HNPCC related tumors
Patient with CRC < age 60 with MSI-H histology
Patient with CRC with 1st degree relative with HNPCC related cancer; one of the cancers at < 50 years
Patient with CRC and 2 or more relatives with HNPCC-related cancer regardless of age
Umar, JNCI, 2004

12. Microsatellite Instability
Normal Cells
-CG-
-CGCGCGCG
-CG-
-CGCGCGCG
-CG
-CGCGCGCG-
-CG-
-CGCGCGCG
Normal Microsatellites
Tumor Cells
-CG-
-CG-
-CG-
-CGCG-
-CGCGCG-
-CGCGCGCGCG-
-CGCGCGCGCG-
-CGCGCG-
-CG-
-CGCG-
Microsatellite Instability

13. Immunohistochemistry
Abnormal or missing MSH2 protein
Abnormal Gene (MSH2)
Lack of MSH2 expression, negative IHC staining for MSH2 protein
MSH2+
MSH2-
Normal tissue
Tumor tissue

14. Testing for Lynch/HNPCC
Family/Medical history meets screening criteria
Amsterdam/Bethesda
MSI-High IHC – loss of protein expression
MSI/IHC
on tumor tissue
MSI normal IHC normal
No further testing
Risks & screening
based on history
Genetic Testing
on blood
No mutation Identified
1. Consider additional genetic testing
2. Risks & screening based on test results
and family/medical history
Mutation Identified
Lynch/HNPCC screening & management
Family members offered testing

15. Rationale for HNPCC/Lynch Syndrome Screening of Newly Diagnosed CRC
Common: ~ 3% of all CRC
Age/screening criteria miss up to 25%
Accurate methods (MSI/IHC) using easily accessible tumor tissue
Benefits of medical intervention
Cascade testing of family members
Surveillance/prevention
CRC treatment decisions
Evidence of cost-effectiveness

16. EGAPP Lynch Recommendation Genetics in Medicine January 2009
GIM, 2009;1:35
May, 2007
GIM, 2009;1:42

17. Summary Statement
“The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found sufficient evidence to recommend offering genetic testing for Lynch syndrome to individuals with newly diagnosed colorectal cancer (CRC) to reduce morbidity and mortality in relatives. We found insufficient evidence to recommend a specific genetic testing strategy among the several examined.”

18. 2.8% of CRC probands with deleterious mutations (n=44)
Columbus-area HNPCC study ( )
2.8% of CRC probands with deleterious mutations (n=44)
Age at diagnosis – 51.4 (range 23-87)
50% diagnosed over age 50
25% did not meet either Amsterdam or Bethesda criteria
Mutations
20.5% MLH1
52.3% MSH2
13.6% MSH6
13.6% PMS2
Hampel et al. New Engl J Med 2005; 352: Hampel et al. J Clin Oncol 2008; 26:5783 18

19. Family Studies of 35/44 CRC Probands
35 CRC probands have had genetic counseling
Degree of Kinship Tested Positive
First
Second
> Second
Total
Hampel et al. NEJM 2005;352: ; Hampel et al. JCO 2008.

20. Theoretical Population Health Benefit
Bellcross, Genet Med, 2012

21. Approved Genomics Objective (Developmental)
Healthy People 2020
Approved Genomics Objective (Developmental)
“Increase the proportion of persons with newly diagnosed colorectal cancer who receive genetic testing to identify Lynch syndrome”

22. 2.5 % with deleterious mutations (n=14)
Endometrial cancer
2.5 % with deleterious mutations (n=14)
Age at diagnosis – 54.1 (range 39-69)
65% diagnosed over age 50
65% did not meet either Amsterdam or Bethesda criteria
Mutations
14.3% MLH1
21.4% MSH2
64.3% MSH6
No PMS2
Hampel H et al. Cancer Res. 2006; 66: Hampel H et al. Cancer Res. 2007;67:9603 22

23. Columbus HNPCC study Family studies of 14 EC probands
12/14 EC probands have had genetic counseling
Degree of Kinship Tested Positive
First
Second
> Second
Total

24. EGAPP Data Interpretation Concerns
“To reduce morbidity and mortality in relatives”
Implies no benefit to proband
Increasing evidence of impact on CRC management – chemotherapy, surgery
Known increased risk for 2nd primary colorectal cancers and other tumors impacts medical management
Does not take into account current practice and insurance coverage (including Medicare)

25. Potential Impact on CRC treatment
MSI-H tumors
Better prognosis (Popat, JCO 2005;23:609)
Lack of impact of 5FU on RFS/OS (DesGuetz, Eur J Cancer 2009;45:1890)
Surgical (Gut 2011;60:950 – 382 LS gene mutation carriers
Extensive colectomy – 0/50 metachronous tumors vs. Segmental resection – 74/322 (22%)
Cumulative risk of metachronous CRC at 10, 20, & 30 yrs = 16%, 41% & 62% respectively

26. Cost effectiveness Data
Targeting screening only to CRCs < age 50 would miss over 50% of LS cases
Mvundura M, et al. Genet Med. 2010;12:93-104

27. Business Analysis by a Healthcare System
Evidence review & computerized simulation models – Intermountain Healthcare
Cost of screening all (unselected) CRC patients for Lynch syndrome <$25,000/LYS
IHC with methylation studies, reflexing to BRAF most efficient
Gudgeon, Am J Managed Care, 2011;17:e288

28. Universal IHC screening for CRC: OSU experience
Began March 1, 2006
270 cases of CRC in first 2 years
57 (21.1%) absent for one or two MMR proteins
54 contacted by genetics with physician consent
5 deceased, reported to next of kin
7 prisoners
34 appropriate for consultation
18 scheduled appointment/9 completed appt
7/9 tested
2 confirmed Lynch, 3 with MLH1 methylation
South et al, Genet Med 2009; 11:

29. Challenges to Implementation
Lack of provider knowledge of Lynch syndrome and testing issues
Question of informed consent
Availability of genetic services
Cost and coverage
Psychosocial impact
Informing relatives – who is responsible?
Patient and provider compliance
Infrastructure needs
Testing limitations (e.g. IHC accuracy by site)

30. It takes a team Surgery Pathology Oncology Gastroenterology Genetics
Gynecology
Patients
Families
Healthcare system

32. LSSN Vision and Mission
to reduce the cancer burden associated with Lynch syndrome.
LSSN Mission:
to promote universal Lynch syndrome screening on all newly diagnosed colorectal and endometrial cancers; to facilitate the ability of institutions to implement appropriate screening by sharing resources, protocols and data through network collaboration; and to investigate universal screening for other Lynch syndrome related malignancies

33. Membership Data

34. Emory LS Screening Team
N. Volkan Adsay, MD Pathology
Cecelia A. Bellcross PhD, MS, CGC Genetics
Amanda Eppolito, MS, CGC Genetics
Alton B. Farris, III, MD Pathology
Natalyn N. Hawk, MD Hem/Onc
Ira R. Horowitz, MD Gyn/Onc
John Kauh, MD Hem/Onc
Namita Khanna, MD Gyn/Onc
Dana M. Meaney-Delman, MD High Risk Gyn
Virginia O. Shaffer, MD Colorectal Surgery
Christine Stanislaw, MS, CGC Genetics
Patrick S. Sullivan, MD Colorectal Surgery
Miranda Chergosky – GC Student Focus Intern

35. Emory LS Screening Protocol

36. IHC Result Interpretation
Frequency
Implications
Follow-up
MLH1 & PMS2 Absent
15%
80% acquired
20% LS due to MLH1 mutation
BRAF (V600E +) and/or MLH1 hypermethylation
Genetics referral & MLH1 DNA analysis
MSH2 & MSH6 Absent 3%
Most LS due to MSH2 mutation
Genetics referral & MSH2 DNA analysis
MSH6 or PMS2 Absent 2%
Most LS due to MSH6 or PMS2 mutation
Genetics referral & MSH6/PMS2 DNA analysis

37. Genetics Follow-up
Access to CoPath – automatic search for all CRC specimens
Monitor if IHC being done – interface with GI path fellows
Review IHC/BRAF results
Enter into LSSN database
Abnormal IHC results
Follow-up letter to MD via EMR
Coordination with RN staff to ensure genetics referral
Subset of IHC positive screens to be seen at point of care (post-op or oncology appt)
Enter follow-up/outcome data into LSSN db

39. What Is Cancer Genetic Counseling?
Cancer genetic counseling is NOT genetic testing!
It is a process of information gathering, risk assessment and education.
The goal of cancer genetic counseling is to provide the individual, family and their health care providers with accurate cancer risk information to facilitate personal management decisions.

40. Initial Genetic Counseling Visit
Review medical history and family history
Assess risk for hereditary cancer
Discuss cancer biology and genetics
Discuss genetic testing options and/or referrals for additional evaluation if appropriate
Discuss implications of testing for the patient and their family
Coordinate testing including review of insurance issues

41. Informed Consent: Potential Benefits of Genetic Testing
Improved cancer risk management
Prevention
Early detection
Avoidance of unnecessary and costly screening and surgery
Relief from uncertainty and anxiety about cancer risk
Information for individual and family members
Lifestyle decision making

42. Informed Consent: Limitations of Genetic Testing
Not all mutations are detectable
Uncertain significance of some mutations
Negative result is fully informative only if mutation has been identified in family
Results indicate probability, not certainty, of developing cancer
Management/screening strategies continually evolving as new data collected

43. Ideally, Begin Testing With an Affected Person
Colon Ca, 42
Test first, if possible
Colon Ca, 38
d.45
Colon Ca, 45
Person seeking counseling (proband)
If a mutation is found in an affected person, testing will be more informative for other family members.

44. Understanding Possible Test Results
Increased Cancer Risk
Positive
NO Increased Cancer Risk Y
Has a mutation been found in the family?
Negative N
Cancer Risk Not Altered
(individualized empiric risk based on family history)
Uncertain Variant

45. Impact of Genetic Testing
Family with known mutation
Colon Ca, 52
d. 50
MSH2?
Colon Ca, 45
MSH2 +
Endometrial Ca, 47 *
30 MSH2+ 37
MSH2 -
Mutation Positive: initiate screening
True negative: no increased risk beyond general population

46. Informed Consent: Potential Risks of Genetic Testing
False sense of security if test negative
Psychological distress
Change in family dynamics
?? Insurance discrimination

47. The Myth of Genetic Discrimination
No well-documented cases of health insurance loss, denial, or rate
increase based on cancer genetic
testing
State and Federal laws exist
which address health insurance and employment
GINA – Genetic Information Non-discrimination Act (May, 2008)
Life/disability/long-term care not protected

48. Result Disclosure and Post-test Counseling
Assess cancer risk based on test results
Discuss any additional testing recommendations
Review of implications for family members
Present screening and management options
Discuss risk reduction strategies
Explore psychosocial adjustment to cancer risk and/or genetic risk

49. Questions Comments Thoughts Suggestions ?
Thank You