By Peter P. Stanich, MD Division of Gastroenterology, Hepatology & Nutrition The Ohio State University OSUCCC - James

1. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Familial predisposition for colorectal
cancers: Who to screen?
Peter P. Stanich, MD
Division of Gastroenterology, Hepatology & Nutrition
4.9.2016

2. • Genetics Clinic Overview
• Who to screen with CRC
• Who to screen with polyps
• How to screen everyone
Outline
2

3. Genetic counseling
 Cancer genetics appointments are about 90 min
 They include:
1. Review of clinical history (personal and family)
2. Differential diagnosis
3. Discussion of pros/cons of genetic testing
4. Ordering, drawing and routing of genetic testing if indicated and patient
provides informed consent (with knowledge of insurance and lab rules)
5. Perhaps most importantly post-result counseling

4. Genetic counseling
 Benefits of genetic counseling and testing:
 Accurate counseling for patients of risks for cancers (both
another colon cancer as well as other cancers)
 Predictive testing of at risk family members
*If positive, prevent colon cancer through screening!
*If negative, save patient from a lot of colonoscopies!
 Federal laws protecting against employment or health
insurance discrimination

5. Genetic testing
 Consists of single blood draw or mouthwash kit performed
during visit
 Can now test for multiple genes (even 70+) if needed for
same cost
 Labs have guaranteed maximum out of pocket costs and
often as little as $100 independent of insurance coverage

6. Why are hereditary colorectal cancer syndromes important?
6
Lynch Syndrome

7. Who to screen?
 Everyone with colon cancer and high risk personal or family
history?
 Everyone with colon cancer?
 Everyone with a family history of colon cancer?
 Eventual answer… maybe everyone.
 The hard part is how? And what type of screening?
7

8. Screen patients with CRC
 High risk personal history
 High risk family history
 Abnormal tumor testing
8

9. When to refer to Genetics?
9
Hampel et al. A practice guideline from the American College of Medical Genetics and Genomics and the
National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med.
2014.

10. When to refer to Genetics?
10
Hampel et al. A practice guideline from the American College of Medical Genetics and Genomics and the
National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med.
2014.

11. High risk personal history
 Prevalence of Lynch syndrome among early onset CRC
patients (from highly selected patient populations)
 8.4% dx <50 1,2
 12% dx <35 3
 13.6% dx <50 4
 Prevalence of other cancer syndromes among early onset
CRC patients (from highly selected patient populations)
 4% dx <50 4
 11% dx <35 3
11
1Hampel et al. New Engl J Med 2005; 352:1851-60
2Hampel et al. J Clin Oncol 2008; 26:5783-88
3Mork et al. J Clin Oncol 2015; 33
4Yurgelun et al. Gastroenterology 2015; 149:604-613

12. Ohio Colon Cancer Prevention Initiative
 All patients with CRC resection in OH in 2013 – 2016 are
eligible
 Free testing and counseling for patients and if mutation
identified for their at-risk relatives

13. Ohio Colorectal Cancer Prevention Initiative (OCCPI)
 Statewide initiative
began 1/1/2013
 Establish prevalence of
hereditary CRC in Ohio
 Increase colonoscopy
compliance among
relatives
 Establish research
infrastructure
 50 collaborating hospitals
13
Ohio
Columbus
Cleveland
Cincinnati
Toledo
Dayton
Akron

14. OCCPI data
365 Ohioans under 50 with CRC in the study
 53 (14.5%) had at least 1 clinically actionable mutations
 8.5% Lynch syndrome
 5.5% other syndrome (including 6 with BRCA1/2!)
 0.5% 2 syndromes (PMS2 and APC mutation)
 If only targeted-testing had been performed, 17 (31%) would
have been missed
 All early-onset CRC patients should be referred for genetic
testing with a comprehensive hereditary cancer gene panel.
14
Pearlman et al. Personal Communication.
Overall OCCPI data to this point:
2601 CRC patients enrolled
Lynch: 3.7%
Other hereditary syndromes: 2.2%
Stay tuned for updated recommendations on who
needs referred based on this data

15. When to refer to Genetics?
15
Hampel et al. A practice guideline from the American College of Medical Genetics and Genomics and the
National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med.
2014.

16. Lynch syndrome
 Amsterdam II Criteria
 The 3-2-1 rule
*Many would also include ovary, stomach, HB
and brain
Giardiello et al. Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A
Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. AJG 2014.

17. Oncologists and family history
 Difficult to obtain family history during busy office visits
 CRC lagging behind breast cancer…
17
Wood et al. Quality of Cancer Family History and Referral for Genetic Counseling
and Testing Amoung Oncology Practices. JCO 2014.

18. Oncologists and family history
 Furthermore, lower percentage of increased risk
for hereditary CRC are referred…
18
Wood et al. Quality of Cancer Family History and Referral for Genetic Counseling
and Testing Amoung Oncology Practices. JCO 2014.

19. Oncologists and family history
 Gold standard for Genetics: 3 generations
 Goal for Oncologists: 2 generations
19
Lu et al. ASCO Expert Statement: Collection and Use of a cancer Family
History for Oncology Providers. JCO 2014.

20. High risk personal and family history
 There are clinical predictive models available
*If concerned, recommend Genetics referral for providers with
expertise and most importantly time!
http://premm.dfci.harvard.edu/

21. Lynch syndrome
 Previously labeled “hereditary non-polyposis colorectal
cancer” in past, but this is vague and potentially misleading
 De novo mutations rare (2.3%), or less likely than paternal
discrepancy (3.7%) [Win, J Med Genet. 2011 and Bellis, J Epidemiol Community
Health 2005]

22. Clinical manifestations of Lynch syndrome
 Development of colorectal and extracolonic malignancies at
young ages

23. Lynch syndrome
 There is rapid progression from adenoma to CRC in
comparison to accepted 10-15 year interval for sporadic
polyps
Edelstein et al. Rapid development of colorectal neoplasia in patients with Lynch
syndrome. Clin Gastroenterol Hepatol. 2011 Apr;9(4):340-3.

24. Lynch syndrome
24
50 weeks laterIndex colonoscopy

25. Clinical care of Lynch patients
 Large-scale surveillance programs have achieved a 62 %
reduction in incidence of CRC and a 65–70 % decrease in
mortality. (Fam Cancer. 2013 Jun;12(2):261-5.)

26. When to refer to Genetics?
26
Hampel et al. A practice guideline from the American College of Medical Genetics and Genomics and the
National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med.
2014.

27. Tumor testing
 Revised Bethesda Criteria: meant to identify candidates for
tumor testing
Giardiello et al. Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A
Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. AJG 2014.

28. Tumor testing
 Bethesda criteria misses 28% of Lynch syndrome
 Why Bethesda criteria is often inadequate…
 Family size shrinking
 Success of CRC screening in decreasing cancer incidence
 Difficulty obtaining full family history in busy clinical setting
Giardiello et al. Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A
Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. AJG 2014.

29. Colorectal (and Endometrial) tumor testing
 OSU, USMSTF and NCCN favor universal tumor testing:
1. Greater sensitivity for the identification of Lynch syndrome
compared with multiple alternative strategies
2. Cost-effectiveness ratio comparable to other accepted
preventive services (e.g., colonoscopy for average risk
patients)
Hampel H. Point: justification for Lynch syndrome screening among all patients with newly diagnosed colorectal cancer.
JNCCN 2010.
Moreira L. Identification of Lynch syndrome among patients with colorectal cancer. JAMA 2012.

30. Tumor testing
 Immunohistochemistry (IHC) is our standard test at OSU
 More commonly performed in US centers
 Utilizes antibodies to the Lynch genes
Absence of staining is abnormal

31. Mismatch Repair Immunohistochemistry
 Normally present
 If protein absent, gene
not being expressed
(mutation/methylation)
 Benefit over MSI testing
is this can direct gene
testing by predicting
likely involved gene
MSH2MLH1
MSH6PMS2

32. MLH1 & PMS2 Absent
 15% of the time if
CRC is MSI
 80% acquired
methylation of MLH1
 20% will be LS
 Reflex to test for
BRAF or MLH1
hypermethylation to
clarify
MLH-1 MSH-2
MSH-6 PMS-2
*If BRAF mutation or MLH1 hypermethylation positive,
tumor is sporadic and no further testing needed.

33. MSH2 & MSH6 Absent
 3% of the time if
CRC is MSI
 Most likely LS due
to MSH2 (MSH6
or EPCAM less
likely) gene
mutation
MLH-1 MSH-2
PMS-2MSH-6

34. MSH6 Absent
 1% of the time if
CRC is MSI
 Most likely LS due
to an MSH6 gene
mutation
MLH-1 MSH-2
MSH-6 PMS-2

35. PMS2 Absent
 1% of the time if
CRC is MSI
 Most likely LS due
to a PMS2 gene
mutation
MLH-1 MSH-2
MSH-6 PMS-2

36. Tumor testing
 Which is better initial test – MSI or IHC?
 Pro of IHC – Faster, Can direct genetic testing to a specific gene, better detection of PMS2 and MSH6
 Con of IHC – Operator and lab dependent, who refers for counseling/testing after result?
 Pro of MSI – May affect Onc plans for chemotherapy
 Con of MSI – Not available in most labs, Does not direct genetic testing, increased need for 2nd tests
(IHC and/or BRAF and/or hypermethylation and/or genetic)
Giardiello et al. Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A
Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. AJG 2014.

37. Tumor testing
 Don’t need to memorize, but remember where to look for this (NCCN
guidelines)
 If any question, refer to Genetics

38. Case
 70 year old female with IC valve mass and hepatic flexure
large 2.5 cm polyp
 Mother had CRC at 65 and maternal Aunt with CRC at 55

39. What to do next with path?

40. Final diagnosis
 Sporadic CRC

41. When to refer to Genetics?
41
Hampel et al. A practice guideline from the American College of Medical Genetics and Genomics and the National
Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2014.

42. The text box should line up with the right side of the
logo. White text is preferable with the black
background.
• Bullet point one
• Bullet point two
• Bullet point three

43. PTEN hamartoma tumor syndrome (AKA Cowden
syndrome)
 Increased risk for CRC (newly described, SIR 10)
 Recommend colonoscopy at age 35
 High risk of other cancers with standardized incidence ratio included:
 Breast cancer – 25 (example of SIR: expected 2.6 in cohort, had 67)
 Thyroid cancer - 52
 Endometrial – 43
 Kidney – 30
 Melanoma – 8.5
43 Tan et al. AACR 2012.

44. Cowden syndrome clinical
manifestations:
• Skin and oral findings are
pathognomic and most common:
1. Trichilemommas – hair follicle
hamartomas
Brownstein et al. Tichilemmomas in Cowden’s disease. JAMA 1977.
PTEN hamartoma tumor syndrome

45. 2. Acral keratoses – papules on hands and feet
3. Facial papules and mucocutaneous papilloma –
often form cobblestone appearance
Stanich et al. CGH 2011.
PTEN hamartoma tumor syndrome

46. When to refer to Genetics?
46
Hampel et al. A practice guideline from the American College of Medical Genetics and Genomics and the
National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med.
2014.

47. Li Fraumeni syndrome
47
Villani et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome:
a prospective observational study. Lancet Oncol 2011.

48. When to refer to Genetics?
48
Hampel et al. A practice guideline from the American College of Medical Genetics and Genomics and the
National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med.
2014.

49. Flowchart for Hereditary Colon Cancer Differential Diagnosis
Presence of
>10 polyps
Type of polyps
- Lynch syndrome
- Familial Colorectal Cancer
syndrome type X
- Peutz-Jeghers syndrome
- Juvenile Polyposis
- Cowden syndrome
-Serrated Polyposis syndrome
-Hereditary mixed polyposis syndrome
- Familial Adenomatous Polyposis
-MYH-Associated Polyposis
- Polymerase Proofreading-Associated
Polyposis
NoYes
AdenomatousOther
Presence of
>10 adenomas or
non-adenomatous polyps

50. Familial adenomatous polyposis
50

51. When to refer to Genetics?
 Can we diagnose patients before they develop colon
cancer?

52. When to refer to Genetics?
52
Hampel et al. A practice guideline from the American College of Medical Genetics and Genomics and the
National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med.
2014.

53. Pre-endoscopy history questionnaire
 A simple and validated risk assessment tool to identify high
risk patients for hereditary colon cancer syndromes
 The questions identified 77 % of high-risk individuals in
large cohorts (Brigham and MN GI) and 95% of Lynch
mutation carriers (Commercial lab database).
 Also endorsed by USMSTF Lynch syndrome guidelines
(published 2014)
Kastrinos et al. Development and validation of a colon cancer risk
assessment tool for patients undergoing colonoscopy. AJG 2009.

54. Pre-endoscopy history questionnaire
54

55. OSU GI Genetics clinics
 Cancer Genetics appointments
 Genetic counselor
 Genetics physician
- Focused on diagnostics
- Clinical recommendations given with results
 Hereditary colon cancer syndrome clinic
- Dr Peter Stanich
- Focused on consultative long term care of patients diagnosed with or
suspected of having an inherited cancer predisposition
- Close collaboration with The James CRC group and Cancer Genetics
55

56. Thank you
 I am happy to answer questions
now or in the future
 I would love to help arrange any
referrals to Cancer Genetics or GI
as needed
 GI office - 614 293 – 6255
 Genetics office - 614 293 – 6694
 Peter.Stanich@osumc.edu

57. Thank You
To learn more about Ohio State’s cancer
program, please visit cancer.osu.edu or
follow us in social media:
57

58. 12% <1% 85%FAP
Sporadic
MIN (MSI+)
(Microsatellite Instability)
CIN
(Chromosome Instability)
Lynch Sx Sporadic MSI(+)
Germline Mutation
MMR genes
15%
3%
•Epigenetic silencing of
MLH1 by hypermethylation
of its promoter region
85%
Colorectal cancer tumor testing
Germline
Mutation
APC