1. Genetics and Primary Care
Familial Cancer Risk Assessment
Colorectal Cancer

2. Case 1:Joan
Joan, age 38, was recently diagnosed with endometrial cancer. Family history reveals:
Paternal grandmother: endometrial cancer, age 50
Paternal uncle: colon cancer, age 48
Father: colonoscopy at age 50; four adenomatous polyps removed
No other significant history
Both sides of the family are Northern European Caucasian

3. Case 2: Ted
Ted is 30 and wants a colonoscopy because his mother was just diagnosed with colon cancer after routine screening at age 54. Family history reveals:
Paternal grandfather: died of CRC at age 79
No hx of endometrial, ovarian, small bowel or ureter/kidney cancer on either side of family
Two maternal aunts: cervical cancer at ages 30 & 34
Maternal grandmother: breast cancer age 85

4. Outline Hereditary colorectal cancer syndromes
Cancer family history – a primary tool
Evaluating your patients for familial CRC risk
Genetic counseling and testing for hereditary colorectal cancer
How, when, where to refer patients for genetic services

5. Colorectal Cancer ~5-8% of all cases of CRC are hereditary
~15-20% are “familial” / multifactorial
~75% of cases are sporadic
Feuer EJ: DEVCAN: National CA Inst. 1999
~75% of cases of CRC are sporadic
only 7% of sporadic cases occur <55
~15-20% are “familial” / multifactorial – genetic testing not generally available for low penetrance genes associated with increased risk of CRC
~5-8% are hereditary (defined cancer susceptibility syndromes caused by single genes)

6. Characteristics of Average Risk
No well-defined threshold between sporadic and familial CRC at this time
Probably safe to include individuals with:
No personal risk factors or family history of CRC
One 2nd or 3rd degree relative with CRC >60 years with no other family history of CRC

7. Characteristics of “Familial” CRC
“Clustering” of colon cancer cases in the family (> 50 at diagnosis) without clear dominant pattern, or
One close relative with CRC <60 yrs and family history does not meet criteria for known hereditary CRC syndromes
Likely to be multiple low pentrant genes plus environmental factors at play
Family members warrant earlier CRC screening
Starting at 40 years or 5-10 yrs earlier than age of diagnosis of the youngest affected relative
Winawer et al., Gastroenterology 2003:124:

8. Characteristics of Hereditary CRC
Multiple relatives with colorectal cancer
One or more diagnosed at an early age (<50)
Sequential generations affected
Except in autosomal recessive syndromes
Other cancers in the family known to be associated with CRC (uterine, ovarian, GI)
Multiple primary tumors or polyps

9. Hereditary CRC syndromes
Hereditary Non-Polyposis Colorectal Cancer (HNPCC)
Variants: Muir-Torre, Turcot
Familial Adenomatous Polyposis (FAP)
Variants: Gardner, Turcot
Attenuated FAP
APC mutation in Ashkenazi Jews
Others:
Multiple adenomatous polyposis syndrome/MYH gene (MAP)
Peutz-Jeghers syndrome (PJS)
Familial Juvenile Polyposis (FJP)

10. In Your Practice: Colon Cancer
In the typical primary care practice, 2 to 8 patients (1/200 to 1/800) are from “high risk” families, with a condition called Hereditary Non-Polyposis Colon Cancer (HNPCC). These patients have a high lifetime risk of colorectal and other cancers with risk starting in their 20’s.

11. HNPCC: AKA “Lynch syndrome”
2-3% of all colorectal cancer cases
Autosomal dominant; high penetrance
Typical age of CA onset is yrs
Multiple affected generations
60-70% right-sided/proximal CRC tumors
Polyps may be present, multiple primaries common. Can overlap with AFAP
Typical age of onset is 40-50, range from yrs
Preponderance of right-sided/proximal tumors – 60%
Polyps may be present (usually few to < 100), multiple primaries common. Can overlap AFAP so consider this diagnosis if >20 colon polyps detected.

12. HNPCC Lifetime cancer risks: Colorectal 80% Endometrial 20-60%
Gastric %
Ovarian %
Biliary tract %
Urinary tract %
Small bowel %
Brain/CNS %
Cancer Risk with HNPCC:
CRC - 80% lifetime,
40% for 2nd primary

13. HNPCC: Clinical Diagnostic Criteria
Amsterdam II Criteria (3-2-1 rule)
3 or more relatives with an HNPCC-related cancer, one of whom is a 1st degree relative of the other two
2 or more successive generations affected
1 or more cancers diagnosed before age 50

14. HNPCC Caused by mutations or deletions in mismatch repair (MMR) genes
MSH2, MLH1, MSH6, (PMS2)
90% of detectable mutations in MSH2 and MLH1
50% of families meeting Amsterdam II Criteria have detectable mutations
Testing/screening options:
Direct genetic testing of MMR genes (in select families)
Initial screening of the tumor tissue by MSI/IHC
Autosomal dominant condition caused by mutations in one of a number of mismatch repair genes
MSH2, MLH1, MSH6, PMS1, or PMS2, others(?)
Sequencing of the MSH2 and MLH1 genes can identify up to 60-70% of HNPCC
Microsatellite Instability (MSI) and Immunohistochemistry (IHC) testing on tumor tissue can be used to screen for possible HNPCC
Genetic testing should be done on an affected family member, only after genetic counseling and informed decision-making

15. Proceed Directly To Genetic Testing After genetic counseling and informed consent!
IF:
Family history fulfills Amsterdam II criteria or
Patient has two HNPCC related cancers or
Patient has CRC and a 1st degree relative with HNPCC-related cancer, with at least one cancer diagnosed <50 years of age
Always test an affected family member first!

16. MSI/IHC screening Microsatellite Instability (MSI) on tumor tissue
can be used to screen for HNPCC in select cases
Immunohistochemistry (IHC) on tumor tissue
can be used to detect the presence or absence of the mismatch repair proteins (MSH2, MLH1, etc.)
“Screen positive” individuals can be offered cancer genetic counseling/assessment and targeted genetic testing

17. Revised Bethesda Criteria, 2004
Criteria for MSI/IHC screening
Revised Bethesda Criteria, 2004
CRC or endometrial CA <50 yrs
2 HNPCC cancers in same person
CRC with “MSI-H histology” diagnosed <60 yrs
Infiltrating lymphocytes, Crohns-like lymphocytic reaction, mucinous/signet ring differentiation, medullary growth pattern
CRC and one or more 1st degree relative with an HNPCC-related cancer, one diagnosed <50 yrs
CRC and two or more 1st or 2nd degree relatives with HNPCC-related cancers, any age
Umar A et al: J Natl Cancer Inst, 2004; 96(4):

18. HNPCC Surveillance Gene carriers or at-risk relatives:
CRC: colonoscopy age 20-25, repeat 1-2 yrs
Women: gyn exam, endometrial aspiration, TV U/S, CA-125 (?) age 25-35, repeat 1-2 yrs
If one HNPCC family member affected w/the following:
Stomach CA: EGD age 3-35, repeat 1-2 yrs
Urinary tract CA: urine cytology age 30-35, repeat 1-2 yrs
NCCN practice guidelines in oncology – v

19. FAP 1 in 10,000 incidence 100’s to 1000’s of colonic adenomas by teens
Cancer risk: colon, gastric, duodenum (periampulla), small bowel, pancreas, papillary thyroid, childhood hepatoblastoma
7% risk of CRC by 21 yrs; 93% by 50 yrs
Autosomal dominant: APC gene mutations
Variants: Gardner, Turcot

20. FAP – surveillance Colon Annual sigmoidoscopy, age 10-12 yrs
Prophylactic colectomy following polyp detection w/continued surveillance of rectum, ileal pouch
Duodenal/gastric
EGD age 25, repeat 1-3 yrs
Thyroid
Annual PE, age 10
Hepatoblastoma
Annual screen by abd U/S & AFP from birth to 5 yrs.
Gastroenterology 2001; 121: 195. AGA Statement

21. Attenuated FAP 20 to 100 polyps, usually more proximal
Onset later than FAP, average AOO = 50
Lifetime risk of CRC = 80%
Extracolonic tumors occur at same rate as FAP
Variant of FAP, mutations in same APC gene
Surveillance:
annual colonoscopy starting late teens or early 20’s
Option of subtotal colectomy
Option of subtotal colectomy if polyps too numerous – AFAP does not generally affect the rectum, although continued surveillance is recommended.

22. Genetic Testing: FAP/AFAP
Test an affected family member first!
After genetic counseling and informed consent
APC gene testing can confirm a suspected diagnosis
Family members of a person with a known APC mutation can have mutation-specific testing
Genetic testing for children at risk for FAP can be considered before beginning colon screening
APC gene analysis (either by protein truncation testing [PTT] or sequencing) can confirm a suspected diagnosis
PTT detects 80-90% of affected persons (FAP)
Gene sequencing detects up to 95% of affecteds
Family members of a person with a known APC mutation can be tested for carrier status
Testing at-risk children – can be considered before beginning screening (10-12yrs)
Detection rate for AFAP is not known

23. APC gene mutation in Ashkenazi Jews
Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)
Found in 6% of the general AJ population
12% of AJs with CRC
29% of AJs with CRC and a positive family history
Lifetime risk of CRC in mutation carrier is 10-20%
Screening: colonscopy every 2-5 yrs starting at 35 yrs

24. MAP syndrome/MYH gene Multiple adenomatous polyposis (MAP) syndrome
Autosomal recessive; mutations in the MYH gene
Median number of polyps = 55
Mean age of polyp diagnosis = years
Polyps mainly small, mildly dysplastic tubular adenomas. Some tubulovillous, hyperplastic, serrated adenomas, microadenomas
30% of individuals with polyps have homozygous mutations in the MYH gene
Genetic testing should be offered if >15 polyps (and APC gene testing negative)

25. Peutz-Jeghers syndrome
<1% of all CRC cases
Hamartomatous polyps of GI tract as early as 1st decade
Mucocutaneous hyperpigmentation
lips, mouth, buccal mucosa, fingers
Usually seen in children < 5 yrs
Cancer risk:
colon, small intestine, stomach, pancreas, breast, ovaries, uterus, testes, lungs, kidneys
Mutations in STK11 gene
found in 70% of familial cases and 30-70% of sporadic cases

26. Familial Juvenile Polyposis
<1% of all CRC cases
Autosomal dominant
5 or more juvenile polyps in colon or GI tract
Appear in 1st or 2nd decade
50% lifetime risk of CRC; AOO in 30’s
Increased risk gastric, GI, pancreatic CA
~50% of cases have mutations in either the MADH4 or BMPR1A genes

28. What can YOU do?

29. CRC Risk Screening: Steps to take
Take a thorough cancer family history
Does family history meet hereditary criteria?
If yes, refer to genetics
Classify based on family history: average, moderate or high risk.
Create surveillance plan based on risk level

30. CRC Risk Screening: Steps to take
Take a thorough cancer family history
Does family history meet hereditary criteria?
If yes, refer to genetics
Classify based on family history: average, moderate or high risk.
Create surveillance plan based on risk level

31. Family Health History
“The family tree has become the most important genetic test of all. The more you know, the more tools you have to practice preventive medicine”
Donna Russo, Certified Genetic Counselor, NY Presbyterian-Columbia Hospital

32. Family History Details to Record
Type of primary cancer(s) in each relative
Age of disease onset in each relative
Cancer status in 1st and 2nd degree relatives
Cancer status in both sides of the family
Other medical findings
Type of primary cancer(s) in each affected relative
Age of disease onset in each affected relative
earlier onset generally confers higher risk for close relatives
Cancer status in 1st and 2nd degree relatives (often discounted)
Cancer status in both sides of the family (paternal family history often overlooked when assessing risk of “female” cancers)

34. CRC Risk Screening: Steps to take
Take a thorough cancer family history
Does family history meet ‘potentially hereditary’ criteria?
If yes, refer to genetics
Classify based on family history: average, moderate or high risk.
Create surveillance plan based on risk level

35. Consider Genetics Referral for:
Two or more family members with CRC* at least one <50
Three or more family members w/CRC*; any age
Patient with colon cancer before 40 yrs
Endometrial cancer and family history of CRC <50
Persons with more than one primary CRC <50 yrs or with both endometrial CA and CRC
Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer, one diagnosed <50 yrs.
*Same side of family
Any patient with 2 or more family members (same side) with early onset CRC (<50 yrs)
Any colon cancer case before 40 yrs
Woman with endometrial cancer <45 and family history of early onset CRC
Persons with more than one primary CRC <50 yrs or with both endometrial and CRC
Autosomal dominant pattern of cancers in the same lineage
Insurance coverage: Some insurers and some plans will cover cancer genetic risk assessment/cancer genetic counseling. Others will not. More difficult to obtain coverage for unaffected person with a family history than an affected person. Pre-authorization recommended.
Pre-authorization for cancer genetic testing is important as tests are expensive. The genetic counselor will facilitate the pre-auth for testing if indicated and if patient decides to have testing.
Insurance discrimination – needs to be discussed before insurer is contacted regarding coverage.

36. Consider Genetics Referral for:
MSI and/or IHC tumor results suspicious for HNPCC
Autosomal dominant pattern of cancers in the family
Persons with 15 or more adenomatous colorectal polyps
Persons with multiple hamartomatous or juvenile GI polyps
Persons with a family history of a known hereditary cancer syndrome

37. CRC Risk Screening: Steps to take
Take a thorough cancer family history
Does family history meet hereditary criteria?
If yes, refer to genetics
Classify based on family history: average, moderate or high risk.
Create surveillance plan based on risk level

38. Empiric Risk of CRC
Risk for CRC based on family history increases with:
Closer degree of relationship and # of affected members
Younger age of onset
Presence of extracolonic tumors, multiple primaries
About 10% of all people have a 1st degree relative with CRC, which increases risk 2-fold
Risk for CRC increases with:
degree of relationship and # of affected members
younger age of onset
presence of extracolonic tumors, multiple primaries

39. Family History: Empiric Risks
Lifetime Risk CRC
General population in US ~2 to 6%
One 1st degree relative w/CRC fold
Two 1st degree relatives w/CRC fold
1st degree relative w/CRC < fold
One 2nd or 3rd degree relative w/CRC ~1.5-fold
Two 2nd degree relatives w/CRC fold

40. Goal: Classification Assessment Risk Classification Intervention
Standard prevention
recommendations
Average
Moderate
(“Familial”)
Personalized prevention
recommendations
Family Hx
Referral for genetic evaluation
with personalized prevention
recommendations
High/Genetic

41. CRC Risk Management Age to Begin Average Risk 50 yrs
No family history CRC OR
One 2nd or 3rd degree relative with CRC
- FOBT annually + Flex sig every 5 yrs; OR
- Colonoscopy every 10 yrs; OR
- DCBE every 5 yrs
ACBE = air contrast barium enema. FOBT = fecal occult blood test

42. Gastroenterology: 2003;124:544-560
CRC Risk Management
Moderate/Family history Age to begin
1. Two 1st degree relatives with CRC any age 40 years*
or one 1st degree relative with CRC < 60
- Colonoscopy every 5 yrs
2. One 1st degree relative with CRC >60 or 40 years
two 2nd degree relatives with CRC any age
- Average risk screening
* Or 5-10 yrs earlier than earliest case in family
Gastroenterology: 2003;124:

43. CRC Risk Management Age to Begin 1. Colonoscopy every 1-2 yrs
HNPCC or suspected HNPCC yrs
1. Colonoscopy every 1-2 yrs
2. Genetic counseling; consider genetic testing
FAP or suspected FAP yrs
1. Flex sig or colonoscopy every1-2 yrs

45. Cancer Genetic Counseling
Full pedigree analysis and risk assessment
Discussion of:
Personal cancer risks based on family history
Genetic testing options and risk of mutation
Advantages, risks and limitations of genetic testing
Personalized, risk-based screening and prevention options
Support resources

46. Cancer Genetic Testing: Elements of Informed Consent
Information on specific test(s) being considered
Implications of positive, negative, uninformative results
Options for risk assessment and management without genetic testing
Risk of passing a mutation to offspring
Technical accuracy of test
Fees involved in testing and counseling
Option of DNA banking

47. Cancer Genetic Testing: Informed Consent (cont.)
Psychological implications of test results
Risks of insurance/employment discrimination
Confidentiality issues
Options for and limitations of medical surveillance and strategies for prevention following testing
Importance of and guidance on sharing results with at-risk relatives
Results disclosure
American Society of Clinical Oncology, March, 2003
Psychological implications of test results (benefits and risks)
Risks of insurance/employment discrimination – current data
Confidentiality issues
Options for and limitations of medical surveillance. and strategies for prevention following testing
Importance of and guidance on sharing results with at-risk relatives
Results disclosure (how and to whom?)

48. Case 1:Joan
Joan, age 38, was recently diagnosed with endometrial cancer. Family history reveals:
Paternal grandmother: endometrial cancer, age 50
Paternal uncle: colon cancer, age 48
Father: colonoscopy at age 50; four adenomatous polyps removed
No other significant history
Both sides of the family are Northern European Caucasian

49. Pedigree: Case 1 French, Irish, Scottish German, English 63 yr 88 yr
Dx 50
61 yr
63 yr
CRC
Dx 48
4 polyps
50 yrs.
Key:
38 yr
35 yr
Endometrial CA
Dx 38
Colorectal CA
Adenomatous polyps
10 yr
8 yr

50. Case 1: Assessment
Joan meets Amsterdam II Criteria and is at risk for HNPCC
Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC
Testing options:
Direct gene testing of MLH1 and MSH2 OR
MSI/IHC screening of tumor tissue with gene sequencing if MSI positive

51. Case 2: Ted
Ted is 30 and wants a colonoscopy because his mother was just diagnosed with colon cancer after routine screening at age 54. Family history reveals:
Paternal grandfather: died of CRC at age 79.
No hx of endometrial, ovarian, small bowel or ureter/kidney cancer on either side of family.
Two maternal aunts: cervical cancer at ages 30 & 34
Maternal grandmother: breast cancer age 85

52. Case 2: Pedigree Italian Irish German Key: CRC 79 d.82 d. 58 MI
BrCa 85 yrs
d.87 84 56 55 58 60
Colon Ca
54 yrs
Cerv.Ca
30 yr
Cerv.Ca
32 yr
Key:
CRC
34 yrs
30 yrs
Breast CA
Cervical CA

53. Case 2: Ted
Verify Diagnoses! Obtain and review pathology reports on all reported cancers, whenever possible
If diagnoses are correct: Ted has no family history indicative of a known colon cancer syndrome (HNPCC, FAP, other)
Ted’s lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (>50)
Moderate/familial risk: Screening by colonoscopy starting at age 40, or 10 yrs earlier than earliest case in family, is reasonable

54. Oregon Genetics Providers
Portland
Oregon Health & Science University
Legacy Health Care
Northwest Perinatal Services
Kaiser-Permanente
Eugene
Center for Genetics & Maternal Fetal Medicine
Bend
Genetic Counseling of Central Oregon (cancer only)
Genetic consultations are available by phone with OHSU medical geneticists. See Oregon Genetics provider list for the phone number.

55. Referral for Genetic Services
Consult “Genetic Services Contact List”
Phone consultations available:
OHSU Genetics Consult Line:
Refer patients by phone, fax, mail, or patient self-referral
‘Indications for Referral’ in resource packet
Preconception/Prenatal
Pediatric
Adolescent/Adult
Again, it is important for patient to check own insurance policy to see if genetics referral is covered. Some patients will not want their insurance notified of a genetics referral because of concerns about insurance discrimination.

56. Resource Materials Patient pamphlets:
‘Do You Have Cancer in Your Family?’
‘Genetic Testing: A Fact Sheet’
Web-based cancer genetics resource list
Hereditary Colon Cancer Association
Resource materials at
Genetics tutorials on