1. Genetics of Colorectal Cancer

2. Cancer is a Disease of the Cell Cycle
“Carcinoma is a genetic disease, it is not necessarily inherited”

3. Knudsen’s “two hit” hypothesis

4. Types of genes which may mutate to cause cancer:
Oncogenes
Suppressor genes
DNA repair genes
p53

5. Adenoma-Carcinoma Sequence Accumulation of Mutations DCC, MCC, p53, K-ras, APC, MSH2, MLH1, etc.

6. Estimated New Cancer Cases of 10 Leading Sites by Gender for the US 2000
Male
Prostate
29%
Lung and bronchus
14%
Colon and rectum
10%
Urinary bladder 6%
Non-Hodgkin’s Lymphoma 5%
Melanoma of skin 4%
Oral cavity and pharynx 3%
Kidney and renal pelvis
Leukemia 2%
Pancreas
All other sites
19%
Female
Prostate
30%
Lung and bronchus
12%
Colon and rectum
11%
Urinary bladder 6%
Non-Hodgkin’s Lymphoma 4%
Melanoma of skin
Oral cavity and pharynx 3%
Kidney and renal pelvis 2%
Leukemia
Pancreas
All other sites
22%

7. Average Annual Age-Specific US Incidence and Mortality Rates of CRC, 1992-1996

8. Prevalence of Adenomas and Incidence of Colon Cancer
Age >50 years with any adenomas: 25-40%
Lifetime risk of cancer at age 50 years
5% for females
6% for males
Persons with advanced adenomas are at greatest risk

9. Risk Factors for Colorectal Cancer (CRC)
Aging
Personal history of CRC or adenomas
High-fat, low-fiber diet
Inflammatory bowel disease
Family history of CRC
Hereditary colon cancer syndromes

10. Risk of Colorectal Cancer (CRC)5%
General Population
Personal History of
Colorectal Neoplasia
15-20%
15-40%
Inflammatory Bowel Disease
70-80%
HNPCC Mutation
>95%
Familial Adenomatous Polyposis
(FAP)
Lifetime Risk (%)

11. Colorectal Cancer Statistics in the US
Second overall leading cause of cancer-related deaths in the U.S.
Estimated 149,000 new cases and 50,000 deaths in the year 2008
Declining trends between 1990 and 1996
Incidence rate: ~2.1% per year
Mortality rates: ~1.7% per year

12. Family History: Empiric Risks
Lifetime Risk CRC
General population in U.S
~2 to 6%
One 1st degree relative with CRC
2-3 fold
Two 1st degree relatives with CRC
3-4 fold
1st degree relative with CRC <50
One 2nd or 3rd degree relative with CRC
~1.5 fold
Two 2nd degree relatives with CRC

13. 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

14. Colorectal Cancer ~5-8% of all cases of CRC are hereditary
~15-20% are “familial”/multifactorial
~75% of cases are sporadic

15. 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

16. 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 years and family history does not meet criteria for known hereditary CRC syndromes
Likely to be multiple low penetrant genes plus environmental factors at play
Family members warrant earlier CRC screening
Starting at 40 years or 5-10 years earlier than age of diagnosis of the youngest affected relative

17. 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

18. 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)

19. HNPCC: AKA “Lynch Syndrome”
2-3% of all colorectal cancer cases
Autosomal dominant; high penetrance
Typical age of CA onset is years
Multiple affected generations
60-70% right-sided/proximal CRC tumors
Polyps may be present, multiple primaries common. Can overlap with AFAP.

20. HNPCC Lifetime cancer risks: Colorectal 80% Endometrial 20-60%
Gastric %
Ovarian %
Biliary Tract 2%
Urinary Tract 4%
Small Bowel 1-4%
Brain/CNS 1-3%

21. HNPCC: Clinical Diagnostic Criteria
Amsterdam II Criteria (3-2-1)
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

22. HNPCC
Caused by mutations or deletions in mismatched repair (MMR) genes
MSH2, MLH1, MSH6, (PMS2)
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

23. MSI/IHC Screening can be used to screen for HNPCC in select cases
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

24. 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

25. FAP - Surveillance Colon Duodenal/gastric Thyroid Hepatoblastoma
Annual sigmoidoscopy, age yrs
Prophylactic colectomy following polyp detection with 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.

26. 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

27. 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

28. 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: colonoscopy every 2-5 yrs starting at 35 yrs

29. 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)

30. Peutz-Jeghers Syndrome
<1% of all CRC cases
Hamartomatous polyps of GI tract as early as 1st decade
Mucocutaneous hyper pigmentation
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

31. 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

33. 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

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

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

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 Management Age to Begin Average Risk 50 years
No family history CRC OR
One 2nd or 3rd degree relative with CRC
FOBT annually + flex sig every 5 years; OR
Colonoscopy every 10 years; OR
DCBE every 5 years

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

39. CRC Risk Management HNPCC or suspected HNPCC 20-25 years
Age to Begin
HNPCC or suspected HNPCC years
1. Colonoscopy every 1-2 yrs
2. Genetic counseling; consider genetic testing
FAP or suspected FAP years
1. Flex sig or colonoscopy every1-2 yrs

40. 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

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

42. Case 1: Assessment Direct gene testing of MLH1 and MSH2 OR
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

43. 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

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

45. 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

46. Chemo Prevention Evidence that ASA, NSAIDs, Calcium, and COX-2
inhibitors may reduce incidence of CA by reducing # of
adenomas
􀂃 40-50% risk reduction for developing colorectal CA regardless of
location in colon, age, gender, and race
Generally performed by RCT’s in patients with prior
colorectal CA followed for recurrence of adenomas
Diet, fiber, and antioxidant vitamins have not been
shown by RCT’s to decrease risk of recurrent adenomas
COX-2i’s and Sulindac have been shown to reduce the
number of adenomas found in FAP alone
􀂃 Not effective for sporadic colon CA
􀂃 Actually can cause regression of adenomas