1. Mechanisms and Epidemiology of Colon Cancer
Anil K. Rustgi, MD
University of Pennsylvania

2. Worldwide Statistics for Colorectal Cancer (CRC)
Estimated 875,000 cases in 1996
 8.5% of all new cases of cancer
Incidence rates vary by ~20-fold
 highest in North America, Western Europe,
Australia, New Zealand, Japan
 lowest in India, Northern Africa
Estimated deaths for 1998: 556,000

3. Estimated New Cancer Cases of 10 Leading Sites by Gender for the US 2000

4. Colorectal Cancer Statistics in the US
Second overall leading cause of cancer-related deaths in the US
Estimated 130,000 new cases and 56,300 deaths in the year 2000
Declining trends between 1990 and 1996
Incidence reate: ~2.1% per year
Mortality rates: ~1.7% per year

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

7. 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 2

8. Risk of Colorectal Cancer (CRC)
General population 5%
Personal history of colorectal neoplasia
15%–20%
Inflammatory bowel disease
15%–40%
70%–80%
HNPCC mutation
>95%
FAP 20 40 60 80
100
Lifetime risk (%) 3

9. Familial Risk for Colorectal Cancer
70%
Approximate
lifetime
CRC risk
(%)
17%
10% 6% 8% 2%
None
One 1°
One 1° and two 2°
One 1° age <45
Two 1°
HNPCC mutation
Aarnio M et al. Int J Cancer 64:430, 1995
Houlston RS et al. Br Med J 301:366, 1990
St John DJ et al. Ann Intern Med 118:785, 1993
Affected family members

10. Causes of Hereditary Susceptibility to CRC
Sporadic (65%–85%)
Familial (10%–30%)
Rare CRC syndromes (<0.1%)
Hereditary nonpolyposis colorectal cancer (HNPCC) (5%)
Familial adenomatous polyposis (FAP) (1%)
Adapted from Burt RW et al. Prevention and Early Detection of CRC, 1996

11. Clinical Features of FAP
Estimated penetrance for adenomas >90%
Risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain, other)
CHRPE may be present
Untreated polyposis leads to 100% risk of cancer

12. Genetics of FAP Autosomal dominant inheritance
Caused by mutations in APC tumor suppressor gene on chromosome 5q
Up to 30% of patients have de novo germline mutations
Most families have unique mutations
Most mutations are protein truncating
Genotype/phenotype relationships emerging

13. The APC Tumor Suppressor Gene
Codon 1309 5' 3' 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

14. Attenuated FAP Later onset (CRC ~age 50) Few colonic adenomas
Not associated with CHRPE
UGI lesions
Associated with mutations at 5' and 3' ends of APC gene

15. Indications for APC Gene Testing
Molecular diagnosis of FAP in patients who present with:
polyposis (>100 adenomas)
attenuated FAP
Predictive testing for FAP in blood relatives of persons with FAP or known APC mutations
Giardiello FM et al. N Engl J Med, 336:823, 1997

16. Clinical Features of HNPCC
Early but variable age at CRC diagnosis (~45 years)
Tumor site in proximal colon predominates
Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumors

17. Failure to meet these criteria does not exclude HNPCC
Amsterdam Criteria
3 or more relatives with verified CRC in family
One case a first-degree relative of the other two
Two or more generations
One CRC by age 50
FAP excluded
Failure to meet these criteria does not exclude HNPCC
Vasen HFA et al. Dis Colon Rect 34:424, 1991

18. Genetic Features of HNPCC
Autosomal dominant inheritance
Penetrance ~80%
Genes belong to DNA mismatch repair (MMR) family
Genetic heterogeneity (MLH1, MSH2, MSH6, PMS1, PMS2)

19. Contribution of Gene Mutations to HNPCC Families
Sporadic
Familial
Unknown ~30%
MSH2 ~30%
HNPCC
Rare CRC syndromes
FAP
MLH1
~30%
MSH6 (rare)
PMS1 (rare)
PMS2 (rare)
Liu B et al. Nat Med 2:169, 1996

20. Cancer Risks in HNPCC 100 % with cancer 80 60 40 20 20 40 60 80
Colorectal 78% 60
Endometrial 43% 40
Stomach 19% 20
Biliary tract 18%
Urinary tract 10%
Ovarian 9% 20 40 60 80
Age (years)
Aarnio M et al. Int J Cancer 64:430, 1995

21. Microsatellite Instability (MSI)
10%–15% of sporadic tumors have MSI
95% of HNPCC tumors have MSI at multiple loci
Routine MSI assays soon available
Normal
MSI tumor
Electrophoresis gel

22. Genetic Testing for HNPCC Susceptibility
Begin genetic testing with
affected family member
Positive result
Negative result
Offer testing to at-risk family members
Continued risk of unidentified familial mutation

23. Features of Familial CRC
Family history of CRC with no clear inheritance pattern
Age at onset typical of sporadic CRC
Multiple causes
Few or no adenomas
Sporadic
Familial CRC
FAP
HNPCC
Rare CRC syndromes

24. Mouse Models of Colon Cancer
Apc (Min)
Smad
DNA mismatch repair
Ras

25. Loss of APC Activation of K-ras Deletion of 18q Loss of TP53 Other
alterations
Normal
epithelium
Hyper-
proliferative
epithelium
Early
adenoma
Inter-
mediate
adenoma
Late
adenoma
Carcinoma
Metastasis
Adapted from Fearon ER. Cell 61:759, 1990

26. Adenomatous polyp Adenomatous polyp
Can take 5-10 years for polyp to develop
Up to 10% of polyps develop into cancer
Size and histology are risk factors for polyp to cancer progression

27. Surrogate Markers for Chemoprevention
Polyp (size/number)
Mouse models, FAP/HNPCC, General population (sporadic)
Biomarkers (mucosa/polyp)
Proliferation
Differentiation
Apoptosis
Gene arrays (functional genomics)
Biomarkers (stool/blood)
Investigational

28. Summary Risk factors for colon cancer Inherited
Acquired (sporadic)-adenomatous polyp, IBD
Genetic basis for colon cancer
Inherited (FAP, HNPCC, to be defined)
Sporadic polyp-different pathways
Preclinical models for colon cancer

29. Summary (continued)
Applications of chemoprevention initially in animal models and inherited forms of colon cancer, and then to general population
Determine efficacy of chemoprevention with surrogate markers