# Presentation: 308205

## Mechanisms and Epidemiology of       Colon Cancer

- Anil K. Rustgi, MD
- University of Pennsylvania

## 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

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

## 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

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

## Slide 6

## 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

## Risk of Colorectal Cancer (CRC)

**0**

**20**

**40**

**60**

**80**

**100**

- General population

- Personal history of colorectal neoplasia

- Inflammatory bowel disease

- HNPCC mutation

- FAP

- 5%

- 15%–20%

- 15%–40%

- 70%–80%

- >95%

- Lifetime risk (%)

## Familial Risk for Colorectal Cancer

- Approximate
- lifetime
- CRC risk
- (%)

- Affected family members

- None

- One 1°

- One 1° and two 2°

- One 1° age <45

- Two 1°

- HNPCC mutation

- 2%

- 6%

- 8%

- 10%

- 17%

- 70%

- 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

## Causes of Hereditary Susceptibility to CRC

- Causes of Hereditary Susceptibility to CRC

- Adapted from Burt RW et al. *Prevention and Early Detection of CRC*, 1996

- Sporadic (65%–85%)

- Familial (10%–30%)

- Hereditary nonpolyposis colorectal cancer (HNPCC) (5%)

- Familial adenomatous polyposis (FAP) (1%)

- Rare CRC syndromes (<0.1%)

## 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

## 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

## The APC Tumor Suppressor Gene

- 3'

- 5'

- Codon 1309

## 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

## 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

## 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

## 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

- Vasen HFA et al.  *Dis Colon Rect* 34:424, 1991

- Failure to meet these criteria does *not* exclude HNPCC

## Genetic Features of HNPCC

- Autosomal dominant inheritance
- Penetrance ~80%
- Genes belong to DNA mismatch repair (MMR) family
- Genetic heterogeneity (*MLH1, MSH2, MSH6, PMS1, PMS2*)

## Contribution of Gene Mutations to HNPCC Families

- Contribution of Gene Mutations to HNPCC Families

*MSH2 *~30%

*MLH1*
- ~30%

*PMS1 *(rare)

*PMS2* (rare)

*MSH6 *(rare)

- Unknown ~30%

- Sporadic

- Familial

- HNPCC

- FAP

- Rare CRC syndromes

- Liu B et al. *Nat Med* 2:169, 1996

## Cancer Risks in HNPCC

- Aarnio M et al. *Int J Cancer* 64:430, 1995

- % with cancer

- 100

- 80

- 60

- 40

- 20

- 0

- 20

- 40

- 60

- 80

- 0

- Age (years)

- Colorectal 78%

- Endometrial 43%

- Stomach 19%

- Biliary tract 18%

- Urinary tract 10%

- Ovarian 9%

** **

## Microsatellite Instability (MSI)

- 10%–15% of sporadic tumors have MSI
- 95% of HNPCC tumors have MSI at multiple loci
- Routine MSI assays soon available

- Electrophoresis gel

- Normal

- MSI tumor

## Genetic Testing for HNPCC Susceptibility

- Genetic Testing for HNPCC Susceptibility

- Begin genetic testing with
- affected family member

- Negative result

- Continued risk of unidentified familial mutation

- Offer testing to at-risk family members

- Positive result

## 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

- Rare CRC syndromes

- HNPCC

## Mouse Models of Colon Cancer

-   Apc (Min)
-   Smad
-   DNA mismatch repair
-   Ras

**Normal **
**epithelium**

**Hyper-**
**proliferative**
**epithelium**

**Early**
**adenoma**

**Inter-**
**mediate**
**adenoma**

**Late**
**adenoma**

**Carcinoma**

**Metastasis**

- Loss of
*APC*

- Activation
- of *K-ras*

- Deletion of 18q

- Loss of
*TP53*

- Other
- alterations

- Adapted from Fearon ER. *Cell* 61:759, 1990

## 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

## 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

## 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

## 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