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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

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slide1

Mechanisms and Epidemiology of Colon Cancer

Anil K. Rustgi, MD

University of Pennsylvania

worldwide statistics for colorectal cancer crc
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
colorectal cancer statistics in the us
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
risk factors for colorectal cancer crc
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
Risk of Colorectal Cancer (CRC)

5%

General population

Personal history of colorectal neoplasia

15%–20%

Inflammatory bowel disease

15%–40%

70%–80%

HNPCC mutation

>95%

FAP

0

20

40

60

80

100

Lifetime risk (%)

familial risk for colorectal cancer
Familial Risk for Colorectal Cancer

70%

Approximate

lifetime

CRC risk

(%)

17%

10%

8%

6%

2%

One 1° and two 2°

One 1° age <45

HNPCC mutation

None

One 1°

Two 1°

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

causes of hereditary susceptibility to crc
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

clinical features of fap
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
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

15

3

7

14

1

2

4

5

6

8

9

10

12

13

11

The APC Tumor Suppressor Gene

Codon 1309

5'

3'

attenuated fap
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
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

Clinical Features of HNPCC
amsterdam criteria
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

genetic features of 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

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

cancer risks in hnpcc
Cancer Risks in HNPCC

100

80

% with cancer

Colorectal 78%

60

Endometrial 43%

40

Stomach 19%

20

Biliary tract 18%

Urinary tract 10%

Ovarian 9%

0

0

20

40

60

80

Age (years)

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

microsatellite instability msi
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

genetic testing for hnpcc susceptibility
Genetic Testing for HNPCC Susceptibility

Begin genetic testing with

affected family member

Positive result

Negative result

Continued risk of unidentified familial mutation

Offer testing to at-risk family members

features of familial crc
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

slide24

Mouse Models of Colon Cancer

  • Apc (Min)
  • Smad
  • DNA mismatch repair
  • Ras
slide25

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

adenomatous polyp
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
slide27

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
slide28

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
slide29

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