Mechanisms and Epidemiology of       Colon Cancer
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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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Mechanisms and Epidemiology of Colon Cancer

Anil K. Rustgi, MD

University of Pennsylvania


Worldwide statistics for colorectal cancer crc l.jpg
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



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Colorectal Cancer Statistics in the US the US 2000

  • 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 l.jpg
Risk Factors for Colorectal Cancer (CRC) of CRC, 1992-1996

  • Aging

  • Personal history of CRC or adenomas

  • High-fat, low-fiber diet

  • Inflammatory bowel disease

  • Family history of CRC

  • Hereditary colon cancer syndromes


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Risk of Colorectal Cancer (CRC) of CRC, 1992-1996

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 (%)


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Familial Risk for Colorectal Cancer of CRC, 1992-1996

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


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Causes of Hereditary of CRC, 1992-1996Susceptibility 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


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Clinical Features of FAP of CRC, 1992-1996

  • 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


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Genetics of FAP of CRC, 1992-1996

  • 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 l.jpg

15 of CRC, 1992-1996

3

7

14

1

2

4

5

6

8

9

10

12

13

11

The APC Tumor Suppressor Gene

Codon 1309

5'

3'


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Attenuated FAP of CRC, 1992-1996

  • 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


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Indications for of CRC, 1992-1996APC 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


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Early but variable age at CRC diagnosis (~45 years) of CRC, 1992-1996

Tumor site in proximal colon predominates

Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumors

Clinical Features of HNPCC


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Amsterdam Criteria of CRC, 1992-1996

  • 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


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Genetic Features of HNPCC of CRC, 1992-1996

  • Autosomal dominant inheritance

  • Penetrance ~80%

  • Genes belong to DNA mismatch repair (MMR) family

  • Genetic heterogeneity (MLH1, MSH2, MSH6, PMS1, PMS2)


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Contribution of Gene Mutations of CRC, 1992-1996to 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


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Cancer Risks in HNPCC of CRC, 1992-1996

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


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Microsatellite Instability (MSI) of CRC, 1992-1996

  • 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


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Genetic Testing for of CRC, 1992-1996HNPCC 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


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Features of Familial CRC of CRC, 1992-1996

  • 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


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Mouse Models of Colon Cancer of CRC, 1992-1996

  • Apc (Min)

  • Smad

  • DNA mismatch repair

  • Ras


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Loss of of CRC, 1992-1996

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


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Adenomatous polyp of CRC, 1992-1996

  • 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


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Surrogate Markers for Chemoprevention of CRC, 1992-1996

  • Polyp (size/number)

  • Mouse models, FAP/HNPCC, General population (sporadic)

  • Biomarkers (mucosa/polyp)

  • Proliferation

  • Differentiation

  • Apoptosis

  • Gene arrays (functional genomics)

  • Biomarkers (stool/blood)

  • Investigational


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Summary of CRC, 1992-1996

  • 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


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Summary (continued) of CRC, 1992-1996

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


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