Familial Risk for Colorectal Cancer

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

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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

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Average Annual Age-Specific US Incidence and
Mortality Rates of CRC, 1992-1996
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(No Transcript)
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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

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Risk of Colorectal Cancer (CRC)
5
General population
Personal history of colorectal neoplasia
1520
Inflammatory bowel disease
1540
7080
HNPCC mutation
95
FAP
0
20
40
60
80
100
Lifetime risk ()
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Familial Risk for Colorectal Cancer
70
Approximate lifetime CRC risk ()
17
10
8
6
2
One 1 and two 2
One 1 age HNPCC mutation
None
One 1
Two 1
Aarnio M et al. Int J Cancer 64430, 1995
Houlston RS et al. Br Med J 301366, 1990 St
John DJ et al. Ann Intern Med 118785, 1993
Affected family members
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Causes of Hereditary Susceptibility to CRC
Sporadic (6585)
Familial (1030)
Rare CRC syndromes (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

• 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

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The APC Tumor Suppressor Gene
Codon 1309
5'
3'
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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

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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, 336823, 1997
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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

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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 34424, 1991
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Genetic Features of HNPCC

• 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 to HNPCC Families
Sporadic
Familial
MSH2 30
Unknown 30
HNPCC
Rare CRC syndromes
FAP
MLH1 30
PMS1 (rare)
MSH6 (rare)
PMS2 (rare)
Liu B et al. Nat Med 2169, 1996
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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
20
40
60
80
0
Age (years)
Aarnio M et al. Int J Cancer 64430, 1995

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Microsatellite Instability (MSI)

• 1015 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 HNPCC Susceptibility
Begin genetic testing with affected family member
Negative result
Positive result
Continued risk of unidentified familial mutation
Offer testing to at-risk family members
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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
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Mouse Models of Colon Cancer

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

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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 61759, 1990
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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

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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

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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

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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