Mechanisms and Epidemiology of Colon Cancer Anil K. Rustgi, MD University of Pennsylvania.
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Mechanisms and Epidemiology of Colon Cancer
Anil K. Rustgi, MD
University of Pennsylvania
Worldwide Statistics for Colorectal Worldwide Statistics for Colorectal Cancer (CRC)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 Estimated New Cancer Cases of 10 Leading Sites by Gender for the US 2000Leading Sites by Gender for the US 2000
Colorectal Cancer Statistics in the USColorectal Cancer Statistics in the US
• Second overall leading cause of cancer-related Second overall leading cause of cancer-related deaths in the USdeaths in the US
• Estimated 130,000 new cases and 56,300 deaths Estimated 130,000 new cases and 56,300 deaths in the year 2000in the year 2000
• Declining trends between 1990 and 1996Declining trends between 1990 and 1996 Incidence reate: ~2.1% per yearIncidence reate: ~2.1% per year Mortality rates: ~1.7% per yearMortality rates: ~1.7% per year
Average Annual Age-Specific US Incidence Average Annual Age-Specific US Incidence and Mortality Rates of CRC, 1992-1996and Mortality Rates of CRC, 1992-1996
Risk Factors for Colorectal Cancer (CRC)Risk Factors for Colorectal Cancer (CRC)
AgingAging Personal history of CRC or adenomasPersonal history of CRC or adenomas High-fat, low-fiber dietHigh-fat, low-fiber diet Inflammatory bowel diseaseInflammatory bowel disease Family history of CRCFamily history of CRC Hereditary colon cancer syndromesHereditary colon cancer syndromes
Risk of Colorectal Cancer (CRC)Risk of Colorectal Cancer (CRC)
0 20 40 60 80 100
General populationGeneral population
Personal history of Personal history of colorectal neoplasiacolorectal neoplasia
Inflammatory Inflammatory bowel diseasebowel disease
HNPCC mutationHNPCC mutation
FAPFAP
5%5%
15%–20%15%–20%
15%–40%15%–40%
70%–80%70%–80%
>95%>95%
Lifetime risk (%)Lifetime risk (%)
Familial Risk for Colorectal CancerFamilial Risk for Colorectal Cancer
ApproximateApproximatelifetime lifetime
CRC risk CRC risk (%)(%)
Affected family membersAffected family members
0
20
40
60
80
100
NoneNone One 1°One 1° One 1° and One 1° and two 2°two 2°
One 1° One 1° age <45age <45
Two 1°Two 1° HNPCC HNPCC mutationmutation
2%2% 6%6% 8%8% 10%10%17%17%
70%70%
Aarnio M et al. Aarnio M et al. Int J CancerInt J Cancer 64:430, 1995 64:430, 1995 Houlston RS et al. Houlston RS et al. Br Med JBr Med J 301:366, 1990 301:366, 1990 St John DJ et al. St John DJ et al. Ann Intern Med Ann Intern Med 118:785, 1993 118:785, 1993
Causes of Hereditary Causes of Hereditary Susceptibility to CRCSusceptibility to CRC
Adapted from Burt RW et al. Adapted from Burt RW et al. Prevention and Early Detection of CRCPrevention and Early Detection of CRC, 1996, 1996
Sporadic Sporadic (65(65%–%–85%)85%)
Familial Familial (10(10%–%–30%)30%)
Hereditary nonpolyposis Hereditary nonpolyposis colorectal cancer colorectal cancer (HNPCC) (5%)(HNPCC) (5%)Familial adenomatous Familial adenomatous
polyposis (FAP) (1%)polyposis (FAP) (1%)
Rare CRC Rare CRC syndromes syndromes
(<0.1%)(<0.1%)
Clinical Features of FAPClinical Features of FAP
Estimated penetrance for Estimated penetrance for adenomas >90%adenomas >90%
Risk of extracolonic tumors Risk of extracolonic tumors (upper GI, desmoid, (upper GI, desmoid, osteoma, thyroid, brain, osteoma, thyroid, brain, other)other)
CHRPE may be present CHRPE may be present
Untreated polyposis leads Untreated polyposis leads to 100% risk of cancer to 100% risk of cancer
Genetics of FAPGenetics of FAP Autosomal dominant inheritance Autosomal dominant inheritance
Caused by mutations in Caused by mutations in APCAPC tumor suppressor gene on tumor suppressor gene on chromosome 5q chromosome 5q
Up to 30% of patients have Up to 30% of patients have de novo de novo germline mutationsgermline mutations
Most families have unique mutationsMost families have unique mutations
Most mutations are protein truncating Most mutations are protein truncating
Genotype/phenotype relationships emergingGenotype/phenotype relationships emerging
The The APCAPC Tumor Suppressor Gene Tumor Suppressor Gene
3'3'5'5'
Codon 1309Codon 1309
1 2 3 4 5 6 7 8 9 10111213 14 15
Attenuated FAPAttenuated FAP
Later onset (CRC ~age 50)Later onset (CRC ~age 50) Few colonic adenomasFew colonic adenomas Not associated with CHRPENot associated with CHRPE UGI lesions UGI lesions Associated with mutations at Associated with mutations at
55'' and 3 and 3'' ends of ends of APCAPC gene gene
Indications for Indications for APCAPC Gene Testing Gene Testing
Molecular diagnosis of FAP in patients who Molecular diagnosis of FAP in patients who present with:present with: polyposis (>100 adenomas)polyposis (>100 adenomas) attenuated FAPattenuated FAP
Predictive testing for FAP in blood relatives of Predictive testing for FAP in blood relatives of persons with FAP or known persons with FAP or known APCAPC mutations mutations
Giardiello FM et al.Giardiello FM et al. N Engl J Med N Engl J Med, 336:823, 1997, 336:823, 1997
Clinical Features of HNPCCClinical Features of HNPCC Early but variable age at Early but variable age at
CRC diagnosis (~45 years)CRC diagnosis (~45 years) Tumor site in proximal colon Tumor site in proximal colon
predominatespredominates Extracolonic cancers: Extracolonic cancers:
endometrium, ovary, endometrium, ovary, stomach, urinary tract, small stomach, urinary tract, small bowel, bile ducts, sebaceous bowel, bile ducts, sebaceous skin tumorsskin tumors
Amsterdam CriteriaAmsterdam Criteria 3 or more relatives with verified CRC in family3 or more relatives with verified CRC in family One case a first-One case a first-degree relative of the other two relative of the other two Two or more generationsTwo or more generations One CRC by age 50One CRC by age 50 FAP excludedFAP excluded
Vasen HFA et al. Vasen HFA et al. Dis Colon RectDis Colon Rect 34:424, 1991 34:424, 1991
Failure to meet these criteria Failure to meet these criteria does does notnot exclude HNPCC exclude HNPCC
Genetic Features of HNPCCGenetic Features of HNPCC
Autosomal dominant inheritanceAutosomal dominant inheritance Penetrance ~80%Penetrance ~80% Genes belong to DNA mismatch repair (MMR) Genes belong to DNA mismatch repair (MMR)
family family Genetic heterogeneity (Genetic heterogeneity (MLH1, MSH2, MSH6, MLH1, MSH2, MSH6,
PMS1, PMS2PMS1, PMS2))
Contribution of Gene Mutations Contribution of Gene Mutations to HNPCC Familiesto HNPCC Families
MSH2 MSH2 ~30%~30%
MLH1MLH1~30%~30%
PMS1 PMS1 (rare)(rare)
PMS2PMS2 (rare) (rare)
MSH6 MSH6 (rare)(rare)
Unknown ~30%Unknown ~30%
SporadicSporadic FamilialFamilial
HNPCCHNPCC
FAPFAP
Rare CRC Rare CRC syndromessyndromes
Liu B et al. Liu B et al. Nat MedNat Med 2:169, 1996 2:169, 1996
Cancer Risks in HNPCCCancer Risks in HNPCC
Aarnio M et al. Aarnio M et al. Int J CancerInt J Cancer 64:430, 1995 64:430, 1995
% with % with cancercancer
100100
8080
6060
4040
2020
002020 4040 6060 808000
Age (years)Age (years)
Colorectal Colorectal 78%78%
Endometrial Endometrial 43% 43%
Stomach Stomach 19%19%Biliary tract Biliary tract 18%18%Urinary tract Urinary tract 10%10%Ovarian Ovarian 9%9%
Microsatellite Instability (MSI)Microsatellite Instability (MSI) 10%–15% of sporadic tumors have MSI10%–15% of sporadic tumors have MSI 95% of HNPCC tumors have MSI at multiple loci95% of HNPCC tumors have MSI at multiple loci Routine MSI assays soon availableRoutine MSI assays soon available
Electrophoresis gelElectrophoresis gel
NormalNormal MSI tumorMSI tumor
Genetic Testing for Genetic Testing for HNPCC SusceptibilityHNPCC Susceptibility
Begin genetic testing with Begin genetic testing with affected family memberaffected family member
Negative Negative resultresult
Continued risk of Continued risk of unidentified familial unidentified familial
mutationmutation
Offer testing to Offer testing to at-risk family at-risk family
membersmembers
Positive Positive resultresult
Features of Familial CRCFeatures of Familial CRC Family history of CRC with Family history of CRC with
no clear inheritance pattern no clear inheritance pattern Age at onset typical of Age at onset typical of
sporadic CRCsporadic CRC Multiple causesMultiple causes Few or no adenomas Few or no adenomas
SporadicSporadic
Familial CRCFamilial CRCFAPFAP
Rare CRC Rare CRC syndromessyndromes
HNPCCHNPCC
Mouse Models of Colon Cancer
Apc (Min)
Smad
DNA mismatch repair
Ras
Normal Normal epitheliumepithelium
Hyper-Hyper-proliferativeproliferativeepitheliumepithelium
EarlyEarlyadenomaadenoma
Inter-Inter-mediatemediate
adenomaadenoma
LateLateadenomaadenoma CarcinomaCarcinoma MetastasisMetastasis
Loss ofLoss ofAPCAPC
ActivationActivationof of K-rasK-ras
Deletion Deletion of 18qof 18q
Loss ofLoss ofTP53TP53
Other Other alterationsalterations
Adapted from Fearon ER. Adapted from Fearon ER. CellCell 61:759, 1990 61:759, 1990
Adenomatous polypAdenomatous 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
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
SummarySummary
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)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
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