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