Sporadic vs. ColitisSporadic vs. Colitis--Associated Colon Associated Colon Cancer: Vive la difference!Cancer: Vive la difference!

Steven H. Itzkowitz, M.D.Steven H. Itzkowitz, M.D.The Dr. The Dr. BurrillBurrill B. B. CrohnCrohn Professor of MedicineProfessor of Medicine

Mount Sinai School of MedicineMount Sinai School of MedicineNew York City, N.Y.New York City, N.Y.

ConclusionConclusionThere There mustmust be a difference between SCC and be a difference between SCC and CAC. CAC. Otherwise, many of us would not get research Otherwise, many of us would not get research funding!funding!

Risk of Developing Colorectal CancerRisk of Developing Colorectal Cancer

0 20 40 60 80 100

General General poppop’’nn

Personal Personal hxhx of of adenoma/CRCadenoma/CRC

IBDIBD

HNPCCHNPCC

FAPFAP

5%5%

15%15%––20%20%

15%15%––40%40%

70%70%––80%80%

>95%>95%

Lifetime risk (%)Lifetime risk (%) ASCO

DysplasiaDysplasia--Carcinoma SequenceCarcinoma Sequence

AdenomaAdenomaNormalNormal

DysplasiaDysplasiaColitisColitis

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are needed to see this picture.

CancerCancer

CancerCancer

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are needed to see this picture.

ClinicopathologicalClinicopathological Features of CRCFeatures of CRCSporadicSporadic IBDIBD HNPCCHNPCC

DysplasiaDysplasia:: polyppolyp flat/polypflat/polyp polyppolypAge @ cancer:Age @ cancer: 6060’’ss 3030’’ss 3030’’ssMultiple cancers:Multiple cancers: 22--3%3% 1010--15%15% 1010--15%15%CRC location:CRC location: distaldistal proxprox>distal>distal proxprox>distal>distalHistologicHistologic typetype

mucinousmucinous:: rarerare commoncommon commoncommonpoorly poorly diffdiff’’dd:: rarerare commoncommon commoncommonlowlow--grade TGAgrade TGA very rarevery rare 11%11% ??

Surveillance intervalSurveillance interval 55--10 yr10 yr 11--2 yr2 yr 11--3 yr3 yrGenetic Genetic v.v. Environ:Environ: EnvEnv>Gen.>Gen. EnvEnv>Gen>Gen Gen>Gen>EnvEnv..

LowLow--Grade Grade TubuloTubulo--Glandular Glandular Adenocarcinoma Adenocarcinoma (LGTGA)(LGTGA)

•• Arises directly from LGD.Arises directly from LGD.•• Accounts for 11% of IBDAccounts for 11% of IBD--associated CRC.associated CRC.•• WellWell--differentiated differentiated adenocarcinomaadenocarcinoma with with

distinct histological features:distinct histological features:–– rounded, oval or tubular glandsrounded, oval or tubular glands––minimal minimal desmoplasticdesmoplastic reactionreaction––minimal minimal intraluminalintraluminal necrosisnecrosis–– lowlow--grade nuclear cytologygrade nuclear cytology

Levi and Levi and HarpazHarpaz, , Am J Am J Surg PatholSurg Pathol 2006, in press2006, in press

Does Inflammation Cause CRC in IBD?Does Inflammation Cause CRC in IBD?Evidence Evidence ““ForFor””

CRC risk is increased with:CRC risk is increased with:•• longer duration of colitis (>7 yrs)longer duration of colitis (>7 yrs)•• greater extent of colitis greater extent of colitis

•• pancolitispancolitis > left> left--sided > sided > proctitisproctitis•• primary primary sclerosingsclerosing cholangitischolangitis•• active inflammation (active inflammation (histologichistologic, , endoscopicendoscopic))

CRC risk is decreased with:CRC risk is decreased with:•• antianti--inflammatory drugs inflammatory drugs

•• 55--ASAASA•• steroids (oral or topical)steroids (oral or topical)

Velayos et al. Am J Gastro 100:1345, 2005

Cancer:

O.R. = 0.51 (0.37-0.69)

Dysplasia:

O.R. = 1.18 (0.41-3.43)

CRC or Dysplasia:

O.R. = 0.51 (0.38-0.69)

6MP is 6MP is NotNot ChemopreventiveChemopreventive in UCin UCProportional Hazards AnalysisProportional Hazards Analysis

1.951.95(0.82(0.82--4.60)4.60)

1.211.21(0.70(0.70--1.02)1.02)

AvgAvg Daily Daily DoseDose

1.491.49(0.52(0.52--4.32)4.32)

1.001.00(0.54(0.54--1.87)1.87)

>>25mg/d25mg/d

1.301.30(0.45(0.45--3.75)3.75)

1.061.06(0.59(0.59--1.93)1.93)

Any ExposureAny Exposure

6MP Exposure6MP Exposure

Advanced Advanced NeoplasiaNeoplasia

HRHR (CI)(CI)

Any Any NeoplasiaNeoplasia

HR (CI)HR (CI)

Matula et al. Clin Gastro Hepatol 3:1015, 2005

Does Inflammation Cause CRC in IBD?Does Inflammation Cause CRC in IBD?Evidence Evidence ““AgainstAgainst””

Why donWhy don’’t patients with t patients with proctitisproctitis have an increased risk of have an increased risk of rectal cancer?rectal cancer?

Why does it take 7Why does it take 7--8 years of colitis before 8 years of colitis before neoplasianeoplasiaoccurs?occurs?

Why do patients with Why do patients with quiescentquiescent inflammation also have a inflammation also have a high risk of CRC?high risk of CRC?

Why do 6Why do 6--MP and MP and AzathioprineAzathioprine appear to have no appear to have no chemopreventivechemopreventive role? role?

Why donWhy don’’t all studies indicate that t all studies indicate that mesalaminemesalamine use use prevents CRC?prevents CRC?

CarcinomaCarcinomaEarlyEarlyadenomaadenoma

IntermediateIntermediateadenomaadenoma

LateLateadenomaadenoma

APCNormalNormalmucosamucosa

PATHWAYS OF COLON CARCINOGENESISPATHWAYS OF COLON CARCINOGENESISChromosomal Instability (e.g. FAP)Chromosomal Instability (e.g. FAP)••AneuploidyAneuploidy••LOHLOH••Tumor suppressor gene mutationsTumor suppressor gene mutations

Microsatellite Instability (e.g. HNPCC)Microsatellite Instability (e.g. HNPCC)••HypermethylationHypermethylation/mutation of DNA MMR genes/mutation of DNA MMR genes••Target gene alterations (Target gene alterations (TGFTGFββRIIRII; BAX; others); BAX; others)

KK--rasras DCC/18q genesDCC/18q genes p53p537070--85%85%

15%15%

CpGCpG Island Island MethylationMethylation (CIMP)(CIMP)••Suppression of gene expression by promoter Suppression of gene expression by promoter hypermethylationhypermethylation••Target genes: hMLH1, MGMT, othersTarget genes: hMLH1, MGMT, others

2525--30%30%

Ahnen 2000

Although the biology of UC-associated dysplasia (p53 lesions early, APC late)and sporadic adenomas differ, the biology of UC-associated cancer and sporadic cancer are remarkably similar

IndefiniteIndefinitedysplasiadysplasia

LowLow--gradegradedysplasiadysplasia

HighHigh--gradegradedysplasiadysplasia

CarcinomaCarcinoma

Colitis; noColitis; nodysplasiadysplasia

EarlyEarlyadenomaadenoma

IntermediateIntermediateadenomaadenoma

LateLateadenomaadenoma

CarcinomaCarcinoma

AneuploidyAneuploidy/CIN/CINMSIMSI

MethylationMethylationCOXCOX--22 p53 LOH kk--rasras

AneuploidyAneuploidyMethylationMethylation

APC

MSIMSIkk--rasrasCOXCOX--22

p53

NormalNormalmucosamucosa

SPORADIC COLON CANCERSPORADIC COLON CANCER

COLITISCOLITIS--ASSOCIATED COLON CANCERASSOCIATED COLON CANCER

APCp53 mut.

DCC/DPC4DCC/DPC4

DCC/DPC4DCC/DPC4

Itzkowitz and Yio, Am J Physiol. 287:G7-17, 2004

p53p53 p53p53DiagnosisDiagnosis No.No. MutatedMutated** AneuploidAneuploid LOHLOHCancerCancer 66 83%83% 83%83% 83%83%DysplasiaDysplasia 5656 48%48% 46%46% 44%44%IndefiniteIndefinite 9696 3%3% 15%15% 00NegativeNegative 5757 29%29% 5%5% 00------------------------------------------------------------------------------------------------------------------------------------------------------*based on *based on colectomycolectomy material from 2 patients with mutations of material from 2 patients with mutations of p53 p53

codoncodon 248 (248 (exonexon 7); PCR 7); PCR -->>Msp1Msp1 endonucleaseendonuclease digestdigest

p53p53 Mutations Correlate with Mutations Correlate with DysplasiaDysplasia

BrentnallBrentnall et al. et al. GastroenterologyGastroenterology 107:369, 1994.107:369, 1994.

p53p53 mutation mutation --> > aneuploidyaneuploidy --> > p53p53 LOHLOH

DiagnosisDiagnosis PatientsPatients APC APC mutationmutationUC CAUC CA 3333 2 (6%)2 (6%)Sporadic CASporadic CA 2323 17 (74%)17 (74%)

APCAPC Mutations in UCMutations in UC

TarminTarmin et al. et al. Cancer Cancer ResRes 55:2035, 199555:2035, 1995

APCAPC mutations are mutations are uncommonuncommon and late in UC and late in UC neoplasmsneoplasms

DiagnosisDiagnosis RedstonRedston MeltzerMeltzer BurmerBurmer ChenChen BellBellCancerCancer 3/7 (43%)3/7 (43%) 1/4 (25%)1/4 (25%) 1/12 (8%)1/12 (8%) 3/5 (60%)3/5 (60%) 8/33 (24%)8/33 (24%)HGDHGD 4/8 (50%)4/8 (50%) 2/6 (33%)2/6 (33%) 0/120/12 1/3 (33%)1/3 (33%) ----LGDLGD 1/7 (14%)1/7 (14%) 0/6 0/6 0/10/1 ---- ----IndefiniteIndefinite 5/14 (36%)5/14 (36%) 0/5 0/5 0/30/3 0/80/8 ----NegativeNegative 0/17 0/17 ---- ---- 0/20/2 ----

KK--RasRas Mutations in UCMutations in UC

RedstonRedston et al. et al. GastroenterologyGastroenterology 108:383, 1995108:383, 1995Meltzer et al. Meltzer et al. Cancer ResCancer Res. 50:3627, 1990. 50:3627, 1990BurmerBurmer et al. et al. GastroenterologyGastroenterology 99:416, 199099:416, 1990Chen et al. Chen et al. GastroenterologyGastroenterology 102:1983, 1992102:1983, 1992Bell et al. Bell et al. Br J CancerBr J Cancer 64:174, 199164:174, 1991

KK--rasras mutations occurmutations occur late in UC late in UC neoplasmsneoplasms

Loci: D2S119,D2S123,D2S136,D3S1067, D5S346, D6S87, Loci: D2S119,D2S123,D2S136,D3S1067, D5S346, D6S87, D8S255, D13S175, D17S87, D17S261 D18S34, D18S35D8S255, D13S175, D17S87, D17S261 D18S34, D18S35

DiagnosisDiagnosis MSI MSI >>1 locus1 locus MSI MSI >>2 loci2 lociLong Term UC:Long Term UC: (mean 20 yrs)(mean 20 yrs)

Negative Negative dyspldyspl.. 6/10 (60%)6/10 (60%) 5/10 (50%)5/10 (50%)HGDHGD 11/13 (85%)11/13 (85%) 6/13 (46%)6/13 (46%)CancerCancer 2/5 (40%)2/5 (40%) 2/5 (40%)2/5 (40%)Short Term UC:Short Term UC: (mean 2.2 yrs)(mean 2.2 yrs)

Negative Negative dyspldyspl.. 5/6 (83%)5/6 (83%) 2/6 (33%)2/6 (33%)Ischemic colitis:Ischemic colitis: 0/90/9 0/90/9

MSI in NonMSI in Non--NeoplasticNeoplastic UC MucosaUC Mucosa

Brentnall et al. Cancer Res 56:1237. 1996.

MSI is an early event in UC carcinogenesis

Tissue Status*Tissue Status* p16p16 methylationmethylationNo No dysplasiadysplasia 7/21 (33%)7/21 (33%)DysplasiaDysplasia/cancer/cancer 18/24 (75%)18/24 (75%)

*tissue taken from 3 *tissue taken from 3 colectomycolectomy specimensspecimens

p16p16INK4aINK4a Promoter Promoter MethylationMethylationin UC in UC NeoplasiaNeoplasia

Hsieh et al. Hsieh et al. Cancer Res.Cancer Res. 58:3942, 199858:3942, 1998

Methylation is an early event in UC carcinogenesis

Tissue Status*Tissue Status* hMLH1 hMLH1 methylationmethylationMSIMSI--HH 6/13 (46%)6/13 (46%)MSIMSI--LL 1/16 (6%)1/16 (6%)MSSMSS 4/27 (15%)4/27 (15%)*only *only dysplasiadysplasia or cancer tissues usedor cancer tissues used

hMLH1hMLH1 MethylationMethylation in UC in UC NeoplasiaNeoplasia

Fleisher et al. Fleisher et al. Cancer Res.Cancer Res. 60:4864, 200060:4864, 2000

Methylation occurs in MSI-H tumors, but also MSS

DiagnosisDiagnosis (Age(Age)) ERER MYODMYOD p16p16 CSPG2CSPG2(% gene (% gene methylationmethylation))

Controls Controls (53.4)(53.4) 7.47.4 3.03.0 2.42.4 30.630.6UCUC--ND ND (42.0)(42.0) 3.03.0 3.03.0 3.33.3 12.312.3UCUC--HGD/CAHGD/CA

NEG NEG (53.2)(53.2) 20.120.1 18.418.4 7.97.9 35.235.2IND IND (40.0)(40.0) 20.020.0 27.727.7 13.013.0 28.828.8HGD/CA HGD/CA (54.0)(54.0) 40.040.0 44.044.0 9.49.4 57.557.5

AgeAge--Related Gene Related Gene MethylationMethylation in UCin UC

IssaIssa et al. et al. Cancer Res.Cancer Res. 61:3573, 200161:3573, 2001

Age-related methylation is enhanced in UC neoplasia

Normal epithelium

Inflamed epithelium (colitis)Inflammatory cells

Environmental trigger• Bacterial/viral infection• NSAIDs• Other toxins

Oxidative stress• Reactive oxygen species (ROS)• NO; H2O2; others

Damaged epithelium

Dysplasia

CancerAdditional genetic changes

Increased epithelial cell turnover• proliferation• apoptosis

Genetic/epigenetic changes:• p53 mutation/activation• damage/mutation of DNA MMR system• methylation of regulatory genes• telomere shortening

Itzkowitz and Yio, Am J Physiol. 287:G7-17, 2004

•• 50% of 50% of bxbx’’eses from inflamed UC tissues exhibited:from inflamed UC tissues exhibited:•• GG--toto--A transition at A transition at codoncodon 248 (C248 (CGGGG-->C>CAAG)G)•• CC--toto--T transition at T transition at codoncodon 247 (AA247 (AACC-->AA>AATT))

•• Only found in UC tissues, not normal controlsOnly found in UC tissues, not normal controls•• In UC tissues, only in In UC tissues, only in ““lesionallesional”” biopsiesbiopsies•• Correlated with NOS2 activity Correlated with NOS2 activity

Chronic inflammation can induce p53 mutationsChronic inflammation can induce p53 mutations

p53 Mutations in Nonp53 Mutations in Non--NeoplasticNeoplastic UC UC TissuesTissues

HussainHussain et al. et al. Cancer Res.Cancer Res. 60:333360:3333--7, 20007, 2000

MSH6MSH6

basebase--basebasemismatchmismatch

DNA Mismatch RepairDNA Mismatch Repair

1 base 1 base insertion/deletioninsertion/deletionlooploop

22--8 base 8 base insertion/deletion insertion/deletion looploop

MSH2MSH2MSH3MSH3

MSH2MSH2

MLH1MLH1 PMS2PMS2 MLH1MLH1 PMS2PMS2

MLH1MLH1 MLH3MLH3

MLH1MLH1 PMS1PMS1

MSH6MSH6

basebase--basebasemismatchmismatch

DNA Mismatch RepairDNA Mismatch Repair

1 base 1 base insertion/deletioninsertion/deletionlooploop

22--8 base 8 base insertion/deletion insertion/deletion looploop

MSH2MSH2MSH3MSH3

MSH2MSH2

MLH1MLH1 PMS2PMS2 MLH1MLH1 PMS2PMS2

MLH1MLH1 MLH3MLH3

MLH1MLH1 PMS1PMS1HH22OO22

HH22OO22

Inflammation Predisposes to Colon Cancer:Inflammation Predisposes to Colon Cancer:In VivoIn Vivo Evidence from Animal ModelsEvidence from Animal Models

Three main approaches:Three main approaches:1. 1. Normal miceNormal mice: :

Induce colitis with noxious agent and monitor for Induce colitis with noxious agent and monitor for development of development of neoplasianeoplasia..

2. 2. Cancer prone mice:Cancer prone mice:–– Induce colitis and monitor for higher rates of Induce colitis and monitor for higher rates of neoplasianeoplasia

--oror--–– Reduce colitis and monitor for lower rates of Reduce colitis and monitor for lower rates of neoplasianeoplasia

3. 3. IBDIBD--prone miceprone mice::Determine whether IBDDetermine whether IBD--prone mice develop prone mice develop neoplasianeoplasia

Itzkowitz and Yio, Am J Physiol. 287:G7-17, 2004

InflammationInflammation---->Cancer>CancerNormal MiceNormal Mice::

•• DysplasiaDysplasia and cancer can be induced after repeated cycles and cancer can be induced after repeated cycles of of dextrandextran sulfate sodium (DSS)sulfate sodium (DSS)

•• Longer disease duration Longer disease duration ----> increased rate of > increased rate of neoplasianeoplasia, , even in the setting clinical remissioneven in the setting clinical remission

•• NeoplasiaNeoplasia associated with more severe degrees of associated with more severe degrees of inflammation, especially in the distal colon.inflammation, especially in the distal colon.

•• Treatment with antioxidant (NTreatment with antioxidant (N--acetylcysteineacetylcysteine) reduced both ) reduced both inflammation and tumor incidenceinflammation and tumor incidence

Cooper et al. Carcinogenesis 21:757, 2000Seril et al. Carcinogenesis 23:993, 2002

CancerCancer--Prone Mice:Prone Mice:⇑⇑ inflammation inflammation ⇒⇒ ⇑⇑ tumors:tumors:

•• APCAPCminmin/+/+ intestinal adenomasintestinal adenomas

•• APCAPCminmin/+/+ + DSS+ DSS intestinal adenomas & cancersintestinal adenomas & cancers

•• MSH2MSH2--//-- small bowel cancersmall bowel cancer

•• MSH2MSH2--//-- + DSS+ DSS colonic colonic dysplasiadysplasia and cancerand cancer

•• p53p53--//-- no intestinal cancerno intestinal cancer

•• p53p53--//-- + DSS+ DSS colon cancer (100%) & colon cancer (100%) & dysplasiadysplasia

•• APCAPCminmin/+/+ colonic adenomascolonic adenomas

•• APCAPCminmin/+/+ + + C. C. rodentiumrodentium more colonic adenomasmore colonic adenomas

•• APCAPCminmin/+/+ x COXx COX--22--//-- fewer adenomasfewer adenomas•• APCAPCminmin/+/+ + COX+ COX--2 inhibitor 2 inhibitor fewer adenomasfewer adenomas•• APCAPCminmin/+/+ x x iNOSiNOS--//-- fewer adenomasfewer adenomas•• APCAPCminmin/+/+ + + iNOSiNOS inhibitor inhibitor fewer adenomasfewer adenomas•• AOMAOM-->DSS>DSS inflamminflamm & cancer& cancer

–– IKKBIKKB-- in epithelial cellsin epithelial cells 75% fewer tumors75% fewer tumors»» ⇑⇑ epithepith. cell apoptosis. cell apoptosis

–– IKKBIKKB-- in myeloid cellsin myeloid cells 50% fewer, smaller 50% fewer, smaller tumorstumors

»» ⇓⇓ propro--inflamminflamm. cytokines. cytokines

CancerCancer--Prone Mice:Prone Mice:⇓⇓ inflammation inflammation ⇒⇒ ⇓⇓ tumors:tumors:

Ohshima et al. Cell 87:803, 1996Ahn and Ohshima. Cancer Res 61:8357, 2001Greten et al. Cell 118:285; 2004

ColitisColitis--Prone MiceProne MiceMouseMouse HistologyHistology NeoplasiaNeoplasia CommentsCommentsIL2IL2--//-- colitis (UC)colitis (UC) dysplasiadysplasiaIL2/IL2/ββ2M DKO2M DKO milder colitismilder colitis dysplasiadysplasia; CRC; CRC APCAPC; ; p53p53; MSI; MSIIL10IL10--//-- enterocolitisenterocolitis CRC (25CRC (25--60%)60%) No No APCAPC,,p53p53,,kraskras,,Msh2Msh2

ILIL--10 rx: 10 rx: ⇓⇓ colitis & CRCcolitis & CRCReq. flora; Req. flora; E. E. faecalisfaecalis

Rag2Rag2--//-- colitiscolitis dysplasia;CRCdysplasia;CRC Requires Requires H. H. hepaticushepaticusILIL--10 rx: 10 rx: ⇓⇓ colitis & CRCcolitis & CRC

Rag2/TGFRag2/TGFββ1 DKO1 DKO dysplasia;CRCdysplasia;CRC Requires Requires H. H. hepaticushepaticusCRC CRC independindepend. of colitis. of colitis

TCRTCRββ/p53 DKO /p53 DKO colitis (UC)colitis (UC) dysplasia;CRCdysplasia;CRC Requires floraRequires floraGpx1/Gpx2 DKOGpx1/Gpx2 DKO ileocolitisileocolitis dysplasia;CRCdysplasia;CRC Requires floraRequires flora

ilealileal cancercancer

Itzkowitz and Yio, Am J Physiol. 287:G7-17, 2004

Lessons From Animal Models Lessons From Animal Models

•• Colonic Colonic neoplasianeoplasia develops in develops in genetically genetically susceptiblesusceptible hostshosts

•• Requires prolonged periods of chronic Requires prolonged periods of chronic inflammationinflammation

•• Requires fecal flora (Requires fecal flora (Helicobacter spHelicobacter sp; others?); others?)

Culture of mucosa-associated bacteria in IBD and colon cancer

Martin et al, Gastroenterology 2004 127(1):80-93

0

10

20

30

40

50

60

% h

aem

aggl

utin

atio

n

Control UC CD Ca Cadistant mucosa

NS <0.02 <0.0001

<0.01

Increased haemagglutinating activity by mucosa-associated E. coliin Crohn's disease and colon cancer correlates with their ability to adhere to and invade intestinal epithelial cells

Martin et al Gastroenterology 2004;127:80-930

200000

400000

600000

800000

1000000

1200000

Attachment Invasion

num

ber o

f bac

teria

per

wel

l Agglutinating E. coliNon-agglutinating E. coli

Inflammation

Unesterified arachidonicacid

Mucosal apoptosisCancer

Common mechanisms for IBD-associated and sporadic colon cancer

Adapted from Rhodes & Campbell Trends Molecular Med 2002

Mucosal bacteria

Mutagenesis

Carcinogens

(Cao et al, PNAS 2000;97:11280-5)

NFkappaBActivation Cox2 activation

Prostaglandin E2-inducednuclear localisation ofBeta catenin

SummarySummary•• There are more There are more clinicopathologicclinicopathologic and molecular and molecular

differences between SCC and CAC than there differences between SCC and CAC than there are similaritiesare similarities

•• This appears to be due to chronic inflammationThis appears to be due to chronic inflammation•• Whether bacteria play a role in Whether bacteria play a role in humanhuman colitiscolitis--

associated associated neoplasianeoplasia (or perhaps even sporadic (or perhaps even sporadic CRC) requires further investigation. CRC) requires further investigation.

SummarySummary--Human Observations Human Observations •• IBD patients are at increased risk for CRC.IBD patients are at increased risk for CRC.•• The risk of CRC rises with increased duration, The risk of CRC rises with increased duration,

extent, and severity of inflammation, and with extent, and severity of inflammation, and with associated PSC.associated PSC.

•• Use of certain antiUse of certain anti--inflammatory medications inflammatory medications (5(5--ASA, steroids) may reduce the ASA, steroids) may reduce the development of CRC in IBD.development of CRC in IBD.

•• Oxidative stress causes genomic instability Oxidative stress causes genomic instability leadingleading to the development of to the development of dysplasiadysplasia. .

•• Molecular markers may help to identify Molecular markers may help to identify patients at increased risk of CRC.patients at increased risk of CRC.