iJo oft

Physical activity, thedirectandindirecteffect of socioe co no micstatus on riskfactor s of color ectal ca ncer inCanada

by

©Jing Zhao

!\lhcsis submittcdtothc SchoolofGraduatcStudics inpartial fulfillment oftherequirementsforthedegree of

Master ofS cienceinMedic ine

Division ofCommunityHealth andHuman ities Facultyof Medicine

Mcmorial Univcrsity of Ncwfllundland

Octobcr2 0l2

SiJolm's Ncwluundland undLabrador

Abstract

Theobjec tiveof thisthesis wasto examine thedeterminants of colorcc talcance r(CRC) fromtwoperspectives:\)theassociations betweenrecreational physical acti vity andthcrisk ofC RC;2) thedirect and indirect effectof soc ioeco nomicstatuson therisk ofCRC.

Higher levels ofphysica lactivity havebeen consistentlyassociated withl owerrisk o f CRCin previousstudies.Nevertheless, the specific mode , intensity,frequency,and duration ofphys icalactivity required forCRCpreventionarenot wellknownand remain controvers ial, The fi rst objectiveofthisstudy isto examine the associationsofwalking, non-wa lking exercise, and total recreationalphysicalactivityoncolorccta lcancerdevelopme nt.Thestudy used thedatacollectedfrom the existing popul ation based case-controlstudyofOntario(ON) andNewfoundlandand Labrador (NL), inwhich personalhistory,life styleanddietary informa tionwerecollected usingthePersonalHistoryQuestionnaire (PHQ),FoodFreque ncy Questio nnaire(FFQ)andFamily History Ques tionnaire (FHQ). Multivariablc logistic regressionanalysiswasusedto estima teoddsratios(OR)and95%confidenceinterval (95%CI)afteradj ustingpotentialconfoundingcovariates.Pooledanalysisin both ONandNL was alsoconduc ted. Resultsfromthis studyshowed that the highestquintile o f walkingwas associatedwithincrease dcolorec talcancerriskforboth males andfemalesinboth provinces (highestVSlowest: ON: OR=1.51,95%CI=l.07 -2. 13;NL: OR=2.01,95'X,CI=1.25-3.22;

pooledanalysis:OR=1.70,95'YoC I=1.09-2.66).However,this resultcould bebiasedbecause ahigher proportio nof casesrespondedtothis item than controls.Non-walkingexercisewas insignifi cantly associatedwitha reducedriskof colorecta lcancerforboth sexes and provinces.Thesefindings sugges tedthatincreasing amount s ofneitherwalkingnor non-wa lkingexercisewas associatedwithreducingthe risk ofcolorcc talcancerMo rc specifiedprospectivestudiesonphysical activityareneededto evaluateeffective frequency, durationand intensity ofphysical activity inrelationto colonandrectalcancer preven tion.

Existing epide miologicstudieshavenotinvestigatedhowriskfactorsworktogetherto increasetheincidenceofCRC;therefore, the trueeffectofeachfactorcouldbeunder-or over-estimated.Thesecondcomponentofthisthesiswastoexplorehowsocio-cconomic status(SES) directlyinfluencesthe riskofdevelopingCRCand itsmediatedeffectonCRC risk throughdietwhileadj ustingfor possible riskfact o rsofalcohol intake,smoking. physical inactivity,andobesity.Using thedata fromjust the NL province,measurement andstructural modelin gwasu sedtotest conccptualmodcls.Exploratorylactor nnalysiswasuscdto identifydietarypatternsmeasuredby 39food groups.Next,the direct and intermediat e eff ec tsofriskfa ct o rswereexamined usingstructuralequation modelin g.The resultsfrom multivariable regression analysis indicatedthatage(OR=l.03),SES(OR=O.89),processed meatintake (OR=I.08).non-screening(OR=2.67), smoking(OR=I.44,1.85(ever,currcnn ), and familyhistory scoreofCRC(OR=l.06 ),weresignificantlyassociated with theriskof CRe.SES(B=O.05)has adirecteffecton theriskofCRCand theindirecteff ec t(B=0.06)of SES onthe risk ofC RCalsoappeared toexistthrough processedmeatintake (fl=O.OI).lower vegetableintake([3=0.0 I).lowerscreening frequency(B=0.02). andsmoking(fl=O.02).This study indicatedthat the Lpopulation hasthreemajordietarypatterns.Also.structural equationmodelingused in this study.arelativelynewapproach inepidemiology studies, provided unique informationofthedirecteffectofSES onthe developmentofCRCand its indirect effectsthroughasciofcandidateCRC riskfacto rs.

KEYWORDS

Colorcctalcanccr, physicalactivity, socioeconomicstatus, dietpattern.directeff ec t,indirect effect.

Acknowledgement

Withthesupportandcontributionofmanypeople,thisresearchprojccthasbeen made possible.First,[wouldl iketoexpressmy gratitudetomy supervisor,Dr.PeterWang,who was abundantly help fulandofferedinva luableassistance, suppor tandguidancethrough the duration of my studies.Iappreciate hisvastknowledgeandskill in manyareas,and his assistancein writingreports(i.c., scholarshipapplicationsrna nuscriptsand thisthesis).In additiontohiscontributionin mystudy,Iam deeplyimpressedbyhissound personalitie s that guidemetodevelopmy charac ter istics.Moreover,Iwould likcto upprccinte mcmb crs of co-sup ervisorcommittee:Dr.BarbaraRoebothan,Dr.QilongVi,and Dr.Peter T.Carn bpcll lortheir assistance thattheyprovided at alll evcls of theresearch proj ecl.

Iwould likeexpressmymanythankstoall the faculty,sta lTandstudentsin thedivision of CommunityHealthand Humanitieslo rtheirgenerousadv ice,encouragement, helpand motivationduringmymaster 'straining.

Manysincerethan kstomyfamilymemb ers!

Iwouldappreciatethe Beatr iceHunterCancer Resea rchInstitute with funds provided by TheTerry FoxFoundat ion StrategicHealthResearchTrainingPrograminCancer Research at CIHRforofferingme atrain ee award lormygraduatestudy.

Special than kstothe participantsinbothOntarioamiNewfoundlandandLabrador who contributed vastoftheirtimeandeffortin thevariouscomponents ofthiswork.

Glossary

Co m pa r a t ivc Fit Indcx (CFI): alsoknownas the Bentle rCom para tive Fit Index.CFIis conside red asimpro vementinnoncc ntralit y(from thenulltothehypothes izedmodel )to the nonccntrality ofthc nullmodelinwh ichassumestha tno intc rre lat ions hipsa mo nganyofthe variablesiindep end encemodelornullmodel).Arecomm end ed valueof CFI is0.9or above [1,2].

Direct Effects: the effec t that goesdirectl yfrom onevaria b le to asecondva riablc [3].

Explo r a tor y Factor Analysis (EFA): it is a statistica l meth odusedtoexpl orethe dimcn s ionalit y (tilcto rs/lat cnt varia ble s) of am casurcm entmod e1byfindin gthesma lles t number ofi nterp retable fa ct orsto exp lainthecorre lationamong aset ofva ria bles [4].

Factor Loading:Thecorrelatio nof thc measured variab leanditsfactor,with high erloa din gs ma kcthcva riablcrcp rcscnt ati ve o f thefilctor.Factorl oadingsgrcatcr than O.3 ar c con sid cred tomeetthe minimal level:loadingsofOAare conside red morc important; andifthc loadin gs arcD.5andgreate r, theyarc consideredpractica llysignificant[5].

Good n css of Fit:How wellahypothesi zed or theoret ica l model , adistr ibuti on, oran cqua tio n lits actualdata[6 ].

Goodncssof Fit Indcx:amcasurc o fth cp rop orti on o f vari an cc andcova rian cethatthe hypoth csi zcd orthcor eticalmod cli s abletocxplain [6, 7].

Indicators:alsoca llcdoh.l'erved,·aria/JIe.l',mcasurcd variub lrs.vwmanifest,·ariah!e.l'.Actual measu red value lo r a spec ific item or qucst ion.ubtuincd either fromrespond entsin respon se toqucsuo nsor Irom obscrvntions by aresear ch er, whichca n bc d ircc tly ll1easurc d.lnd ica tors arcrepresen tedby sq uares or rectang les.Byconventio n.ind icato rsshould ha vepattern coefficients(factorloadings) ofD.3orhigher on theirlatentfiicto rs.

Indirect Effects: theeffec tsbetween two variablesthataremed ia tedby one morcmcd iating

varia bles[J].

Latent Variables:alsocalledjilc/ol"s,constructs orII/W ;" I'CI1 'CI!variab les.Themain cha rac teristicoflate ntvariablesisthat theycanno tbedirectly observedormeasured ;it hypothetically existsinastudytoexpl ain vari ablesthatcanbeobservedor measured.They aremeasuredbyasetofobse rvedvariab les.Latentva riablesarcrepr esent ed by circlesor ovals[S].

Mediatin gVariable:A varia bleoccursin acasualpathwayfromanindep endent to a dependentvaria ble.Itcausesvariationin the depende ntvariab lesbutalsoitisinfluencedby the va riation o ftheinde pendent va riables,Synonymsareintervenin g va riable,mediator variable,intermediatevariable, andcontingentva riab le[9].

Nor me d FitIndex(NFl)orNo n- n or rncd fit index (NN FI):alsoknown asTucker-Lew is Index,the chi-squarevalueofthenull modelis com pared10that ofa proposedmodel.A recomm ended valueofNFland NNFIisO.9 0rhigher[ 1,2].

RootMeanSq u a reErr o rof Approximation(R MSE A):ameasureof thediscr epancyper degree offreedom in themodel. Valueslessthan0.05orO.06 indicate reasona b lefit[I,2].

St r nct u ralEq ua t io n Mod eling (SEM) :Structuralequa tion modelingisamultivari ate techniq ueincorp oratingmultipleregression(examiningdepende ncerelat ionships) andfactor analysis (representing obse rved (mea sured ) and unobse rved(latentfactors)variables) to estimatethedirect and indirectrelatio nships ofmea suredvar iablesandlaten tfactors[10].

WeightedRoot MeanSq ua re Residual (WRMR):Thisis arelativelynewlitindexthat is belicvedtobe bellcrsuitecategoricaldata.WRM RvalucslessthanI.Odepictagood lill ing model [1,2].

Abbreviations

Blvl l Bod yMassIndex

crA ConfirmatoryFact orAnalysis CFI ComparativeFit Index Cl Confidcnccl ntcrva l CRC Colo rcc talCancer ErA Explorat o ryFactorAnalysis rFQ Food Freq ue ncy Questi onn aire FHQ Famil yHistor yQuestionnaire IIRT Horm o neRe placem ent Thera py ICD Internatio nal Cl assili cationof Disease NFCCR cw lound la nd FamilialColorcctalCancerRegi stry

IFl Nonnc d FitIndex

NL New foundlandand Labrador NNrl Non-nor mcd Fit Indcx

NOCS Newfoundl andandOntario ColorcctalCa ncerStudy NSA ID Nonstero idalAnti-inflanunatoryDrug OFCCR Ontari o Fa m ilia lColorcc talCa nc er Registry

ON Onta rio

OR Odds Ratios

PHQ Per son al History Questionnaire RMSEA RootMean SquareError of Approx ima tion SEM Structural Equa tion Modeling SES Socio-eco no m ic Status WRMR WeightedRootMeanSq ua re Residual

Tabl e of Content s

Abs tr a ct 11

Acknowledge ment IV

Gloss ary V

Abbre viatio ns VII

2.22 Canad ianlncidcnccand Mortality...

2.3 RiskFactorsAssociatedwitheRC . 2.3 .llIc rcditary I'ac to rs...

2.3.2Enviro nme nta lFacto rs .

. X

. 9

2.3.2.4Smoking....

2.3.2.5Alcoho lConsumpti on....

2.3.2 .6Obesi tyandAbdo mi nalFatness...

3.4.2Respon seRates inNe wfo undlandandLabrador. 25

3.5DataMeasurcm enr....

3.5.ll'crso nal llis loryQlIcstionnairc (I' IIQ ). 3.5.2FoodFreq uencyQuestionnaire(FFQ) .

3.5.3Fnmilyllisto ryQlles tionnaire(FIIQ)...

3.5 .4 SI11dy O lltcomesandExposllreYariablc s 28

3.6 . 1 Desc ript iveAnalysi s 30

3.6.21\111ltivnriahIcR eg res s io ns...

3.6.3Struet u ralEquationModelling 31

Chapter 4 ProjectI:\Va lking,Non-wa lkingExercise andColoreeta lCance r -alar ge

po pul ationbased case-contro lstu dy inCanada 34

4.1Abstrac t 34

4.2Introdllction 35

theDirec t and Indirect Effec tsofSocioeco no mic

5.3.2Data Collect ion 58

5.3 .3Stat isticalAnalysis...

5.4.1 DescriptiveCharacte ristics...

5.4.2Explor atory FactorsAnalysi s(EFA)...

5.4 .3Regressi onResu lts ....

5.4.4Struc tura lEquation Modelin g...

. 62

. ...63

Cha pter6 Summary 73

Chapte r I Introduction

1.1Background

Color eeta lcance r(CRC ) hasbecom e ahealthproblemofinc reasi ngsigni ficance in Canada.with anestima ted22,500 ne w cases and9.100death sin2010 [I I].CRCisthethird most com montyp e of canc eramongCa na d ian malesand femal es[II] .Thepro vinceof New fo undlandand Lab rad or (NL)hasthehigh est age -standardizedinci dencerateofCRC in Ca nada at86/100,00 0 [II];indeed .thisis oneofthehig hestincidenceratesofCR Cinthe world.Onta rio exp eriencestheave rageCa nadianincidencerate at51/100,000[11].

Physicalactiv ity haslongbeenconside redaneffec tive stra tegyforcance r preven tion [12].Comprehens ive review sfound tha tincreasedphysicalactiv ity isasubs tantialprotecti ve Iact nr ugainstcolonor colorc ctalca ncer[13-16]. Numerousprospecti ve[17-20] ami cas e-co ntrol[21,22]stud ieshave foundstatisticallysignificantassoc iatio nsbetweenphysical activi tyandcolo ncanccr,espec ia lly fix men.Few stud iesofrect alcancer ind icated no associations[23 -25 ].Themeasur em entofphysic alactiv ity inthesestud iesvariedandwas baseduponlimi tedtypes ofactivity.The type.T requ en cy,durationand inten sit y ofphys ical activityareallim po rta ntto reducerisk ofcolorectal cance r [12, 26];ho wcvc nthiskindof inform ati onislimited.InCanada,fe w stud ieshave focusedon examinin gtherelati on ships between spe cifi c physic alactivit y ami colorcctalcan cerrisk,es pec ia llyinalargepopulation.

Ep idem io logicalresearch to date has suggestedthat a wide range ofenviro nmentaland lifest yle factorssuchasdietaryfact ors,phys ica linactivi ty,smoking.ulcoho lconsump tion andsocioe cono mic slalusmayco ntribute to theinc reas ed inc ide nceo fCRC;howeve r,most of theresultshave beeninconsistent [27-36].TheWorldCance rResearch Fund(WCRF)and the Ame rica nInstitute ofCa nce r Resear ch(AI CR)secondexpertreportclassifi edriskfacto rs

intolllllrmaj orgroups accordingtothestrengtho fthe evidence.Physicalactivity, consumptionofredmeat, orprocessedmeat,excessive alcohol drinking(above JOg/day ), body andabdo minalfatness,andadultattained heightareconvincingrisk factors ofCkt";

intakesofdietaryfi bre,garlic,milkandcalc ium probabl y reduceCRC risk;non-starch y vegetables,fruits,Illlate,selenium,lish and vitaminDhavelimitedsuggestiveevidence of deelining CRCrisk;whileintakes ofiron,cheese, Illodcontaining animallilt, and sugars have limited butinco nclusive evide nce of raising CRCrisk.

Alargenumberof epidemiologica lstudieshavefocusedonexaminingmaj orriskfactors ofintcrestwhile controllingforothercova riates.Thisoversimplifies lhecomplicated, interdep endent relationshipsamongvariouslactors ofinterest[J7]. Consequently,most reportedstud ieshavebeen unab le to specify howvariablesworktogetherto give risetoCRC and tendtounder-estimatethe trucctfcctofcach li\ctor [J 8-40].Thereforc. xtudicsthntare able to delineate and testhow variouslactors arcinterrelated nndjointlyaffcctoutcomes wouldbeexpected toprovideimportantinsightsinto CRCetiology.Although the inter-dependentrelationships amongsocioeconomicstatus (SES),lifestyles,diet,and health arc wellrecognized[41-4J], theircomplexinter-relationshipsin relevanceto CRC havenot beenexamined.Wehypothesizedthat 10wer SESpred isposespeople to certain risk factors (e.g.poordietary intake,smoking, alcoholconsumptionandobesity),whichintummay interactwithgeneticfactors andleadtothedevelopmentofcolorectalcancer.Alarge population-basedNewfound landand Onta rioColorec talcancerStudy(NOCS) wasexpected to providevaluableinsightsonthe risk IactorsofCkfrand potcntialprcvcntionstratcg icslor thisdisease.

1.20bjcctivcs

Theobj ectiveof the firstcomponent ofthis

thesis was

to cxaminc thcassociation bctwecn colorectalcancerriskandseveraltypesof physicalactivityIwa

lking, non-walk ing

exercise and totalphysicalactivity).

Thcsecondcomponentofthisthesiswas

toac hievcthe l()lIowing

specilicobjectives:

I)explore the potential association

amongriskfact or sofcolorectalcancer;2) posita conceptllal modcl thatdclineates

the inter-rclationships with res pec t to how

SES,

dietary

factors,and lifestyle

factors work togetherto givcriscto CRC; 3) operutionalize thc proposcd

conceptllal mode l llsing thc da tabaseofNe w follndlanda ndOntarioCo lorce tal-cance rS tlldy

(NOCS).It is important to note that only the NL data was used in thesecond

componentof

this thesis,

1.3 Organization

Thisthesis

is

divided into sixchapters.Chapter I isanoverall

introduction to this study.

Chapter 2 reviewstheepidemi ologicdescriptionandassociatedriskfactor sofCRe.Chapter 3present s

the research

methodsemployed in this study. Chapters4 and5a

re

both results sections.whicharewritten ina

manu script format,

includingits ownintroduc tiournc thods.

reslllts. anddiscllssion.Somc rcpe titionof

methodswas unavoidab le.Chaptcr

6sllmma ries

lhe key

lindingsand discllssesim plications o fth estlldyresult s.

Chapter 2 Literature Review

2.1Colorccta lC anccr

Colorcctalcance r (CRC) enco mpassesmalignancie s orig ina ting fromtheep ithel ialcells

of gastro intes tinaltract,whichinc ludes thecolon,rectumand appen d ix[44].Thecolonisthe firstfourtofivefe etofthelar ge intestine, whic hconsists0fthccccum,the ascendi ngcolon, the tran sversecolon,the descend ing colon,and thesigmoidcolon(Figu re 2.\).Themain func tionofthe colon istoremove waterand nutrien tsfromthefoodmassandconvert therest intowaste [4 5].The rectumismad e upof thelastseve ra l inches of thedigestivetract [45].Its maj o rfunctionistostore wastematerialpriortoexcr etion.

Figure2.1:Thecolonand rectumpolypand cancer

Colon Can~'er ^{and Polyp}

Source:II'ww.enco!.!nitive.com/l1ot!e/I0376

CRCusua llybeg insasanon cancerouspolypwhich may eventuallybecomeaca ncerous growth.Thisproces smay varyfromseveralyearstodec ades.\nitiationand prog ress ion

throughthe adeno ma-ca rcino masequence islinked withaccum ulateddefectsintumor suppressorgenes,oncog enes, and DNArepai rgenes [46],The tumorgenesis maybestarted by extem alagentsand/orinhe ritedgene ticfacto rs[47].

2.2Ep id em io logy ofCo lo r ccta lCa ner 2.21WorldwidcBurden

CRC isoneofthe most com moncauseof can cerdeath seach yea r in men (663 000cas es, 10.0%ofthe tota l)and the seco nd inwomen(571000 cases,9.4%oftheto tal) worldwide [48 ].The maj ority (60%)ofthe cases occurin developed regions.whichincl udes Aus tralia/New ZealandandWesternEuro pe [49].Onthe otherhandthefewestcas esoccurin Africa(exceptSouthe rnAfr ica)andSout h-Ce ntra lAsia [49]. Men usuallyhavehigher incide nc e rate sthan women(overa llsexrati o1.4:1)[49].Theworldw ideestima ted deaths from colorecta lcancerare about60S 000death sper year; CentralandEaste rnEuro pe exper ie nc e the high estmortalityratesin bo th sex esesti ma tedas20.l pe r I00,OOO l'llI· males and12.2pcr100,000fo rfemal es.Middle Africaexperie ncesthelo west mal eandfemale mo rtalit yrates 01'3.5 and 2.7respectively [49].

2.22Ca na d ia n Incidenceand Mortality

InCana da,22,500diagnose sand9,100deat hs wer eexpectedfromcol orc ct alcance r in 2010 [II ].CRCisthefour th mostcom mo nmulign ancy nnd the second lead ingcause of dea thfr omca ncerinmen and womencomb ined[II].ln 201 0 .the age-standa rd ized incidence rateofCRC was62pe r 100,000among menand41per100.000amo ngwomen.and the

age -standardizedmort alityra tewas25 per100,000men and 16pe rI00,OOO wol11en[ll ].

Morethan 50 perce ntof newlydiagnosedcolorcc ta lcancercase swilloccur umo ng pcopl c aged70years orolde r [I I]. Althoughthe age-s ta ndar d izedrates a rchigh e r in men,the nUl11bero f preval ent casesandd eath sisappro ximate ly eq ual betw eenthesex esbecau se of the tendency ofwomentolivelon gerthanmen.

The2010Canad ia nCancerStati sticsreportedthe fluctuationofCRC incidence:the

incide ncerosebetween1980 and 1985;n exl.theineid eneedeclinedtothemid-1990s{m ore strong ly in femalesthanin males),thenrose through2000, only todeclin e significantly therea ftcrjll ]. Reeent decl inesinmol1ality ratesi nb oth sexesmayb e due toh igh sc reen ing rates, improvedcontrolsand/ortreaune nts.

Interprovincial variations lorcolorectal incid ence and mortality ratesareobvious[II].

Newfoundlandand Lab radortypicallyhasthchighest ratesofcolorcctalcancerinCanadaat arate o f 88per100,000 for menand 52per100,000forworncninZu lO.Ontario ranksin the middle amongCanadian provinces at arateof 59 per 100,000Ill!"men and 40 per 100,000for women in20IO.BritishColumbiahasthe lowestincidencewitha rateof 54 per 100,000 for men and37per100,000for women.The high colorcctalincid enceinNewfoundland and Labrad ormay bepartly explained by ahighprevalence oflamilicswitha predispositi on10 hered itary coloncancer [50].Howcvcr. cnvironmcntnl factors urcalsoan important component tothe CRCrisk.

2.3Risk FactorsAssociate dwithCRC

Theexact causesofcolorcc talcance rarc unknown [45].Whilefamil yhistoryis a strong riskfactorlor CRC.inheritedfamilialCRC isresponsibleforIO%-15°A.of allCRCcases [51-53] andthemaj ority of CRC cases arc aresultof gene-e nviro nmcntinteract ions[52, 54, 55]. Lifestyle and dietaryfacto rsplayanimportant role. About75to X5percentofC RCare sporadic,suggestingthatmodiliablefactorsarcof publichealthimportanceand etiology.

Important modifiableriskfact orsIll!'CRe includetobaccousc,unhealthydiet,physical inael ivitya nd theeo nsumptiono fa lcohol[ 47].

2.3.1 Her editaryFacto r s

Thosewithafamilyhisto ry ofC RCoradeno matou spol yp s in anyfirst-d eg reerelativ e younge rtha nage 60. or in two or mor efirst-de greerelati ves atanyagearcconsi dered at increase drisk forthedisea se.Amongfamilialcases, appro ximate ly5'X.-I0%ofCRCarc a consequenceofheredita ry gene tic mutation s, which mai nly consistoffa m ilialndcnomutous pol yposis (FAP).and he reditary non-polyposi s CRC(I-INPC C)[56.57].

Pa tien tswhohaveFAPtypicallydevel ophundreds ofpolyp sin theircolonandrec tum duringtheages01'5 to40years.FAPis commo nlycaused bymutations of theadc no matous pol yposis coligene, which resultin inope rativ etumorcellgrowthand fin allylcadstothc grow thofhundred sofpol ypsinthecolonandrectum.Overti me.gene mutationsin the cells of the pol yps cause thepolyp stobecome cancerous[58 ].FAl'accountsli.Jrlesstha n l%of allCRC patients [59].

HNP C C accounts for1%-6%ofallCRCs [60-62].Thissyndromealsodevel op s whe n peop le arerelati vely young.Patients with I-INP CCha vefewer pol yps,unlikehun dred s of polypsasis seenin pat ientswithFAP.I-INPC C syndromeis cha rac te rize dby earlyonsetof CRCwith microsatclli te ins tability.Microsat cllitcinsta bil ity ofthe can certumoris a mol ecula rmarkerfor DNAmism atch repairdeficiency.Mutationsin misma tchrepa irgenes arcdet ected among85%of HNPCCpatie nts[58].

2.3.2Environmental Factors

Existingstudiesshow that immigrantsrapid lyacqui rethe inc idencerates of the irhost country,sugges tingthatenviro nme nta lfact o rsplayacrucialrolcinC RCdcv elopmcnt

[63-65].Asmention edinCha pterI. the WCR FandAICRsec ondexpe rt report classifie d risk factorsinto four maj orgroups accordingto thestreng thofthe evidence.Evidencelinking physical activity to CRC isconv inci ng aswellasredmea l,proce ssed meat.excessi ve alcoho l drinking (above 30g/da y) ,bod yandabdom inal fatness, andad ultatta ined height (the differencebetweencuITentwe ighta ndweighta t theirage of20s) ;inta kes ofdieta rylibre, ga rlic. milkandcalc iumprob ablyred uceCRC risk;intak es ofnon-starch y vegetables,fruits, folate,selenium,fishandvitam inDhavelim itedsuggestive evide nceof decl inin gCRC risk ;

in ta kes ofiro n,cheese.Ii.)Odcon tai ni ngan i ma l l~ll,andsugars arclim ited butinco ncl usive

evidence of raising CRC risk . Th isexpertrepo rt also suggestedCRC ismostl ypreven table byappro pr iate diets andassociatedfactors.

2.3.2.1Socio-c co no m ic Status (SES)

Therearcgreatgeog raphicvariat io nsin incid encerates.Rateshavebeenshowntobe higherin the weste rncountriesandlower inde veloping countrics.Countrieswith high incomesha vebeenshow n tohavehighercolorectalcanccrincideneerate sthantho sewit h lo werincomes[66].Th ismaybepa rtlyexpla ine dby the1~ICIthatresiden tsinthedeveloped countries have a"western ized" dietarypatternwithlessphysical activityassocia tedwithboth oecupatio nandlransportation d ueloinduslrialisalion.Findingsfromseve rals llldies suggestedthat the risk ofdev elopingCRC increased withahigher ed ucatio n level andsoci al class [6 7. 68].On the othe r hand .lowSESpredi sp osespeopleto certa in riskfact ors(e.g.

poordietaryintake andobesity ).whic h in turn mayinteractwithgeneticfact orsand leadto the occurrenceofcolo recta lca ncer.Therearc differentsocialclass corre latesIi II'co lo n and rec ta lcance r[67].Thetwo sitesshou ld not be comb inedinstud iescons ide ring lifestyle 1:1ctor sinlheaetiology oftheseneoplasms[6 7].

2.3.2.2DietaryFactors

Dietaryfactorshavebeen regardedasstro ng lyassociated with theincidence ofC RC [53, 6lJ],par ticu larlywhe nanunhea lthydict isintcn n inglc d withob esity,wei ghtga in,physical inactiv ity,smoking orexcessivealco hol consumption[18,34,70-74 ].Onestudyhas indicate dthatabout70%ofC RCcanbepreventedbychangesindietandlifestyle [73],but estima tesvarywidely[53].Althoug hepidem iologicstud iesand/orclin ical trial sha ve attemptedto examinetheassociations amo ngspecificfoods,nutrientsandCRC,the result s produ ced areinconsistentand uncon vincin g.

The'Wcstcrnrlict, known tobehighinanima l lilt,redand processcd meatsbut lowin fruit, veg etableand librecont ent ,hasbeenlinkedtoanincr easedrisk ofCR C.Thi stypeof dietis commo n11)1'peopl e who livein Japan, NorthAme rica,Northweste rnEuropeand Austra lia.

2.3.2.2.1Total Energy

The2007WorldCancerResearchFundand the Ame rica nInstituteforCancer Resear ch expert rep ort concludedthattotalene rgy hasnosim ple rela tionwithCRC risk.Data are incon sistentforcarbohydrates, proteins andcholes terol[75). Severalstudieshavesugg ested thatlota l energyintake ispositively associatedwithCRCrisk[76- 7XJ.High energyintak es cou ldcause aglyce micoverload, acom pensatory incr easeofserum insulin,andrelated insulingrowthfact or-l(IGF-I ),lead ingloani nc reascdeellpro liferation,reduce da poptosis, andthcrc byincr cnsetheriskof tumorigen esis[79-82].Thismayhelptoexplain whypatients withnon-insu lindependent diabe teshaveincre asedCRC risk[8I,83-86J.Inadd itio n, the cffcctsofhy pcrinsu line mia and type 2diabeteshavebeenshown tobeassociatedwith increased riskofproximal mthe rthandistalcol on cancer[84, 87].l'atientswithtype 2 dia betes arepred isposed tolowersurvivalratesandhigherrecurrencerates.Anotherpossible

explanationcould be thatpeople

with

CRCandtype2diabctcs sharcsimilar unhenlthy lifcstylesjSd].

2.3.2.2.2 Fruit, Vegetables and Fibre

Ever since Burkitt

proposed that

a

lower CRC mortality

inblackscomparedto

the

whites was attributableto

dietary fibre intake.the riskof

colorectalcancer

in

relationship to

fruit.

vegetables and

fibre hasbeen examined by hundredsof

epide miologic studies

[56J. The 1997 WCRF/i\I CR expert panel

reviewed21case-controland four cohort case-cont rolstudies and concludedthatvegetableconsumption convincingly

reduces the risk ofcolorectal cancer but

theevidencesupportingfruitconsumptionwas

limited

[88J.Subsequently,

the2003 1i\ RC

evaluated 27case-controland 13cohortstudies andsuggested that higher

intakesof

vegetable

probably declinesthe CRC risk and highcr intakcsoffr u itspossibly reducesrisk

[49J.Thelatest 2007

WCRF/i\I CRexpert report

indicated thatfibre

is probably

associated withCRCriskreductionand thatnon-starchyvegetables andfruitshave

limited suggestive

evidence ofde cliningrisk [56].

Overall,case-controlstudiesshowed thatfibreprovidedapproximately a 40%-50'Yo of reductioni

n the risk fllr colonc

anccrw hilc prospectivecohortstudiesindicated a weak associution betwcen

dictury

Iibre intakea ndcoloncancer[32].0

nc rncta-unalysis showed that an

increaseof

10

g

fibreper day

wasresponsible for a

10% reduction inCRC risk (RR:

0.')Oand9 5%CI:O.84-0.97) [56].

With this beingsaid,

somestudies suggest that the effects offruit,vegetables

and fibre may

only be evident for a

person who has lowbaseline intake

Ievcls[3 2].

[\·lally

li1.lits, vegctables and

grainsa

re richi n libre.F ruitsa nd

vegetablcs are sourcesof

dietaryfi bre,carote no ids,fol at e, selenium,glucosi nolatcs,vita mi nsand minerals[56J.The precise mech anism sexp lai ning the bene fic ia lroleoff ib re.fru itsandvegeta blesarc not clea rlyunderstood. Theprotcct ivccflcc toffibrc ma ybelink ed with thefactthat fi bre dilu tes fccal conrents,decr ease stran s ittime and inc reasesstoolweight[32,S9 J, which helps tu red uce thetime of exposureto carcinogensor tumor prom ot ersintheintestinal lumen [90J.

The ben efi c ialeffec toffruitsandvege tab les maybe attributedto thecom binedinfl ue ncesof constituentsonseveralcarcinog enesis pathw ays. Antioxi da ntscont ained inthcfruitsnnd vegetab lescould prot ect agains toxida tio n da magethroughtrappingfrccradicalsand rcacu vc oxygen molecul es[3 2,56].Sho rt-chain fattyacidsprodu cedin thefc rmcntauon process mightinduce a popt osis;lhercfllrealsopossib lyc ontributingtotheirben efi cialrole[32].

2,3,2.2 .3Mea tandFa t

Forthepurpose ofthisthesis,thete rm",.ct!meat"refe rsto beef pork,lamb andgoat from domestica tedan ima lsand"p rocesse d meat"refe rsto meats prese rved by smoking.

cur ing,orsa ltingor by theadditio nof preservatives[56].Red and processedmeathas been postulated to increase CRCris k throu ghse vera l mecha nis mssuchastheproduc tio nof heterocycl ic amincs and pol ycycli c aroma tic hyd roca rbo ns with hightemp e ra ture cooking meth odsuchasfrying,grilling,and barb ecuing [91.92J;increased exposure tomutageni c nitrite s,nitrat es.N-nitrosocom pounds andsa lts[93J;stim ulatio nofcndogc no us iusulin whic hcancausecellprolifera tion[32];or incre as cd iron intakc.whichis considc rcdun emergi ng carcin ogenthatmayincreasetheform ationofoxyge nspec ies andco ns equently lead toDNAandchro moso me damage[27,94].

The exper tpanelcond uc tedameta -anal ysis of16 coho rtstud ies whichindicat edthat a dailyincreasein the cons ump tio n01'50gramofred meat wasassociatcd withu15%inc rease

inCRCrisk[56].The panel alsoshowed that a daily50 gram increasein the consumptionof processed meat of waslinked witha 21%increaseinCRC risk [56].Therefore, thepanel concl uded thattheevidencelinking redand processedmeat consumptionwith riskofC RC is convincing.

Dietary meat alternatives includ ingIish and poultryhavebeen associatedwith deceased CRC riskin most,but not allstudies[33, 35, 56, 95, 96].The mcchnnismisnotclear.It has been proposed that n-Jpolyunsaturated1;1ttyacids in fishprotectagainst CRC byreducing inllammationa nciregulating DN1\ methylation [97- 102].1\nimal trialshaveindicatedthat fi shoilsupplements decreasethenumber ofcolon tumors[103].Long-chainn-3PUF1\sin fishoilscaninhibit tumor cell prolilcrationbymodifying signaling pathways[104,105].The evidencetosupportthatfishand poultryintakes are associated wiIhareduction of CRC risk islimited[56].TheEPIC studysuggested thattheconsumption ofredand processedmeat increases colorcctalcancer riskwhiletheintake offishdeereascsit Ivx].

I'vleatisamajorsource of dielmybt,especiallyofsaturaledfat[32]. Somestudieshave shownthatanincreased riskofCRCisassociatedwithanincreasedintakeofto talsaturated fatwhileintakesof monounsaturated andpolyunsaturated

';IlS

havebeen found to be associatedwithareducedrisk[106, 107].1\diethighinanimal fats reflec tshigher consumptiono f meatsanda lowerco nsumptionofvegetablesa ndfrnits.Suche nergy-de nse dietshavebeendirectlylinked withincreasedC RCriskormediatedthrough obesity.

1I0wever,thew omen ' shealthstudy[10 8] andap rospeclive cohort sludyofmalehealth professionals[79] showed thaidietslowinfathad noeffect onCRCriskreduction.Thereis limitedevidence suggestingthatdietaryanimal fatis associated with risk ofC RC.

2.3.2.2.4Mincralsand Vitamins

Calcium,sel enium,vitaminD, vitam in Bcomplexes, betacarotene andantioxidantsha ve anti-carc inog e niceffec tsand thusdecre a se CRC risk[109-111], whe reasiron hasbeen sho wn toincre ase stheris k [112].Oneofthemostwellstudied mine ral sinCRCprevcn tion is calcium.which ismainlyfound in dairyproducts andsuppleme nts,Ca lcium isknownto bind secondarybileacidsandioni zedlatty ac ids in the colon lumen toforminsolub le calcium soa ps,preve ntingbileacidsand tatty ncidsfrom damagin gthemucosa oftheintcstin allumcn byinh ibitingtheirprolifera tive eff ects [I IJ].Calc ium mayalsoI'unctionby reduci ngcell prolil 'cra tion ,stimula ti ngdifl'crenti at ion,inducinga poptosi s,andregu latingthecell-cy cleof norm aland tumorcolorcctalcells[114-11 7]. The rolesof dieta rycalciumandvita min Dar e highl y correlatedbecauseboth partic ipateincellgrow th restra ining,d irf'crent ia tion and apoptosisinintestina l cellsandvitam in Dregul atesthe absorption ofcnlcium.Somcofthc eff ec tsof dai ryintake onCRCriskred uc tion ismediatedthroughcalcium,altho ughother bioncti vc constituc nts mayhave potent ialeffectsaswell.

Thevita mi n Bcomplexes arelinked withcarcinoge nesis throu gh DNAsynthes is,rep a ir andmethylati on [I I I,lIS,119].lIigh intake o fltllate and its co lilct or s (vitaminsB6and B12) arc associa tedwitha 30%reduct ioninCRCrisk[111,120- 122].Onemeta-analysishas suggestedtha t folate foundin naturall yin foodsratherthan fola te in theform ofsupp lements has abene ficia leffec t.Th ismightsuggest thatfolutecom binedwitho thcrconstituents,orin its certa inactiveform ,istrulyeffectiveinCRC pre vent ion[32,1 23].

Antiox idants, incl udi ng ca rotene;vitam insA,C, andE;andselenium mayprotectaga inst CRC through theirantioxidantoranti-iuflununatorycha racte ristics[122].Findi ngs of observa tionalstudies,meta- ana lysesandp lac cbo trialsareno tconsiste ntastheypertai n to

theprotectiveeffectofanti -ox idants,either assing leagentsor incom bina tionwithothe r ant iox ida nts [124- 127].

2.3.2.2.5DietaryPatterns

Most availablestudies in nutritionalepidemiologyha veinvestiga tcdthecffcctof individual foodsaud nUlrients[ 32].Although diet andcoloncanccrrelat ionship shave been

studiedcxtensively.uheimpactofmany die taryfacto rsoncoloncarc inogenesisrem a ins unresolved[27,79,90,12X-138] . Foodsarcoftencons umed togeth er undsimilar nutrients cancome fromdifferent food s:therefore, exam inatio nof thespecificeffect of eachfoodis likelytobe confo unde d byothe r foods consumed through outthe diet[139,140].

Conseque ntly,aninc reasingnumber ofstud iesin thc past decadehave exam inedthe associa tionsbetween dietarypatterns andCRC [36, 71,141-14X].Anumber of foodpatte rns havebeenidenl ified[ 56] , suchasAsian,plant-based,M editerran eanandweslern ized d iets.

Ncvc rthc less.xiverullthe evide nccismea gerand heterogeneit y ofdividingfood groups exists.

2.3.2.3 Physical Activity

Physicalacti vityincludes aclivitiesthat arc assoc ialed withoccuputionuuwork),hom e, recre at ion(le isure)andtransport ation(suchaswa lking,ridi ng,andcycl ing).Eng ag ingin physicalactivity haslon gbeenconside redan effective strateg yforCfcCprevention[12j.

Under taking 150minutes of modcratephys icalactivityeach week can redu cethe riskof brea standcolo ncancers.Inind ustria lizedcountrieswithhighincom es,sede ntary life is norm alwit hoccupatio naland hou seh oldphys icalactivities beingdramat ica llyredu cedin recent decades- 31%oftheworld 'spopula tion isnotphysica llyactive[56,149].

Syste matic revie wsha vefound thatincreasedphysicalactivityisasubsta ntialprote ctive lactoraga instcolonorcolorcctalcancer [13-1 6].Iumerou sprospective [17-20 ]and case-contro l [21,22]stud ieshavefoundstatistica llysignificantassociutionsbetweenphysical activityandcolorcctalcancer,parti cu larlyin men.Howe ver.a fewstudieshavenotfound significantassociations [23 -25].Thebenef icia lroleof physicalactivityinpreventio nof colonand/or rectal cance rvaried insub-sites andsex [17.21. 25.26.150-153].The WCRF andAICR [154] summarized24coho rtstudies and foundthat allbuttwo ofthesestud ies haverepor ted decreasedrisk.High erlevelsof recreat iona lactivitywerefoundtohelpprotect against coloncancerinboth menandwomenwithasignifica nt invcrsc trendbeingreport ed insix01'24 cohortstudies.Physical activitywasnot associatedwithdecreasedrisk ofcanccr oftherectum.

A fewprevious studieshaveindica ted thatinte nsephysicalactivitieshave a greaterCRC risk redu cti on. Researchersha vedem onstratedthat alack ofl ifetimevigor ousleisure-time activitywa sassociatedwith increased riskofcolo ncance r lorbothmen and women [155 ].

2.J .2ASmoking

Tobacc ouscisthesinglemostimportant riskfacto r forcancerl-lZ].Thismaybe explained bythe carcinogensthat arc rele asedthrough smoking[32,156].Highe rsmoking prevalenceinAtlanticCanadais assoc ia tedwith higher rates oflungcancerin thisregion [I I].Tob accouschasbeenassociatedwithcolorcctuladenomaandcancer;howe ver.the association hasbee nobserve d tobestro nger lorrectal cance r[72.157]andproxima lcolon cancerrela tivetothedistalcoloncancer [158,159].l-ligherlevcIso fdailyciga relle cons umptionandlon ger durationofsmo king(pack-years), oltcnassociatcdwithuncarlicr ageofinitiation,wereassociatedwith higherCRCrisk.This suggests thepresenceofa

strongdo se-responserel at ionship betweensmo kingandincreasin g CRC risk[72].Past smokers appea r toha ve ahigh er incidence ofCRCas comparedto curre ntsmokers;howeve r.

thismaybe confo unde dbytheearlydamagecausedbyearlyini tiat ion ofsmoking [32].

2.3.2.5 AlcohoICon sllmption

Most stud ies, but not all,ind ica tethat alco ho lconsumptioninc rea ses CRC ri sk, Meta-analysis of cohor t datasugges ted thata10gdailyethanolintakesincreaseCRC riskby 9'%[56]. Alcoho l maymediateprostagland inprod uction,incr easeIip idperoxidationand oxida tivespecies,andconseq ue ntlyresultin increasedcarcinogenesisthroughthe mechanisms ofabno rmalDNA methylat ionand/oractivationof cytochro me p 450enzy mes [56,160.161]. Alco ho lispred icted tohavetheIuncti on ofactingus a solve ntfor carcinoge nicmoleculesinmucosalcell s[56].

2.3.2.6Obesityand Abdominal Fatness

Obesity(BodyMassIndcx>30kg/m²)and abdomin alfatness(me as ure dbywaist circ umfe rence>102cminmen and>XXeminwome nor wa isttohip ratio 01'>0.9forme n

and>0.X5for wome n) arc conv inci nglyassociatedwithCRC risk [56].The associa tionwas

stronge r tormen compa red towomenandforthe colonrelativetorectum[32.16 2].The 2007WCRF/AICR expertrep ortshowsa15%inc rease dCRC riskper 5 kg/nr'BMI incr ea se and5'X,increasedrisk perinchofwaistcircum fe re nce [56] .Sev eralbiologica l mechani sm s ha vebeenpro posed toun derstandthe associa tions.Ob esityresuItsin insulinresista nce, which lead sto can cer pat hogenesismed iatedbythemitogenicprop ert y of insu linand hyp erinsul inemia.lnsulinstim ulatesincrea sed free insul in g rnwthlilctorswhichpromote carci nogenes is[163- 165].Obes ity anda bdomina l liltnessa lsohav erelation shipwith

oestrogcns,leptin,andchron icinflammation. whichareallassociatedwith increasedCR C risk[166- 170].

2.3.2.7 Medications

Clin icaltrials, coho rtandcase-controlstud iesha veshown thattheuseofas pirinand non-aspirinnon-steroidalanti- inflam ma torydrugs(NSAIOs)wasassociated withdecreased CRC risks[171-1 73].Theanti-cance reffectsorNSAIOs and asp irin maybeexert edthrough the inh ibitio nofc yclooxyg cna se and lipoxygen aseenzymes[173],inhib ition nuclear I:lctor- Kb [ 174 ], ind uct iono ra po plosis byac tiva tiono r kinase[ 175],a nd po lya m ines catabolism [176]. Allor lhes elilctors playkey roles in theru nctionofvariousce llu lar metaboli sm s.

Chapter 3 Research Methods

3.1Data Sources

TheU.S.Iationa lCancerInstitu teesta blished theOntar io Fam ilialColor ec talCance r Registr y(OFC CR)as oneofsixinternationalsites in theconsorti umofColo nCanc er Fam ilia l Regis trie s(C CFR )in1997 [177. 178].TheCIIII?TeaminCO/O"CC/ II/CII//CC,.

(CTCC ) aimedtoimprovetheknowledge of thedeterm ina nts,impact.andcontrolof colo rcc talcanccrasa rcs u lt th is tcamcs ta blished the Ncw lllUnd la ndFami lialColorcctal Cancer Registry(NF C CR).whichwa smodeledonOFC CR(deta ils on the projectcanbe foundat: hltp://ww w.mshri.on.ca/colorectalc ancer/).Thestudy add ressedbythisthesisused thedatabase ofapopu lation- basedNewfound landandOntar ioColo rcc talCa ncerStudy (NOC S) .Ethics appro valwasobtaine d fromthe ResearchEthics board ofMemo rial Un ivers ity.

The origi naldata-base cleaning involvedchec kingandve rify ingmissin gdata.

cond uc tingrangeandvaluechec ks.andconductinglogic and rever selogicchecks [31].The databasecleaningprocessinvol vedtheconvers ionofcellvalues, varia ble names,varia ble typ es. varia b lelengths, andcolumnwidthsintheorigina ldata.whichhasallbeendone by previou sOFC CRandNFCCRrese arch team members .However.fi ll'thisthesis study.

add itio nalvariables req uired fllra nalys iswe rede r ivedandva ria ble nameswere adaptedlllr spe c ificsoft war e requ ireme nts.

3.2Study Design

BothOntarioandNL colorc ctulca ncerstudies useda population -basedcase -cont rol study designto collectnecessaryin forma tion.Cas econtrolstud ioscan identifyriskIacto rs of disease, esp eci allyforrar ediseases,by compa ring theoddsofgiven risk fac tors between

cas es andcontrols.Theincid en ce rateorC RCinCa nadameetsthiscrite rion for arare disea se:conseq uently,acase -contro lstudydesignmakes senseforthestudy.Alleligib le cases identified through theOnta rio Cancer Regi stry andtheNewfound landCa nce r Treatmentand Resea rch Foundationwereinvited toparti c ipa te in thisinterdisciplin a ryCRC study.Controlswerelive-year agegroupandsexmatch ed tocase s.Thedetail eddescription orinclusi oncriteriawou ldbeoutlinedin thenextsection:studypo pu la tion.

J.J StudyPopulation J.J.ICases

The OntarioCance r Registryand theNew found landCa ncer Treatm ent and Research

Foundationwereusedtoidentifynewl ydiagnosedcases ofcolo norrcct al cnnce r:andcases wererecruitedintotheOFC CRandNFC CR.Pathol ogist sin thestudyconfirm edthe patho logyrep orts ofcases.Inclusioncriteria lorcases[179]:

I)Incidentprimaryinvasivecolonor recta lcance r [pathol ogy confirmedIntcm ati on al Classificatio nofDiseases9^threvi sioncodes:153.0-153.9,154 .1- 154.3and154.R(ON

&NL); orICD-I O codes:18.0-18.7,19.9, 20.9(NLonlyl]:

2)Diagn osedbetweenJuly1997and June2000(phaseone)orJanuary200 3andApril 2006(phasetwo)inON.Diagn osedbetweenJanuary1999and Decem ber200 3in NL;

3)Diagnoscdatagcs ofJn to74yea rs old (phase one)orugcsofJuto50years (phase

lW O)in Ontari o;and

4)Reside ntsorO NandNLat the time or diagn osis.

The pathologist s ofthis study identi fi edelig ible casesbyview ing pathologyreport s generated bytheOntarioCancerRegistry andtheIcwfoundlandCance r Treatme ntand

Research Founda tion. Initial contact

was

made through the surgeo n/physician identified on

thepathologyreport.1\

letter was sent

to

the physician thatdescribed the

studyand requested permissionto contac t the

patien t. Once

physic ianconsentwas obtained, individuals werethen contactedby

researchers to

inform them of

the study. Pa rtic ipants who

indica ted the ir willingness to participate thestudy weresent, inscqucnee,awriuen conscntform,Family

History Quest ionna ire

(FHQ).Then,cases werecategorizedinto high,

intermed

iate,and low risk ofCRC(based mostly on

family histo ry).Subsequently,

100%of high and interm ediate, andonly25% of thesporadiccases

were invited to lill in Personal History Quest ionn aire (l'HQ), Food Frequenc yQue

stionnaire

(FFQ).

InNLonly, theorigina lstudy packetalso containeda bloodrequisition l'lmn.

If a participant did not return fin ished questionnaireswithin threc wccks.u nd u Iollow-up

telephonecallwas

made to ensure the

study package

had been received. lncertain

circumstances, atelephone

interview orassistance

wasoff ered.especia llywhen illiteracy or physicaldisabi litywasa conce rn,Subjec tswere

provided witha toll-tree telephone number

asaway

to contact

study staff'

ift hey had questions regardingany

of the items on questionna ireor proceduresrequire d lor

the

study. Multiple telephonefollow- upswere conduc tedifeligible particip antsdid not

respond to survey

questionnaires.

[fa subjec t made

anyindica tionof

not wanting to participate

in thestudy,the

intcrvi ewer

auc mptcd to

determ ine and

record the

reason.No further contact

was made with these subjects.Family

history questio nnaires were used to classify famili es as high, intermed iate orlow risk I'lH

· genetic counseling.

ln

NLwherebl ood sample swere eolleeted ,th e sampleswere sent

directly li'OI11the laboratory closest to theparticipant to a ccntral laborutory for investigation

ofgenetic

markers.

':U .2 C ont rols

Contro ls recruit edby the OFC CR andNFCC Rwere compri sed ofarandom sam p leof resident saged 20-7 4years ineach pro vin c e.Within afrcqucncymat chcdcusc-cont rol study, contro lswere5-yea ragegro upa ndsex ma te he dw ith thcco lo rce ta Icanc ercas es.InOnta rio, contro lswereide ntifiedthro ug ha listof reside ntia l phonenumbersprovid edbyBellCana da during1999 and2000.Info-direct , a serv ice fromBell Canada,provid edin forma tio n pert ainin gtopot ent ial controlsubjec ts, whichincluded theirnames,te lephon enumbers,and add resses.Househ old swer e rando m lyselec ted from thislistand telephonedtoobta ina ce nsuso fho us eho ld mem bers (ag ea ndsex )as a methodto identifyeligiblepersons.One eligib le personwithineachhou seholdwasra ndo ml yselec tedandinvitedtoparticipateinl he OFCCR.Toincre asethe sam plesizeand matchthecase to controlratiowas1:2;theref o re, add itio na lcontro ls wer eidentifiedfrompopul ation-ba sed ass essm ent rollstown er sand occupa nts) pro vid ed bythepro vincial govern me nt during 2001and2002.The detailed descripti on ofcontro lsselec tio ncan hefoundwithinothe r publ icati on s of this inte rdiscip lin'lIyC RCs tudy[ 180, 18 1].

InNL,controlswereidentifi edthrou ghrand omdig itdialing[IS2 ].Initially, a sct o f 192,000 possible resid enti altelepho ne numbers weregenera ted andrando m lyarra nge d. A research assista ntwith prior expe rie ncein tel eph on e survey ing madetheinitialcontac ts by dialingthosenumber sinaseq ue ntialorde r untilthedesirednumherofcontro ls wasreach ed.

A screening intervi ew was conductedamo ng potent ialcontrolsubj ectstoidentify if therewas an eligiblehouseh oldmemb erbased ontheirsexandage and whetherthatpersonwaswilling to receive a mailedfamilyhistoryquesti onn aire .

Inbothprovin c es,onceverba lconse nt torparticip ati onwas obtai ne dthro ug h telephon e

contact,asurveypackage was forwardedto each potentialparticipant.Thepackageincluded aninformatio npamphl etwithgenera linformation conce rning the study,aconsent 1(\("111, PersonalHistory Questionnaire (PHQ), FoodFrequency Questionn aire (FFQ),Family HistoryQuestionnaire(FHQ),aswellasaself-addressedstamped envelope,lfaparticipant did not returncomplete questionnaireswithin threeweeks, a1'011ow-up telephone call was madeto ensurethatthestudypackagehadbeen rcccivcd.Atelcphonc intcrvicw or ussistancc was off eredwhen illiteracy orphysicaldisabilitywasaconcern.

3.4 Response Rates 3.4.1 Response Rates in Ontario

Duringphase-one of the OFCCR(1997-2000).atotal 01'3776eligibleCRC caseswere identifiedinOntario.After the initialcontactwith the physiciansandeligibleCRC cases , 1593 werewillingandable topart icipate in the registryourofw hichI 187cases(75%) completedthe PHQ and 1143 cases (72%)completed theFFQ.

Phasetwo ofthe OFCC Rwasinitiatedin Janu ary 2003 andscheduled to continuetothe end01'2006.Consequently,phasetwodatawhich wereavai lable up toApril2006 were used inthisthesis. Duringthisperiod,a mongthe1263 eligible patientst hatwerecontacted,727 of whichagreedtoparticipate in the registry,I'HQs were return edby64 1(88%)casesandFFQ werereturnedby279 (3S%).

Population controls in Ontariowere contactedviatelephone ca lls.Atota lof2736 control subjec tsfrom Omar ioagrecdtoparti cipatein thestudyofw hich 1957(72'Yc.)completedall three questionnaires(FHQ,I'HQ.andFFQ).

Figure3.1.ONpopulationsample sizeand responseratestudaptcdfromSun [IS3])

Cases

( - )

Phase I:

1997-2000

Phase II:

2003-2006

1957conlrolsrcturIlcd I'IIQandFFQ(72'X,)

3776 eligiblecases contacted

1263 eligiblecases contacted

3A.2 Respon seRat esinNewfou nd la ndand Labrador

In total, among 1126eligible NLCRCcases,705 (63%)participated and returnedthe rHQ,and608 (54%)returned the FFQ.Population controls inNewfoundlandand Labrador were contacted throughrandomdigitdialing.The totalnumberof telephone callsmade was notrccorded.TnJuly2005,1,603controls had agreed toparticipatein thestudy insomeform.

720controls(45%)returned therHQ and687controls(43%)return edthe FFQ.

Figure 3.2.NL populati on samplesizeand respon se rates (ada pted Irom Sun [183])

( 1,126 eligible )

~

cases

705

cases

returned

PHQ(63%)

608casesreturned FFQ(54%)

3.5 Data Measurement

720

contro ls

returned

PHQ(45(%)

687contro lsreturned FFQ(43%)

Allparticipant s in theinterdisciplinaryCRCstudy were asked to complete self-ad ministeredmailedepidemiologiequestionnaires,which includethePersonal llisto ry Questionnai re(PHQ),theFoodFreq uencyQuestionnaire(FFQ),and the Family History Questionnaire(FHQ ).OFCCRandNFCCR usedthesameI'HQandFHQbut the FFQ betweenONandNLhadsome arcdifferences,

3.5.1PersonalHisto r y Quest ionnai re(PHQ)

ThePHQ wasdesignedtoinvestigate74 items of inform al ionpertainingtoparticipants.

addressingdetaile didentifyinginfonuatioutdcmographic churacteristicstage,sexand ma rital status}.bowelscreeninghistory(hemoccult test,sigmoidoscopy, colonoscopy,andendosco py

test} and healthhisto ry (dia betes,high cho les terol.hightrig lyce ride,etc},med icati onusc (non-steroida lanti-infla mma tory drugs,bulk-fo rm inglaxatives.othc r laxat ivesj.phys ical activity(specificactivitiessuchas walki ng,jogging,and running duri ng the ir 20's,JO-4(J's, and50's},alco ho lconsum ption(heel',wine, sake,liqueursduring their20's,JO-40's,and 50's},to hacco use, so cio-dcmograp h icfacto rstcd uca tio n.inco meand residen ce} and anthro pome tric measures(he igh t,body mass index).Amo ngfemaleparti c ipants, add itiona l question s add ress ingmenstruati on:pregnan cy; ages at men arch e;firstbirth; andmenopause;

pari ty;hyste rectom y;oopho rec to my;menop ausalstatus;andreason lormenop au se we re survey ed.Thisquestionnair ecanbefound in Appendix 1.

3.5.2 Food Freq ue ncyQuestionna ire(FFQ)

TheFFOad m inistered in the ONpopulati onwas origi nallydevelop edlo rtheHaw ai ian amiCalifornianpo pulat ion sby theEpide mio logyProgram of theCancer Research Centerof Ilawaii, whi chhas been previouslydescri bedand vali dated aga inst 24-hrecallsof a mult i-e thnicHawai ian/South ern Califo rnia n popul ation [I S4,IS5].See Appe ndi x2.TheFFO surveyedregularfoodconsu mption,andcooking meth odsof170 commo nfoods abo utone yearsbeforethe irdiagnos isforcases orthe ir interv iewforcontro ls.Participa ntswere asked to choo sethe portio nsize of their usualservi ngforeach listed tood item from 'Regu lar', 'Small'or'Large'.Thefrequencyoffood cons umption was assessed us ing S options(neve r orha rd lye ver,o neea month,2-J times amont h,onc e a wee k,2-Jtimes aweek,4-6timesa week,o ncea day,2ormore times a day }.Subj eelswe re alsoasked lo prov idein lllrlllationon the irusc of multi- or singlevitami nand/ormineralsuppleme nts.jncluding thcusualbrand , dosage,and durationofsuppleme ntintak e.

FFOadministe redinNL wasde veloped fromtheFFOusedinOnta rio to ada pt to the

uniqucl()()(( co nsumptionpattcmif thcp rovincc.Pa rticip ant swcrc askcdlo csl imat cthc frequen cyand port ion sizeoflovfooditemsoneyear priortotheirdiagn os is or parti cip ati on in this study. Forcachlllodilcm , subjcctswcrcaskcdlocstimatethefrcqucncy ofll)()d co ns umptio n (daily,weekly,month lyand neverscales) and the ir usualportionsizctuvcr age, smallerorlarger)abo utoncyea r their diagn osi sfor casesor theirintc rv icw forcontrols.The inlllrlnatio nonvita m insa ndo thc r d ictarysupp lcmcnts was alsocollCClcd.

3.5.3Family Histor yQucsti onna irc (FUQ)

ThcFHQ helpedtoco llccti n!(lrInati onofthcdiagn oscdtypeofcanccror tumour histor y of participants.Thesamcqucst ionswcrcuscdto surv cythcparticipant'smother,father, child re n, broth e rsandsiste rs, moth er' sbrother sandsiste rs (Nt. only).fathcrsbrothers and sistcrs(NLo nly)andothe rrelativeswho had cancer.

3.5,..1St udy Outcom es andExpos ureVaria bles

Forbothcasc sandcontro ls, CR Cwastheoutcomeint histhesis.For thefirstobjective of thisthesi s,themainstudyexposure wasrecreationalphysicalacti vit y.1\wa smeasured by

self-reported datafromthc PHQonCUITentand past ac tiv itiesofpartici pant s:thefrequen cy

anddurat io nof walki ng . jogging,running,bicy cli ng,swi m m ing,tcnni s. xqua sh/racquctball, calisthe n ics,aerob ics,vigo ro us dance ,football. socce r/rug by,basketballandsubj ec ts

self-reported parti cipationinotherspo rts whena participantwasbetweentheage s of~0-30,

30-50 , and 50orolder.The questionsregardingphysica lactivitywe re"Inyour~os.didyou pa n icipa tcregula rly in physicalactivityforatotalof at least 30minutesa week?Please desc ri be youractiv ities below.Walk ing-yes orno:For howman y ycar s'?Duringtho se years, forhowman ymonth sper year'?Duringthosemonth s, onuvcrage.Torho wman yminut es or

hour sperweek'?"Thesamequestion swereaskedof jogging,running,bicycl ing, swim ming andsoonadd ressingthreepe riod sin total(20-30s,30-50s,and 50splus).Particip antswere askedto spec ifythefrequ encyanddurationof activitiesnotincludc dun thequestionnnirebur participantsdid considertoberecreati onal exercise.

Thederived limetakingfrequencyand durati onintoconside ra tion,that the particip ant spentoneachexercise afte r they reached theageof20 wa smultipli cdbyits spec ific metab oliceq uiva le ntsscore (METs)toyieldaMET-hourscore[186,187).Averageweekly METhour sliJrwalkin g,non-walkingexer ci seandlotalrecr eati onalphysicalactivit ywere calculat ed.After calcul ati on,walking,non-w alkin gexercise and totalrecreational physical activi tywerefurtherdividedintoquintilesaccordingtopercent agedistributi onolco ntrols

«020,<0 40,<060,<080,2':080).

For thesecondobjectiveof thisthesis,thecomplexinter-relation shipsamo ng socioecono micsta tus(SES), lifest yles,diet,and healthinvol ve awidernngc ofcxpos ures . Theco revariableswer edivided intoseveralas pects . Putativecova riates forthe main exposure variables incl uded:I)dem ograph icfactors:age(18-39,40-49,50-59,60-69,70+), sex (ma le,fem ale),marit alstatus(sing leor ne vermarried,currentlymarriedor livin gas ma rried , separated,divorced orwido we d),2)soc io-eco no micsuuus-c ducational lcvels.

hou seholdincome(0-SII ,999,$12,OOO-S29,99 9,S30,OOO-$49,999,$50, O00plus),residence (rural,urban); 3) medi calhistory:anyscreening procedurewhichincludcdhemocculttcst, sigmo idoscopytestand colonoscopy,indicat edas dichot om ous(yes/no);sel f-reported health conditions werecode das "yes/no" : polyps,familialadenomatouspol yposis, Crohn's,colitis, diabetes,high trig lyccridcs/c ho lcstcml:use ofmedicat ion sandsupp lemcnts:non -steroidal unti-inflummatorydrugs,bulkfunningla xatives,non-bulklimn inglaxat ives;4)dietary

patternsmeasur edbyfood groups(units: gra m orserv ings/day );5) averageweekly MET hou rsof physicalactivity level atages of20-29,30-49,50+,and lifet ime;6) alcoho l consumpt ion: ave rage weeklydrinksatages of 20-29,30-49,50+,and lifetim e;7)smoking:

cigarettesmoki ngstatus (curre nt, former and never)and pack- years;8)8MIcategor ized by World HealthOrga nization(W HO )criter ia: underwe ight«18.5 kg/nr' ):normal weight (18.5-24.9kg/m):overwe ight(25 -29 .9 kg/rn"): andobes e (2:30kg/m).Two8M! indice s were usedforthisana lys is:first,rcccnt-Blvllwa s ca lculated frombod ywe ightduringthe refer enc eperi od( one yearpriorlodi agn osisfor ca se s or one yearpriortoparticipati onf(lr contro ls);seco nd, 8Mlataboutthe age o f 20waseslimat edlromthcirsc lf-rc po rtcd bod y weighl atthea geo f 20 .0lherprimalyexpo sure sofinterestinclud ed adultweight gain , whichwasderi vedby gett ing the difference betweentheir weight(kg)at20yearsofageand recent weight (kg),andad ulthoo d height(m).Amon gwomenonly,additionalpotential confoundersincluded:agesat menar che .firstbirth,and men opau se:parity;hysterect om y;

oophorectomy;men opau salstatus;andreason formenopause.The mainstudyvaria bleswere alsoasse ssed fllrconfound ingin llue nceo neac hothe r.

3.6 Data Analysis

To ana lyzethedata collec ted forthefirstobjec tive,SASsta tistica lso ft wa re(version 9.1 SASInstitut e,Cary,NC, USA)wasused.M-PLUS5.0software (Muthcn8:.Muthcn) were usedtoperf orm sta tistica l analyseslo rtheseco ndobj ective0Ithisthesis.

3.6.1Descriptive Analysis

Uni-variatenna lysiswasdonetoexamine distr ibut ion s and detectoutlicrs.Theexposure variablesof cas es andcontrols werecompared by /tests l(lrcontinuous varia b les.and

chi-squa retestforcategoricalvariables.All test sorstatistical infcrcn cccmp loyed a two-s ided alpha le vel 01'0.05.

3.6.2 i\lultivariablcRcgressions

To add ress thefirst obje ctiveof thisthesis.sex spec ific age-adjustcdand multivariate adjustedodds ratios(OR)andtheircorrespo nding 95%confi denceintervals(CI)were calcu lated usingunconditionallogi stic reg ression toasse ssthe associations betw eenphysical

ncuv ity undCkf.risk .Tests Iorlincartrcnd were donebymodelingthcrncdianvaluc ofcach quintileorphysicalaetivilyllleasuredbylllet ab oli c equi valent(MET)hour sperweek intothe logi sti cregressionmod el.

3.6.3 Structural Equation Modelling

The directandindirec teffects forvariousrisktilctor s oncolorec la lcancerweretesled usingstructuraleq ua tion model ing(S EM) .SEMis amultivariat etechniquecombining

aspects ofmuItipleregressionsexaminingdepende ntrclationshipsand facto ranalysis representing non-directlymensurab leconceptorlatent va riab lesmca surcdthrou ghmulti plc indicat or sto simu ltaneo us lyestimateaseries ofi nte rrelated dependencerclati on ship sjlSx,

IX91·

SEMana lysis isprima rily con firma tory in natureand basically consistsortwoprimar y cOlllponenls, lhemeasurelllent modeland thes lruelura leq ualion lllode l [ IXX,IX9]. T he measur ement mode l invol vesusingfactoranal ysi s10developanaccepta b le model.which reduces obser vedllleasured va riablesloaslllallernulllberorl atent va ria bleslilctors andto ens urethattheindicat orvariablesload edsign ifi cantly on underlyin glatent factors .The

structuraleq uat ion modeldefinestherelationships amo ngthese0bservedvariab les ,lat ent factorsundco variat es.

Trad itional tec hniq ues,suchasreg ressionandpathanalysis,analyze onlymeasure d variab les;howeve r,SEMtakesinto accountofmeasurement error and cou lddealwith latent variableswhicharcnotdirectl ymeasura b le.Factors aresignifiedwithcirclesand the observedvariablesarcrepresent edwithrect angles.Using measured varia b lesasindicat ors of latentfactorsrather thansimply takingthesumor average ofthemeasureditemsasascale allowsforesti ma tionand removal of the measurem enterro r associate dwithobserved va riab lcs [ IS8].

Food gro upsdietarypatternsand lifestyl eswe re re presented bylatentvariab les. Howe ve r, duetothecomplexityof thedietar yand lifestylesfact ors, seve ralapproaches(single laten t, multiplel atent,and ma nife stvar iables)we re exp lor ed a nd compared.Thiswasgu idedby exploratoryfactorana lysis,andour unde rstanding oftheassocia tionsofinterest.Genetic facto rsshouldbeconsidere d in buildingmodel s sothisstudytookthefam i lyhisto ry scoreof CRC(prev iouslyderive d)asacontinuous variableintocons ideratio n. Wefeltthis simplificationwasnecessaryinordernottolosesightofthcmain obj ccuvc.DtherIactors.

suchasage,gende r,andcomo rbid iticshavealsobeenconsidered.However, sinceothe r variablesarenot our prim ary interest,thisstudyonlyconsid eredsomemaincom mo n cand idate riskfac torsofC RCaspotenti al confound ingfactors.Theconce ptua l mod elswould alsoberevisedandcomparedwithanumber ofcom pe tingmod els.

Modelli ti nd iceswere evalua tedbasedo nthe lllllowing :Col11parativeFitIndex(CFI), theTuck erLewisIndex (TLI),RootMeanSqua reErro rofApproximatio n(RMSEA ),

We ight edRootMean Sq ua re Residual (W RM R),andSta nda rdized RootMean Sq ua re Residu al (SRMR).

Cha pte r 4 Project I:Wal king, Non-wa lking Exercise and Co lorecta l Cance r - a large population based case-control study in Canada 4. 1Abstract

Background:

High erlevel s ofphysicalactivityhavebeen co nsistc ntlyassocia tcdwithalowcrriskof colo rcc talcancerK'Rt" ) inpreviou s stud ies.Neve rthcless.jhespec ificmodc.intensit y, frequency,and durationofphysical activityrequiredforcolo rcc talcancer preventionarcno t wellknow nandremaincont ro ve rs ial.Thisstudy examined theassociatio nsamon gwalking, non-walki ngexercise,tot alrecr eati onal physica lactivityandcolo recta lcancer risk, Methods:

Th isstudyused datacollec ted from anexistingpopulat ionbased case-controlstudy in OntarioandNewfoundlandandLabr ad or,whichcollect edparticip ant'sperson alhisto ry.lilc

style and diet aryinformationusing aPersonalHisto ryQuestionnaire (PHQ) .FoodFrequency Ques tion na ire(FFQ )andFamily Histo ryQuestionnaire (FHQ ).Mu ltiva riatelogistic regression analysis wasusedto estimateoddsratios (OR) and95%confide nce interval (95 'X,CI)afteradjus tingpotentialconfoundingcovariatcs ,

Result s:

Resultfromthis studysho we d thatthehighestquintilc o fwalki ngwas associatedwith inc reasedcolorec talcance rrisk for bothmale s andfema lesinboth pro vinces (highestVS lo west:ON:OR=I.5I.95%CI=I.07-2.13:NL: OR=2.01.95%CI=1.25-3.22:pooledana lysis:

OR=I.70.95%CI=I .09-2.66).Howe ver,thisresu ltcould be bia sedbecause ahigher proportion ofea sesrespon dedtothisitelllthanconl rois. Non-walkingexercisewasnot sig nificant lyassociatedwith reduced risk ofcolorectalcanceI'forbothsex andpro vinc es.

Total recreati o nalphysical activitywasnotsubstantiallyassoci ated withCRCrisk.

Concl us io ns:

These findings suggest thatincre asin gamo untsofnon -walk ingexercise sugges teda non -significantl y red uce d risk of coloreetaIcancerwh ilewalkingdoc snot. further large populationbasedprospecti ve stud ieson physic alacti vity(walking,non -walking, and total activities ) arc neededto cvalua teeflec tive frequ en cy,dura tionandintensityof physical activityin rel ati onto colonand rectal cancer prevent ion .

4.2 Introdu ction

Colo rcctalcancer (CRC)is thethirdmostcomm oncancerinCanada, withanestimated 22.5 00new case sand9,100 deathsin20 10[II]. Engaging in physicalact ivit yha slongbeen consideredas aneffective stra tegy forcanc e rprev ention[12]. Comprehensive reviewsfound that incr eased physical activityisasubsta ntialprotectivefactoragainst colo norco lorecta l cancer[13 -16].Alargenumbero f prospective [17-20 ]andcas e-control[21,22]stud iesha ve IlHlIldstatistically signiticant associa tionsbet weenphysicalactivityandcolo ncancer, espec iallyformen . whileafewstud ieshave exa mine dassociationsin rectum canc er indi catednosign ificant associations[23-25] .Stud ieshaveindicatedthat physi calactivityhas differe ntia leffects onsub-s ite ofcolorcctalcancer [190-194].There fore,thebeneficialrole of phys ical activityintheprevention ofcolonand/or rectal canceris inconsistcntundvaricd betweenwome n and men [17.21. 25.26.150.151 ].The measurement of physicalactivi tyin thesestud iesvariedandwasbasedon limitedtyp e ofactivi ty.Thetype,frequen cy,duration and intensit yofactivi tiesarc import antcomponentsof publichcalthknowl cd gcasthey pertaintoredu cerisk ofcolorec talcancer [12,26] ;howe ver,thiskindofi n formationis lim ited.

Walkingis oneoft he most com mo n form s otmodcratclevel physical activity amo ng .15

middle-a gedandolde r peopl e[195].ItsimpaetonCR Criskhas onlybcencxam ine d bya few stud ies [196-198].Guide linesfrom theWHO Libra ry Cata log uing in PublicationData [199].Centers lorDisease Controland Pre vention .AmericanCollegeof SportsMed icin e [200].as wellastheSurgeonGeneral'sReport on PhysicalAc tivityand Hea lth[2DI]. all recommen dedat least3Dminutesof mod erateinten sityphysical activity on live ormoredays aweekandadvisesome regularvigorousexerc isellxbe lter hea lth.Thisdiffersfrom earlier guidelinesthatadvisedvigorousexe rc iseforat least 20 minut esthrceor mo retimesperweek [202].Altho ug h the guidelinescan beeasilymet bymostof thepopulauouthcpot cnt ial benefit sofm oderateintens ityphysica lactivity.parti cul arl ythespecific roleofwalki ngin canc er prevention.arcunclear.In addition.the actualrolc of'non-wa lkingexerc iseaga ins t colo rectalcancerrema insrelat ivelyunexpl or ed.

The purp oseofthispape r wastoI)exam ine the associations ofwalking.non-walking exercise.tot alrecreational physical activi tyandcolorec talcancerrisk usin gthedata-b as eofa largepopulatio n basedcase-controlstudyinCanada;2) com pa re theroles of walking. and non -wal kingexerciseincolorectalcanccr risk :3) exami newhetherdifferenteffects of phys icalactiv ityoncolore ctalcancerex istsbetweenOntar io(ON)and ewfound landand Labrador(NL).

4 ..1Methods SIIl(~Vpopulation

This studyusedthe dataofNewfoundlandand Ontario Colo rec ta lCancercase-contro l study.IncidentCRCcaseswer e recru ited fromtheprovincialcancer registries,resultin gin the establishmentof Onta rioFam ilialColo rectalCance r Registry (OFCCR)and NewfoundlandFamilialColorectalCancerRegistry(NF CCR). Cases aged20-74yearsand

diagnosed during

1997-2000 (phaseI), 2003-2006

(phase

II) inON, and

2003-2006

in L

were identified:and their

pathology reports

were veri tied by study staff( pathologyconlirmed

ICD

9threvisione ode s:

153.0-1 53.9,154.1-154.3,and 154.8; or ICD -Ocode s:18.0-18.7, 19.9, 20.9).

Controls werea

rando msample of

residents

aged 20-74 years old inONand

L. In

Ontario,c

ontrolswererec mited throughal istofreside ntial phone numbers or population-based assessment

rolls provided

byBell Canada andtheprovinc iulgovcrnmc nt, respect ively.In NL,controlswere ident ifiedthrough rando m digitdialing.

Datu collection

Once verbalconsent

forpart icip ation was

attained through telephonecontact, asurvey packa ge was forwarded to each poten tial participant. The package contained a

pamphl etof generalinformation

concerning the study, a consent

form ,

a

self-administered Personal Histo ry Questionnaire

(PIIQ), Food Frequency Questionnaire

(FFQ), FamilyHistory

Questionnaire (F HQ),and as elf-auuresseustampede nvclo pe.

lfa particip antdid notreturn

comp letequestionnaires within6-S wecks. und a

foll ow-uptelephone call weresent to ensure

that part ic ipants

received and return edthestudy

package.Atclc phone

interview orass istance

was ol1credwheni lliteraeyo r physicaldi

sabilitywas a conce rn.

Measu resofexp osu re

The PHQ was

designedtoinvestigate 74

items ofi nformation on participant s, addressing

detai leddemographic characteristics.medical conditions,physical activity,screeninghistory, useof medication, and

the consumption of'ulcoholand tobacco.Among

femalepart icipants.

additionalquestions

regarding reprod uctive

concerns wcrcsurvcyed.The FFQadministered

in theONpopulationwasthe well-known Hawaii FFQ.The FFQinNLwasadapledto address theuniquefoodconsumption patternof thatprovince.TheNLFFQ was arevisionof theFFQ usedinOntario.Part icipantswereasked to estimate thefrequency andportion size of food items oneyearpriortotheirdiagnosis or participationin this study.

Recreationalphysicalacti vitywas measuredusingPHQ bythefrequ ency and duralion of walking.jogging,running,bicycling. swimming, tennis,squash ra cquetball,calistheni cs, aerobics. vigorousdance,football,soccerrugb y,basketball andsubjeets'self-reported participationinsportsduringthcirZtl-Ju's, 30-50·s.a nd 50'sand beyond.The questions regardin gphysicalacti vitywere "Inyour20's,didyou participateregularl yin physical activityforatotalof at least30minutes aweek?Pleasedescribe your activitiesbelow.

Walking-yesorno:For howmany years? Duringthosemonths.onaverage,forhowman y minutes orhoursper week?"Thesamequestionswereaskedof jogging.funning,bicycling.

swimmingandsoonaddressingthreeperiods in total(20-30's,30-50 's,and50'splus).

Partic ipants wereaskedto specify thefrequencyand durationof activitieswhichoursurvey questionnairedidnotspecifybutyetparticipants consideredbeingrecreationalexercise.

The derived lime.lakin gfrequ encyandduration into consideration,spentoneach exerciseafter the participant reachedthe age01'20 wasmultipliedbyitsspecifi cmetabolic equivalentsscore (METs)toyieldaMET-hourscore[IR6.IR7].Averagewee klyi\IET hours 11)1'walking,non- walkingexerciseand totalrecrcationalphysicalactivitywcrcca lculuted.

Next.walking, non-w alking exerciseand totalrecreationalphysicalactivitywere further dividedintoquintilcsaccordingtopercentagedistributi on ofcontrols «Q20,<Q40.<Q60.

<QRO.?:( 80).

Fortheanalysis,pa rticipa nts withimp lausiblyhighorlowtot alene rgyintakes{<2.5'X.

or>2.5% :inNL,925and 4700kcalIormen ,liDO and 4900kcalforwomen:in ON,104 0

and5200 kcalformen,835and 4100kcalforwomen ) [183],and the patientswho had familialadeno ma touspolyposis (FAP)andan in-s itutumor wereexclude dfromtheanalysis . Afterthese exclusio ns, based onthosewhocomple tedboth thePHQandFFQ ,3102subjec ts (1272cases and1830 contro ls) from ONand 1139 subjec ts(488eases and651contro ls) from NLremainedlorthe ana lysis.

Statistica l analvsis

I'ot entia lconfo und ing co vari ate swere scl ectedbased on thei rob servedrelatio nshipsto colorectalcancer throughChi-s quare testin g(P<O.IO)and previou s studies thatsugg ested plau sibl e associationswith physic alactivity andcolo rcc talcanccrCova ria tcsincludedin the final multiva ria temodel wereage;sex;house hold incom e{<12,000,12,000 -29, 999.

30,000-49,999,:::':50.(00);educa tion {lowe rthanhigh schoo l.high sc hoolgrad ua te,college, bachcloror higher);ma ritalstatus{ ma rried,singleor neverma rried,separatedo rdivo ree dor widowed); diabete s (yes orno );hyper cholc ste rolcmi a{ yes orno );use ofaspi rin tycsor no ), non -steroidalaru i-inflam matorydrugs(yes orno ),laxatives {yes0r no),andalcohol{uni t in gram);total inta ke of iron(uni tin milligram), calcium (unit in mi lIigram ),vitaminD {unitin mic rogram ),dietaryfibre (uni tingra m), folate ac id (unit in micro gram)andsaturatedfat (unitingram );totalene rgy intake (kCal);pack yearsofsmo king (<Iyea r.<10 ,<20.<40,

:::':40);BodyMassIndex (under weight<18.5,normaI 18.5-25, overweight:::,:25) andBMIchange

(I3MI2 yearsbeforediagnosisminusBMI in their20 's).

Descriptive statisticswere used to compa recharacteris ticsofcases andcontro ls.The study used multivar iatelogisticregressionto estima teOdds Ra tios(OR) anda 95%