Published by Maney Publishing (c) Liverpool School of Tropical Medicine cancer. to schistosomiasisof24%forcoloncancer,and(amongthehepatitis-negativepopulation)one27%liver cancer (oddsratio to besignificantlyassociatedwithbothlivercancer(oddsratio China, onlydatafromhepatitis-negativepairswereusedintheanalyses.Previousschistosomalinfectionwasfound with thesubjectsortheirrelatives.Givenextremelystrongassociationbetweenhepatitisandlivercancerin somiasis-control stationsorhealth-surveillanceunits,and,whennowrittenrecordcouldbefound,byinterviews was determinedbyexaminingthemedicalrecordsatcountyhospitals,searchinglocalschisto- diagnosed, whenthecontrolhadbeenfoundtohaveanillnessotherthancancer.Previousschistosomalinfection cases). Eachcontrolwasselectedusingthehospitalrecordsforsameyearmatchedcaseofcancer Meishan (66liverand54coloncases),Pujiang(1622cases)Xichang(4566 hospital recordsofthreeSichuancounties(allwhichhavesomelevelendemicschistosomiasisjaponicum): matched, byage,gender,hospitalandtownship,withoneortwocontrols.Thecancercaseswereidentifiedfromthe in ruralSichuan,China.Thedataanalysedcamefrom127liver-cancerand142colon-cancerpatients,each A studyofliverandcoloncancerstheirassociationwithapreviousdiagnosisschistosomiasiswasperformed Accepted 17September2004 Received 9March2004,Revised15September University ofCalifornia,Berkeley,CA94720-7360,U.S.A. † * D.-C. QIU*,A.E.HUBBARD Schistosoma japonicum A matched,case–controlstudyoftheassociationbetween 5815. E-mail: [email protected]; fax: Reprint requeststo:A.E.Hubbard. et al Sichuan hasalreadybeen described (Spear ology ofschistosomalinfection inrural the studywerecollected.Thebasicepidemi- live inSichuanprovince,wherethedatafor 850,000 individuals,ofwhomabout10% S. japonicum fically liverandcoloncancers.InChina, cers plausiblylinkedtothisinfection,speci- pathogen, the associationbetweeninfectionwithone The aimofthepresentstudywastoexamine infections bypathogens(Pisani of thoseinthedevelopingworld)resultfrom An estimated15%ofallmalignancies(22% rural China Annals ofTropicalMedicine&Parasitology DOI: 10.1179/136485905X19883 DOI: © 2005TheLiverpool SchoolofTropicalMedicine Division ofEnvironmentalHealthSciences,140WarrenHall,SchoolPublicHealth, Sichuan InstituteofParasiticDiseases,10UniversityRoad,Chengdu,610041,China ., 2004). Schistosoma japonicum = now infectsapproximately 3.3; 95%confidenceinterval et al. † , B.ZHONG*,Y.ZHANG* and R. C.SPEAR , Vol.99,No.1,47–52(2005) , andcan- + 1 510642 , 1997). and = 1.8 -

liver andcoloncancers,in 6.1). Theresultsindicateafractionofdiseaseattributable certain cancers withschistosomalinfection. Previous evidence doeslinktherisk of colo-rectal andlivercancers, respectively. wall andportalcirculation canleadto discussed below,thedamage totheintestinal It isspeculatedthat,byvarious mechanisms tributaries, causinggranuloma formulation. lation, wheretheylodgeinsmallportal wall, orarecarriedintotheportalcircu- an inflammatoryresponseintheintestinal these veins,leadingtoulcerativelesionsor in thefaecesorurineareeitherdeposited mesenteric veinsandtheeggsnotreleased granulamotous reaction.Theadultsresidein in thefaecesorurinearetrappedbya and layeggs.Theseeggsareeitherreleased blood totheliver,wheretheymature,mate, cercariae, theparasitesmigratethrough = After humansareinfectedbyschistosome 3.7; 95%confidenceinterval = 1.0 - 13) andcolon † Published by Maney Publishing (c) Liverpool School of Tropical Medicine baboons, At leastduringexperimentalinfectionsof carcinogen (Hicks subcarcinogenic dosesofaknownbladder tumour focithathavebeeninducedby to acceleratecancergrowthfromlatent to supplytheproliferativestimulusnecessary ment ofneoplasms(Mostafa eggs inthebladdercanpromotedevelop- result fromtheimmuneresponsetoparasitic indicate thattheinflammatorylesions studies onhumansandothermammals Egypt (Mostafa S. haematobium association betweenbladdercancerand Specifically, several studieshaveshownan 48 mansoni evidence alsoexistsforlivercancerand 1967) et al of marginalstatisticalsignificance (Zhang association wasfoundtobeweakerandonly cancer (rectal),however,thecorresponding mutations inthe et al of significantly associatedwiththepresence cancer tumours,forexample,appeartobe Particular mutationsin tumours co-occurringwithschistosomiasis. tively highfrequency,incertaincancerous suppressor genehavebeenfound,atrela- Specifically, mutationsinthe in studiesofcancerandschistosomiasis. dence ofinducedmutationshasbeenfound genotoxic effects(Rosin N-nitrosamines andintheinductionof implicated intheformationofcarcinogenic endogenous oxygenradicals,whichare phages andneutrophils)aresourcesof initiation. Inflammatorycells(e.g.macro- are directlyassociatedwithincreasedcancer tion andirritationinducedbyschistosomes tions haveshownthatthechronicinflamma- focused onthe associationbetweencancer only afew epidemiological studieshave established (Mostafa cancer and The resultsofbasicbiochemicalinvestiga- Although anassociationbetween bladder S. haematobium ., 1998). ., 1990).Intheonepublishedstudyon . QIU infection inmice(Domingo S. haematobium ET AL. S. haematobium p53 et al infection, particularlyin et al (Alaa, 1996;Thomas gene, ., 1999).Datafrom et al et al ., 1980).Similar infection appears p53 S. japonicum ., 1995,1999), has beenwell ., 1994).Evi- inbladder- et al p53 tumour- ., 1999). et al and S. ., and the Sichuan counties ofMeishan,Pujiang cancer diagnosed between1995to2002 in Records ofallthecases liverorcolon Data Collection of Sichuan. three ruralcountiesintheChineseprovince using recordscollected,retrospectively,in incidence ofliverorcoloncancerisexplored, history of study, thelevelofassociationbetweenany A case–controlstudyinJapan(Inaba endemicity andlivercancerwasobserved. positive associationbetweenschistosomiasis and cirrhosisweredetermined,asignificant standardized mortalityratiosforlivercancer areas (forschistosomiasisjaponicum)and divided intoendemicandnon-endemic 1973 and1992.Whentheprefecturewas disease intheYamanashiprefecturebetween study of (1998) reportedtheresultsofanecological S. japonicum significant association,however,between selection ofcontrols).Theyobservedno OR between4.5and8.3(dependingonthe (Guo miasis andthoseattributedtocoloncancer rates ofmortalityattributedtoschistoso- significant correlationbetweenthereported 49 Chinesecounties,forexample,revealeda ecological studyofnutritionandcancerin the resultsofseveralsubsequentstudies.An 1981), anobservationthatwassupportedby schistosomiasis noted thecoincidenceofcoloncancerand 9.5. Duringthe1970s,researchersinChina history, withaestimatedoddsratio(OR)of develop livercancerthanthosewithnosuch S. japonicum 1984) revealedthatthosewithahistoryof rectal cancerand province andfoundanassociationbetween of colonandrectalcancersintheJiangsu reported theresultsofacase–controlstudy In thepresent,matchedcase–control S. japonicum. SUBJECTS ANDMETHODS et al S. japonicum S. ., 1993).XuandSu(1984) and coloncancer.

infection weremorelikelyto japonicum

at thepatientlevel(Zhao, InJapan,Takemura S. japonicum infectionandliver infection andthe that gave et al et al ., . Published by Maney Publishing (c) Liverpool School of Tropical Medicine control status ofthepatient. infection data wereblindedtothecase/ unexposed. Theresearchers collectingthe of schistosomalinfection was considered A subjectwithnorecord(from anysource) subject’s historyofschistosomal infection. subject’s familywereinterviewed aboutthe the subject(ifalive)ormembersof the subjectwascontacteddirectlyandeither of historicalinfection,thenthefamily written recordscheckedprovidedevidence were examined.Finally,ifnoneofthe surveillance officeinthesubject’stownship station, thentherecordsathealth- previous infectionwasfoundatthecontrol nosis) wereexamined.Ifnoevidenceof county inwhichthesubjectresidedatdiag- somiasis-control station(i.e.thatinthe tion thentherecordsatrelevantschisto- yielded noevidenceofschistosomalinfec- each subjectwereexaminedfirstbutifthese had beenchecked.Thehospitalrecordsof mation onpreviousschistosomalinfection somiasis orthelastpossiblesourceofinfor- had beenfoundtohaveahistoryofschisto- labour-intensive wereuseduntilasubject retrieval thatwereprogressivelymore whether acaseorcontrol,systemsofdata tis Bwhilehospitalized).Foreachsubject, gated hadbeenroutinelycheckedforhepati- in hepatitis-Btests(allthesubjectsinvesti- see ifthesesubjectshadbeenfoundpositive of theirmatchedcontrolswerecheckedto case.) trols wereidentifiedtopermittwocontrols/ cancer cases,toofeweligiblematchingcon- selected, wereinvestigated.(Fortheliver- mately 10,000)butotherwiserandomly lation inatownshiptheseareasisapproxi- and townshipofresidence(themeanpopu- matched withthecasebyage,occupation (liver cancer)ortwo(coloncancer),each eases). Foreachcancercase,onecontrol (predominantly heartandrespiratorydis- period butfordiseasesotherthancancer admitted tothesamehospitalsover county hospitals.Thecontrolswerepatients and Xichangwerecollectedfromthethree The recordsoftheliver-cancercasesand CANCER ANDSCHISTOSOMIASISINCHINA S. japonicum of associationbetweenevidenceprevious Day, 1980)wasusedtoestimatethelevel Conditional logisticregression(Breslowand Statistical Methods whom theywerematched). examined thanthecolon-cancercaseswith removed duringsurgeryandmicroscopically tissues thatcommonlycarryschistosomeeggs controls wereconsideredlesslikelytohave a schistosome-exposedsubject(sincethe schistosome eggswasnotusedtodefine unwanted bias,however,thedetectionof removed duringsurgery.Toreduce histological examinationsofcolontissue eggs hadbeenrecordedduringtheroutine patient werecheckedtoseeif terms, ahigh significance ofthemultiplicativeinteraction In theWald-typetestsusedtoevaluate the potentialmultiplicativeinteractions. was included,however,inexplorationsof hepatitis andschistosomiasis].HepatitisB to examinethepotentialinteractionof et al. such astrongpredictoroflivercancer(Inaba were analysed[ashepatitisBinfectionis that hadbeenfoundnegativeforhepatitisB ction, onlythedataforcase–controlpairs between livercancerandschistosomalinfe- cancer. Inexploringtherelationship of effectmodification. cases ( nantly agricultural counties,nearlyall the expected giventheirresidence inpredomi- there weremoremalesthan femalesand,as from Meishancounty.For bothcancers, ity (52%)oftheliver-cancer caseswere for 35%oftheliver-cancercases. Themajor- from Xichang(46%),whichalsoaccounted of thecolon-cancercasesinvestigatedwere data availableforthepresentstudy.Most Table 1containsthelimiteddemographic Demographic Characteristics The hospitalrecordsofeachcolon-cancer , 1984)andthereweretoofewsubjects i 95%) werefarmers. Most(60%)of infectionandliverorcolon P -value indicateslittleevidence RESULTS S. japonicum 49 Published by Maney Publishing (c) Liverpool School of Tropical Medicine families revealed 9%,71%,9%and11% lance-office records andinterviewswith the study, hospital,control-station andsurveil- pairs remainedavailable.In theliver-cancer of apositivehepatitistest, only 48matched those case–controlpairsthat hadnorecord data analysesforlivercancer werelimitedto for hepatitisBwhilehospitalized.Whenthe matched controlshadbeenfoundpositive the liver-cancerpatientsbutonly4%oftheir 50 QIU ET AL.     colon-cancer andliver-cancerstudies TABLE 1. Hepatitis B 254 Age (years) 127 Gender Occupation 127 County Investigated 427 Age (years) 142 Gender Occupation 285 County Investigated oiie5()7 6)81(32) 76(60) 173(68) 51(40) 5(4) 180(71) 122(96) 3(1) 96(76) Positive Negative 31 251(99) 1(1) 84(66) > 32(13) 126(99) 132(52) 43(34) 90(35) 45(35) 2(2) 125(98) 16(13) Male 66(52) Female 45(35) 16(13) Farmer 66(52) Other Xichang 265(62) Pujiang 161(38) Meishan 26(6) 85(60) 403(94) 57(40) > 180(63) 11(8) 131(92) 66(15) 198(46) 104(36) 163(38) 66(46) 272(95) 15(5) 22(15) Male Female 54(38) 132(46) 44(15) Farmer Other 109(38) Xichang Pujiang Meishan 82 1)2 1)42(17) 48(19) 21(17) 91(36) 73(29) 22(17) 46(36) 21(17) 38(30) 26(20) 45(35) 35(28) 68 61–68 50–60 27–49 95(22) 111(26) 27(19) 109(26) 112(26) 45(32) 33(23) 68(24) 37(26) 66(23) 76(27) 75(26) 68 61–68 50–60 27–49 Demographics, bycase–controlstatus,forthesubjectsof otosCssAllsubjects Cases Controls tion, forallthe subjectsinthecolon-cancer The dataon historical schistosomalinfec- Infection Association withSchistosomal tively. study were35%,52%,3% and 10%,respec- corresponding valuesforthecolon-cancer schistosomal infection,respectively.The of thesubjectswithevidenceprevious No. and(%)of: 2)74(29) (24) Published by Maney Publishing (c) Liverpool School of Tropical Medicine cancer (among hepatitis-negativesubjects). cancer and27% (CI mated at24%(CI table toschistosomalinfection canbeesti- population, thefractionof diseaseattribu- prevalence ofschistosomal infectioninthe disease assumption’andassuming a14% odds ratiosdeterminedandusingthe‘rare- cancer. Inthepresentstudyarea,given to thediseaseburdenofbothliverandcolon S. japonicum This studyprovidesfurtherevidencethat cancer thanthosewithnosuchhistory. times morelikelytohavecolonorliver schistosomal infectionaremorethanthree that hospitalizedsubjectswithahistoryof results. Thus,thepresentdataindicate gender didnotsubstantivelychangethese 3.6; CI japonicum (CI) cancer [OR between lar, significantlevelofpositiveassociation case–control status.Theresultsshowasimi- study, areshowninTable2,splitby negative forhepatitisBintheliver-cancer study andforthecase–controlpairsfound = 1.8 = 1.0 S. japonicum - infection andlivercancer(OR = 6.1; infectionmightbecontributing - 3.3; 95%confidenceinterval DISCUSSION a hepatitis-Btest. *These resultsexcludeallsubjectsknowntohavegivenapositiveresultin     with andwithoutevidenceofhistoricalschistosomeinfection TABLE 2. 13.1; netgtd125 173 51 122 History ofschistosomalinfection? Investigated netgtd2512427 142 285 History ofschistosomalinfection? Investigated P e 6(3 7(3 33 140 17(33) 34(67) 16(13) 106(87) Yes No e 1(4 2(0 83 344 42(30) 100(70) 41(14) 244(86) Yes No < = P 0.01] asbetween 10% = = infection andcolon 0% 0.05). Adjustingfor The comparativefrequenciesofcolonorlivercanceramongthepatients * - - 42%) forcolon 63%) forliver CANCER ANDSCHISTOSOMIASISINCHINA = S. otosCssSubjects Cases Controls funded by the NationalInstitute of . types ofcancer. but mayalsoreducetheincidences ofsome of thedirectmorbidity schistosomiasis, have immediatebenefits,from thereduction of schistosomiasisjaponicumwillnotonly tions, itappearsthatreducingtheprevalence previous observationsofsignificantassocia- S. japonicum have beensuggestedaslinksbetween Thus, giventheplausiblemechanismsthat present at,orbeadmittedto,ahospital. patient sufferingfromaseriouscancerwould significantly affecttheprobabilitythata historical schistosomalinfectionwould source ofbias,anditseemsunlikelythat infection shouldhaveminimizedthefirst search foranyevidenceofschistosomal present study,however,thelabour-intensive with canceronly(Berkson’sbias).Inthe be morelikelytohospitalizedthanthose with bothschistosomiasisandcancermight cannot, however,beexcluded.Also,subjects infection thanweretheirmatchedcontrols likely tohavebeentestedforschistosomal possibility thatcancercasesweremore more localsourcesofinformation.The S. japonicum was madeinassessingpreviousexposureto In thepresentstudy,considerableeffort No. and(%)ofsubjects , bylookingatprogressively and liver/coloncancers, Thiresearch was 51 Published by Maney Publishing (c) Liverpool School of Tropical Medicine Domingo, E.O.,Warren,K.S.&Stenger,R.J.(1967). 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