Population-based multicase-control study in common tumors in Spain (MCC-Spain): Rationale and study design

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Special article

Population-based multicase-control study in common tumors in Spain (MCC-Spain): rationale and study design

Gemma Casta˜no-Vinyals

^a,b,c,q,^∗^,u

, Nuria Aragonés

^d,q,r,u

, Beatriz Pérez-Gómez

^d,q,r

, Vicente Martín

^e,q

, Javier Llorca

^f,q

, Victor Moreno

^g,h,q

, Jone M. Altzibar

^i,q

, Eva Ardanaz

^j,q

, Sílvia de Sanjosé

^g,q

,

José Juan Jiménez-Moleón

^k,q

, Adonina Tardón

^l,q

, Juan Alguacil

^m,q

, Rosana Peiró

^n,q

,

Rafael Marcos-Gragera

^o,q

, Carmen Navarro

^p,q,s

, Marina Pollán

^d,q,r,u

, Manolis Kogevinas

a,b,c,q,t,u

, MCC-Spain Study Group

aCentreforResearchinEnvironmentalEpidemiology(CREAL),Barcelona,Spain

bIMIM(HospitaldelMarMedicalResearchInstitute),Barcelona,Spain

cUniversitatPompeuFabra(UPF),Barcelona,Spain

dEnvironmentalandCancerEpidemiologyUnit,NationalCenterofEpidemiology,InstitutodeSaludCarlosIII,Madrid,Spain

eUniversidaddeLeón,León,Spain

fUniversidaddeCantabria,Santander,Spain

gIDIBELL-CatalanInstituteofOncology,L’HospitaletdeLlobregat,Spain

hDepartmentofClinicalSciences,FacultyofMedicine,UniversityofBarcelona,Barcelona,Spain

iSubdireccióndeSaludPúblicadeGipuzkoa,Donostia,Spain

jInstitutodeSaludPúblicadeNavarra,Pamplona,Navarra

kInstitutodeInvestigaciónBiosanitariadeGranada(ibs.GRANADA),HospitalesUniversitariosdeGranada/UniversidaddeGranada,Granada,Spain

lInstitutoUniversitariodeOncología,UniversidaddeOviedo,Oviedo,Asturias,Spain

mCentrodeInvestigaciónenSaludyMedioAmbiente(CYSMA),UniversidaddeHuelva,Huelva,Spain

nFundaciónparaelFomentodelaInvestigaciónSanitariayBiomédicadelaComunitatValencianaFISABIO–SaludPública,Valencia,Spain

oEpidemiologyUnitandGironaCancerRegistry,OncologyCoordinationPlan,DepartmentofHealth,AutonomousGovernmentofCatalonia,CatalanInstituteofOncology, GironaBiomedicalResearchInstitute(IdiBGi),Girona,Spain

pDepartmentofEpidemiology,MurciaRegionalHealthAuthority,Murcia,Spain

qCIBEREpidemiologíaySaludPública(CIBERESP),Madrid,Spain

rIISPuertadeHierro,Majadahonda,Spain

sDepartmentofHealthandSocialSciences,UniversidaddeMurcia,Murcia,Spain

tSchoolofPublicHealth,Athens,Greece

a r t i c l e i n f o

Articlehistory:

Received31July2014 Accepted12December2014 Availableonline19January2015

Keywords:

Case-control Epidemiology Colorectalcancer Prostatecancer Breastcancer Gastriccancer

Chroniclymphocyticleukemia

a b s t r a c t

Introduction:Wepresenttheprotocolofalargepopulation-basedcase-controlstudyof5commontumors inSpain(MCC-Spain)thatevaluatesenvironmentalexposuresandgeneticfactors.

Methods:Between2008-2013,10,183personsaged20-85yearswereenrolledin23hospitalsandpri- marycarecentresin12Spanishprovincesincluding1,115casesofanewdiagnosisofprostatecancer, 1,750ofbreastcancer,2,171ofcolorectalcancer,492ofgastro-oesophagealcancer,554casesofchronic lymphocyticleukaemia(CLL)and4,101population-basedcontrolsmatchedbyfrequencytocasesbyage, sexandregionofresidence.Participationratesrangedfrom57%(stomachcancer)to87%(CLLcases)and from30%to77%incontrols.Participantscompletedaface-to-facecomputerizedinterviewonsociode- mographicfactors,environmentalexposures,occupation,medication,lifestyle,andpersonalandfamily medicalhistory.Inaddition,participantscompletedaself-administeredfood-frequencyquestionnaire andtelephoneinterviews.Bloodsampleswerecollectedfrom76%ofparticipantswhilesalivasamples werecollectedinCLLcasesandparticipantsrefusingbloodextractions.Clinicalinformationwasrecorded forcasesandparaffinblocksand/orfreshtumorsamplesareavailableinmostcollaboratinghospitals.

Genotypingwasdonethroughanexomearrayenrichedwithgeneticmarkersinspecificpathways.Mul- tipleanalysesareplannedtoassesstheassociationofenvironmental,personalandgeneticriskfactors foreachtumorandtoidentifypleiotropiceffects.

Discussion:Thisstudy,conductedwithintheSpanishConsortiumforBiomedicalResearchinEpidemiol- ogy&PublicHealth(CIBERESP),isauniqueinitiativetoevaluateetiologicalfactorsforcommoncancers andwillpromotecancerresearchandpreventioninSpain.

Abbreviations:CLL,ChronicLymphocyticLeukaemia;FFQ,FoodFrequencyQuestionnaire;EBV,Epstein-BarrVirus.

∗ Correspondingauthor.CentreforResearchinEnvironmentalEpidemiology(CREAL)DoctorAiguader,88108003Barcelona,Spain,Tel.:+34932147303.

E-mailaddress:[email protected](G.Casta˜no-Vinyals).

uEqualcontribution.

http://dx.doi.org/10.1016/j.gaceta.2014.12.003

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G.Casta˜no-Vinyalsetal./GacSanit.2015;29(4):308–315

Palabrasclave:

Caso-control Epidemiología Cáncercolorrectal Cáncerdepróstata Cáncerdemama Cáncergástrico Leucemialinfáticacrónica

Estudiomulticaso-controldebasepoblacionaldetumorescomunesenEspa ˜na (MCC-Spain):razónydise ˜nodelestudio

r e s u m e n

Introducción: Presentamoselprotocolodelestudiocaso-controldebasepoblacionalde5tumores comunesenEspa˜na(MCC-Spain)queevalúafactoresambientalesygenéticos.

Métodos: Durante2008-2013,sereclutaron10.183sujetosentre20-85a˜nosen23hospitalesde12 provinciasespa˜nolas,incluyendo1.115casosdecáncerdepróstata,1.750demama,2.171colorrectal, 492gastro-esofágicos,554deleucemialinfáticacrónica(LLC)y4.101controlespoblacionalesempare- jadosporfrecuenciaporedad,sexoyregiónderesidencia.Lastasasdeparticipaciónvaríandel57%

(cáncerdeestómago)al87%(casosdeLLC)ydel30%al77%encontroles.Losparticipantesrespondieron unaentrevistapersonalinformatizadasobrefactoressocio-demográficos,exposicionesambientales,ocu- pación,medicación,estilosdevida,ehistoriamédicapersonalyfamiliar.Además,cumplimentaronun cuestionarioalimentarioyrealizaronentrevistastelefónicas.Serecogiósangredel76%delospartici- pantesysalivaparaloscasosdeLLCyparticipantesquerechazaronladonacióndesangre.Enloscasos,se recogióinformaciónclínicaysedisponedemuestrasdetumorfrescooparafinadoatravésdelosbioban- cosdeloshospitales.Serealizóelgenotipadoconunarraydeexomasuplementadoconmarcadoresen pathwaysespecíficos.Sehanplanificadodiversosanálisisparaevaluarlaasociacióndefactoresgenéticos, personalesyambientalesparacadatumoreidentificarefectospleiotrópicos.

Discusión: Esteestudio,desarrolladoenelConsorciodeInvestigaciónBiomédicadeEpidemiologíay SaludPública(CIBERESP),esunainiciativaúnicaparaevaluarfactoresetiológicosdetumorescomunesy promoverálainvestigaciónencánceryprevenciónenEspa˜na.

INTRODUCTION

Apopulation-basedmulticase-controlstudy(MCC-Spain)was launchedin2007bytheConsortiumforBiomedicalResearchinEpi- demiology&PublicHealth(CIBERESP)toevaluatetheinfluenceof environmentalexposuresandtheirinteractionwithgeneticfactors inthreeofthemostcommontumoursinSpain(prostate,female breast, colorectal),¹ in which etiological causes remain largely unknown.Gastriccancerwasalsoincludedduetoitslargegeo- graphicalvariation withinSpain,² whichpoints tothenot well identifiedpersistentenvironmentalexposureinhighriskareas(i.e.

CastillayLeón).Afifthneoplasm,chroniclymphocyticleukaemia (CLL)wasincludedlater,asaresultofthecollaborationwiththe InternationalCancerGenomeConsortium(ICGC).

Diet,physicalactivity,obesityandfamilyhistoryarecommon riskfactorsforthetumoursexamined^3,4.Moreover,environmen- talandoccupationalfactorshavealsobeeninvestigatedinrelation tothesetumours,^5–7butnotintheSpanishpopulation.Regarding infectioushypothesis,thebestestablishedriskfactorforstomach cancerisinfectionwithHelicobacterpylori(H.pylori),whileinfec- tiousmononucleosisandhighlevelsofEpstein-BarrVirus(EBV) antibodies have beenassociated withCLL.⁸ Non-steroidal anti- inflammatory drugs(NSAIDs) and statinsmaybeprotective for severaloftheincludedtumours.GenomeWideAssociationStud- ies(GWAS)haveidentifiednumerouslowpenetrancevariantsfor colorectal,breast,andprostatecancerandCLL.^9–12However,in spiteofalltheresearchconductedsofar,thecausesofthisgroup oftumoursarenotwellunderstood.

The aim of this study is to assess the association between environmentalexposuresandindividualfactors,includinggenetic susceptibility,and the occurrence of thesecancers in Spain. In summary, MCC-Spainintends toexplore andcombinedifferent approaches in order to identify new risk factors of to provide new data that might help to prevent their occurrence in the future. The specific objectives of the study are related to: a) environmentalexposures,includingdrinkingwatercontaminants, heavymetalsandendocrinedisruptorsexposure;b)socioeconomic factorsand occupational exposures, includingdisruption ofthe circadianrhythm throughshiftwork;c)lifestyle factors,smoking,nutrition,obesityandphysicalactivity;d)medicalhistoryand

consumptionofspecificdrugs;e)hormonalfactors,includingexpo- sures in earlystages of life; f) infectious agents;and g) family historyofcancerandgeneticvariation.Maineffectsandinterac- tions,specificallywithgeneticfactors,willbeanalyzedtogether withanevaluationbytumoursubphenotypes.

METHODS Studydesign

MCC-Spainisapopulation-basedmulticase-controlstudycar- ried out between September 2008 and December 2013 in 12 Spanishprovinces(Asturias,Barcelona,Cantabria,Girona,Granada, Gipuzkoa,Huelva,León, Madrid,Murcia,Navarra andValencia).

Recruitmentofcasesandcontrolswasperformedsimultaneously:

studypersonnelcontacted newlydiagnosedcancercasesin the 23 collaborating hospitals, and invited through the telephone populationcontrols, whohad beenrandomlyselectedfromthe administrative records of selected primary care health centres locatedwithinthesehospitals’catchmentarea.Intotal,thestudy recruited10,183subjects(Table1).Allparticipantshadtobe20-85 years,tohaveresidedinthecatchmentareaforatleast6months priortorecruitment,andtobeabletoanswertheepidemiological questionnaire.Eachprovincerecruitedcasesofatleasttwodiffer- enttumoursites.Caseswereidentified,assoonaspossibleafterthe diagnosiswasmade,throughactivesearchthatincludedperiodical visitstothecollaboratinghospitaldepartments(i.e.gynaecology, urology,gastroenterology,oncology,generalsurgery,radiotherapy, andpathologydepartments).Weincludedhistologicallyconfirmed incidentcasesofcanceroftheprostate(InternationalClassifica- tionofDiseases10^thRevision[ICD-10]:C61,D07.5),breast(C50, D05.1,D05.7),colonorrectum(C18,C19,C20,D01.0,D01.1,D01.2), stomach(C16,D00.2),lowerthird oftheoesophagus(C15.5),or chroniclymphocyticleukaemiaandsmalllymphocyticlymphoma (C91.1),withnopriorhistoryofthedisease,anddiagnosedwithin therecruitmentperiod,whichdifferedbyprovince;inCLLpreva- lentcaseswerealsorecruited.Controlswerefrequency-matched tocases,byage,sexandregion,ensuringthatineachregionthere wasatleastonecontrolofthesamesexand5-yearintervalforeach case.Foreachcontrolneeded,atotaloffivepotentialparticipantsof

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Table1

Numberofcasesandcontrolswithcompleteinterviewsbytumourtypeandgeographicarea.

Area(numberofhospitals) Controls Colorectal Breast Prostate Stomach/Oesophagus CLL Total Start(month/year) Finish(month/year)

Asturias(2) 232 77 70 16 15 53 463 11/08 2/12

Barcelona(4) 1,037 702 292 405 107 402 2,945 9/07 12/13

Cantabria(1) 378 151 142 175 26 22 894 4/10 7/12

Girona(2) 82 47 30 159 3/12 7/13

Granada(2) 187 166 65 5 47 470 4/10 6/13

Gipuzkoa(2) 362 119 226 707 2/08 7/10

Huelva(2) 178 74 115 52 16 435 4/10 5/13

León(1) 441 406 228 127 1,202 2/09 6/12

Madrid(2) 733 233 342 315 121 1,744 12/08 5/12

Murcia(1) 42 36 2 80 1/08 6/10

Navarra(2) 274 125 227 59 685 10/08 3/11

Valencia(2) 155 82 61 87 14 399 7/10 4/12

TOTAL 4,101 2,171 1,750 1,115 492 554 10,183 9/07 12/13

similar age, sex and hospital catchment area were randomly selectedfromthegeneralpractitionerlists.Ifcontactwiththefirst personofthislistwasnotpossibleafteraminimumoffivetriesat differenttimesoftheday,orifhe/sherefusedtoparticipate,the followingpersonofthelistwasapproached.

InTable2wepresentthemaincharacteristicsofthestudypop- ulation.

Responserates

Response rates were calculated using subjects interviewed in the numerator, and all subjects including refusals in the denominator.^13,14Forcases,theseresponserateswere68%forcolo- rectalcancercases,71%forbreast,72%forprostate,57%forgastric and87%forCLL.Incontrols,meanparticipationrateofcontrolswas 53%andvariedbyregion.For22%ofthesubjectsthephonecontact wasnotpossibleduewrongphonenumberorno-answer.

Questionnaires,biologicalsamples,hospitalrecordsand anthropometricmeasurements

Astructuredcomputerizedepidemiologicalquestionnairewas administered by trained personnel in a face-to-face interview (http://www.mccspain.org). The average duration of the inter- viewwas70minutes(range30-130).Informationwascollected onsocio-demographicfactors,residentialhistory,lifelongretro- spectiveenvironmentalexposures,includingwaterconsumption anduse(showering,bathing,swimminginpools),occupationalhis- tory-includingnightshift-,medication,lifestyles–smoking,alcohol consumption, physical activity,useof cosmetic products-,sun- bathingandsleepinghabits,personal/familymedicalhistoryand qualityoftheinterview.Missingvaluesonkeyvariablesandspe- cificquestions onadditionalstudy objectives(e.g.questionson disruptionofthecircadianrhythm)werecompletedthroughsub- sequenttelephonecontact.Themaincharacteristicsofthestudy populationarepresentedinTable2.Aftertheinterview,biologicalsamples and anthropometric data wereobtained following thestudyprotocol.Heightandweightatdifferentageswereself- reportedandwaistandhipcircumferenceweremeasuredwitha tape.Subjectswereprovidedasemi-quantitativeFoodFrequency Questionnaire(FFQ),whichwasamodifiedversionfromaprevi- ouslyvalidatedinstrumentinSpain¹⁵toincluderegionalproducts.

Itincluded140fooditems,andassessedusualdietaryintakedur- ingthepreviousyear.Portionsizeswerespecifiedforeachitem, andphotographswereusedtodefinedegreesofdoneness.Infor- mationonconsumptionofvitaminandmineralsupplementsand onimportantchangesondietaryhabitsinthepast5yearswere alsocollected.TheFFQwasself-administeredandreturnedbymail orfilledoutfacetoface(globalresponserate88%).

Whenfeasible,27mlofperipheralbloodwasdrawnfrompar- ticipants,whichwerealiquotedinwholeblood,plasma,cellular fractionforDNAextraction,andserumandstoredat-80^◦C.Saliva wascollectedforsubjectsrefusingtodonatebloodandforallCLL cases,withtheOragene®DNAKit andstored atroomtemper- atureuntil DNA extraction.We collectedbiological samplesfor DNAextractionfor96%ofparticipantswithinterview(76%blood and27% saliva)aswellastoenailandhairsamplesweretaken fromparticipants(79%and84%respectively).In4centres(Madrid, Cantabria,AsturiasandHuelva,whichincludeapproximately1/3 ofthestudyparticipants)casesand controlsalsodonatedurine samples(60ml)thatwerealiquotedand frozenat-80^◦C.Fresh tumourbiopsiesorparaffinembeddedsamplesareavailableinall participatinghospitals.

Standardisedbasicclinicalandpathologicalinformationonthe diagnosisandtreatmentoftumourswascollectedfromhospital recordsusingapredefinedformat.

Sociodemographic,lifestyleandenvironmentalfactors

MCC-Spain will examine the Socioeconomic status will be examinedusingmultilevelapproachesthatallowtheevaluationof theroleofstructuralsocioeconomicfactorsonhealth.Environmen- taljustice,proximitytogreenspacesandenvironmentalpollution willbeassessedthroughanevaluationofexposuresproximateto theplaceofresidence.

Lifestyleexposuresareoneofthemainobjectivesofthisstudy.

Dietisexaminedthroughsummaryintakesofrelevantfoodgroups basedonreportedintakefrequenciesandportionsizeinformation.

Foodcompositiontables weredeveloped andwillbecombined withreportedintakefrequenciesandcookingmethodpreferences toestimateintakesofnutrients,foodcontaminants(e.g.polycyclic aromatichydrocarbons)andfoodproperties(e.g.totalantioxidant capacity.AnaprioriMediterraneandietscore,alternativedietpat- ternsandafactor-analysisderiveddietpatternwillbeexamined.

Generalandcentralobesityisexaminedtogetherwithleisuretime physicalactivityandsedentarylifestyle.Numerousotherpotential riskfactorsthatcouldbeassociatedwiththecancersinvestigated areexamined.Theseinclude,amongothers,smokinghabits,expo- suretomedicalradiation,useofcosmetics,useoftightclothesand belts,exposuretosunorsleepingpatterns.

Useof medicaldrugswascollectedthrough personal inter- views,mainlybyindication.Informationwascoded(Anatomical Therapeutic Chemical-ATC code) to assess individual exposure todifferentdrugsincludingstatinsandanti-inflammatorydrugs, analgesics,hormones,antihypertensives,beta-blockers,bisphos- phonatesandcorticosteroids.

Hormonalfactorsandendocrinedisruptionarealsoexam- ined. Sex dimorphic phenotypes (finger ratio and anogenital

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Table2

MaincharacteristicsofthepopulationoftheMCC-Spainstudy.

Controls Colorectal Breast Prostate Stomach/Oesophagus CLL

N=4101 N=2171 N=1750 N=1115 N=492 N=554

Area

Asturias 232(5.7%) 77(3.5%) 70(4%) 16(1.4%) 15(3%) 53(9.6%)

Barcelona 1037(25.3%) 702(32.3%) 292(16.7%) 405(36.3%) 107(21.7%) 402(72.6%)

Cantabria 378(9.2%) 151(7%) 142(8.1%) 175(15.7%) 26(5.3%) 22(4%)

Girona 82(2%) 47(2.7%) 30(5.4%)

Granada 187(4.6%) 166(7.6%) 65(5.8%) 5(1%) 47(8.5%)

Gipuzkoa 362(8.8%) 119(5.5%) 226(12.9%)

Huelva 178(4.3%) 74(3.4%) 115(6.6%) 52(4.7%) 16(3.3%)

León 441(10.8%) 406(18.7%) 228(13%) 127(25.8%)

Madrid 733(17.9%) 233(10.7%) 342(19.5%) 315(28.3%) 121(24.6%)

Murcia 42(1%) 36(1.7%) 2(0.4%)

Navarra 274(6.7%) 125(5.8%) 227(13%) 59(12%)

Valencia 155(3.8%) 82(3.8%) 61(3.5%) 87(7.8%) 14(2.8%)

Sex

Men 2063(50.3%) 1387(63.9%) 1115(100%) 336(68.3%) 334(60.3%)

Women 2038(49.7%) 784(36.1%) 1750(100%) 156(31.7%) 220(39.7%)

Age,mean(sd) 62.9(12.1) 67.0(10.8) 56.4(12.6) 66.1(7.33) 66.2(12.3) 66.1(10.3)

Education

Lessthanprimaryschool 753(18.4%) 696(32.1%) 271(15.5%) 261(23.4%) 147(29.9%) 147(26.5%)

Primaryschool 1307(31.9%) 822(37.9%) 567(32.4%) 441(39.6%) 186(37.8%) 160(28.9%)

Secondaryschool 1182(28.8%) 429(19.8%) 579(33.1%) 242(21.7%) 106(21.5%) 149(26.9%)

University 859(20.9%) 224(10.3%) 333(19.0%) 171(15.3%) 53(10.8%) 98(17.7%)

Race

White 4034(98.4%) 2147(98.9%) 1703(97.3%) 1099(98.6%) 474(96.3%) 549(99.1%)

Non-white 67(1.63%) 24(1.11%) 47(2.69%) 16(1.43%) 18(3.66%) 5(0.90%)

CLL:lymphocyticleukaemia.

distance)willbeevaluatedinrelationtothedevelopmentofbreast andprostate cancer. Theratioof thelengthoftheindex finger andmiddlefingerofboth hands(2D:4D)weremeasuredusing calliperswitha resolutionof 0.05mm,¹⁶ a validation studyhas showna goodrepeatabilityoffingermeasurements.¹⁷ Anogeni- taldistancewasassessedinasubgroupofprostatecancercases andcontrols.¹⁸ Theinfluenceof reproductivehistory,hormonal treatments (contraceptives, hormone replacementtherapy) and influenceofhormonaldevelopment(patternoffatdistributionat differentages,andheight)willbeexamined.Endocrinedisrupt- ors(xenoestrogensandotherpersistentorganicpollutants)willbe measuredinserumthroughadeterminationoftheglobalxenoe- strogenicburden(TEXB).¹⁹

Among environmental pollutants, evaluation of drinking watercontaminantsfocuses ondisinfectionby products(such as trihalomethanes and haloacetic acids), nitrates and metals.

Exposuredatafromwatercompaniesandmunicipalities,national surveillancedataandnewwateranalyseshasbeengathered.^20,21 andmodelledtoestimatehistoricallevelsofpollutantsindrinking waterandcombinedwithindividualdatafromthequestionnaire.

Urinarytrichloroaceticacidwasmeasuredinasubsetofcontrols.

MCC-Spain willalsostudy environmentalexposuretodifferent metals,includingCd,Ni,Cr,As,Pb,Se,andZninrelationtothefive combiningbiomarker-basedestimationswithinformationbased ontheepidemiologicalinformation.

Occupational exposures will also be studied. All jobs con- ductedformore thanoneyearwererecordedwithinformation regarding specific tasks, exposures and timing of thejob. Jobs werecodedbytwoexpertsfollowingtheSpanishNationalClas- sificationofOccupations(CNO-94).TheSpanishJEM,MatEmEsp, will beapplied.²² Detailedinformation onwork shift (rotating and night) and disruption of the circadian rhythm was also collected.

Otherpossibleetiologicalfactorshavealsobeenincludedinthe project.Amongthem,severalinfectionswillbeevaluatedinrela- tiontocolorectalandgastrictumoursandCLL.TheroleofH.pylori

infectionwillbeestimatedusingseroprevalenceagainstseveral virulence antigens.In relationtoCLL,seroprevalenceof several polyomaviruses,herpesviruses,andChlamydiatrachomatiswillbe evaluated.AdditionallytheantibodyresponsepatterntoEBVwill alsobemeasured.

Extensive information on family history was collected to identify familial cases. This information will allow describing thetypicalfamilystructure ofstudyparticipantsand, ifgenetic effects are identified, estimating their penetrance using Kin- cohort methods. In addition, genetic analyses will be carried outwithinMCC-Spainandalsothroughparticipationininterna- tionalconsortiasuchastheprostatecancerconsortiumPRACTICAL (http://ccge.medschl.cam.ac.uk/consortia/practical/).TheInfinium HumanExome BeadChip from Illumina was used to genotype

>200,000codingmarkersplus6,000additionalcustomvariantson thepathwaysofinterestsuchasinflammation,circadianrhythm ordetoxification.

Ethicsandavailabilityofdata

TheprotocolofMCC-SpainwasapprovedbytheEthicscommit- teesoftheparticipatinginstitutions.Allparticipantswereinformed aboutthestudyobjectivesandsignedaninformedconsent.Con- fidentialityofdataissecuredremovingpersonalidentifiersinthe datasets.ThedatabasewasregisteredintheSpanishAgencyfor DataProtection,number2102672171.Permissiontousethestudy databasewillbegrantedtoresearchersoutsidethestudygroup, afterrevisionandapprovalofeachrequestbytheSteeringCom- mittee.Moredetailsontheorganizationoftheprojectcanbefound onlineathttp://www.mccspain.org.

DISCUSSION

CancerlocationsandhypothesesexaminedinMCC-Spainwere selectedwithapublichealthperspectivetoprovideinformation

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usefulforcancerprevention.MCC-Spainalsoaimstofosteranet- workofresearchincancerepidemiologyinSpain.

Theoptionofasinglesetofpopulationcontrolsandasingle questionnaireforalltumourshasthemainbenefitoftheoptimiza- tionoftheeconomicresources.Thisapproachhasbeensuccessfully usedpreviously.²³Ontheotherhand,themaindrawbackisthe needtousethesametoolstogathertheinformationregardingrisk factorsforalltypesofcases.

Theadvantages and problemsof theselection ofpopulation versushospitalcontrolshavebeenextensivelydiscussed.^24,25The evaluationofavarietyofexposuresmakeshospitalcontrolsless suitablegiventhepotentialassociationbetweenmultiplediseases and exposures of interest. As expected from otherpopulation- basedstudies,participationratesofcaseswerehigherthanthose ofcontrols.Selectingcontrolsthroughlistsofgeneralpractitioners providesarepresentativesamplingframegiventhealmostuniver- salpubliccoverageofthenationalhealthsysteminSpain.However, errorsintheselistsconcerningpersonaldataresultedinalower thanexpectedresponserate.¹⁴

Thestudyispopulation-basedsinceweintendedtorecruitall caseswithafirstdiagnosisofthestudiedtumorsintheselected healthareas,usingforthispurposethereferencehospital/hospitals ineachareaandidentifyingeverynewdiagnosisofthestudiedcan- cers.Wecouldnotusepopulationcancerregistriestoascertainthe numberofcaseslostsinceinmostoftheregionsincludedinthe studytherewasnotanysuchregistry,butwecancertainlyassume tobefew.Potentialmisclassificationofexposureisamajorlimita- tionofcase-controlstudies.Theimplementationofacomputerized questionnaire,trainingandcontinuousfeedbacktointerviewers, andrepeatedinterviewstocompletemissing valuesis likelyto reduceerrors.

Achallengeofcurrentcancerepidemiologyresearchistoaccu- ratelydefinethemolecularphenotypeoftumourssothatspecific risk factors can be identified for each molecular subtype. All tumourshavepathologyslidesinthereferencehospitalsthatcan beretrievedandsomehospitalsalsohavetumourbanksthathave collectedfreshtumourtissueforsomecases.

Finally,networking isamongthemajorachievements ofthe study.MCC-Spainincludes17differentcentresandhasfollowed organizationalprocedurestopromotetheexchangeofknowledge andexperiencesbetweencentres.

Editorincharge AlbertoRuano-Ravina.

Statementofauthorship

All authors have contributed to the conception and design of the study, and have acquired data, have been involved in draftingthemanuscript.Allauthorsreadandapprovedthefinal manuscript.

Funding

The study was partially funded by the “Accion Transversal delCancer”, approved on the Spanish MinistryCouncil onthe 11^th October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359, PS09/00773, PS09/01286, PS09/01903, PS09/02078, PS09/01662, PI11/01403, PI11/01889, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270,PI12/00715,PI12/00150),bytheFundaciónMarqués deValdecilla(API10/09),bytheICGCInternationalCancerGenome ConsortiumCLL,bytheJuntadeCastillayLeón(LE22A10-2),by theConsejeríadeSaludoftheJuntadeAndalucía(PI-0571),bythe

ConselleriadeSanitatoftheGeneralitatValenciana(AP061/10), bytheRecercaixa(2010ACUP00310),bytheRegionalGovernment oftheBasqueCountrybyEuropeanCommissiongrantsFOOD-CT- 2006-036224-HIWATE,bytheSpanishAssociationAgainstCancer (AECC) Scientific Foundation, by the The Catalan Government DURSIgrant2009SGR1489.

Samples:BiologicalsampleswerestoredattheParcdeSalut MAR Biobank (MARBiobanc; Barcelona) which is supported by InstitutodeSaludCarlosIIIFEDER(RD09/0076/00036).Alsoatthe PublicHealthLaboratoryfromGipuzkoaandtheBasqueBiobank.

AlsosamplecollectionwassupportedbytheXarxadeBancsde TumorsdeCatalunya sponsored byPla Directord’Oncologia de Catalunya(XBTC).Biologicalsampleswerestoredatthe“Biobanco LaFe”whichissupportedbyInstitutodeSaludCarlosIII(RD09 0076/00021)andFISABIObiobanking,whichissupportedbyInsti- tutodeSaludCarlosIII(RD090076/00058).

Genotyping:SNP genotypingserviceswere provided bythe Spanish“CentroNacionaldeGenotipado”(CEGEN-ISCIII)¨andbythe BasqueBiobank.

Conflictofinterest

Theauthorsdeclarethattheyhavenoconflictsofinterest.

Acknowledgements

Wethankallthesubjectswhoparticipatedinthestudyandall MCC-Spaincollaborators(thelistscanbefoundbelow).

Anexx1.

MCC-Spain study group:Maria Teresa Alonso, Pilar Amiano, Cristina Arias, Mikel Azpiri, Yolanda Benavente, Elena Boldo, Aurora Bueno, Mariona Bustamante, Francisco Javier Caballero, ElíasCampo,RafaelCantón,Rocío Capelo,CarmeCarmona, Del- phine Casabonne, María Dolores Chirlaque, Judith Cirac, Juan Clofent,EnriqueColado,LauraCostas,MartaCrous,RosadelCampo, MarianDíaz Santos,Trinidad Dierssen-Sotos,María Ederra, Ana Espinosa, Marieta Fernández Cabrera, Ana FernándezSomoano, TaniaFernándezVilla,EstherGarcíaGarcía-Esquinas,PalomaGar- cía Martín, Inés Gómez-Acebo, Cristina González Puga, Esther Gràcia,MarcelaGuevaraEslava,ElisabetGuinó,JoséMaríaHuerta, VirginiaLope,GonzaloLópez-Abente,CarlosLopez-Otín,Bego˜na MartinezArgüelles,SergioMerinoSalas,BenitoMirónPozo,Anto- nioJoséMolinadelaTorre,EduardoMoreno,ConcepciónMoreno Iribas,NicolásOlea,GemmaOscaGelis,LaiaParé,MiquelPorta, MontsePuig,ManuelRivasdelFresno,ClaudiaRobles,MartaMaría RodríguezSuarez,BeatrizRomero,AnaIsabelSáezCastillo,Maria SalaSerra,DoloresSalasTrejo,AnaSantaballa,MiguelSantibá˜nez, ÁngelesSierra,AnaSouto,CristinaMVillanueva.

Annex2.

BARCELONA

CREAL: Estela Carrasco, Yasmin Sabaté, Cecília Persavento, MireiaGarcía, GlòriaCarrasco,Ainara Expósito,H. Mar:Montse Andreu,XavierBessa,MercèPiracés,JoséAntonioLorente,Ignasi Tusquets, InmaCollet, FelipBory, Manuel Pera; EugèniaAbella, FrancescGarcia,AntonioSalar;H.GermansTriasiPujol(CanRuti):

MartaPi˜nol,JaumeFernandez-Llamazares,MartaVicianoMartín, Elisenda Garsot, Luis Ibarz Servio,Montse Arzoz,Luisa Suarez, José Manuel Ruiz. H.Clínic: Antoni Castells, Anna Serradesan- ferm, AnnaBosch, Montse Mu˜noz,Montse Fontanillas,Antonio Alcaraz,LourdesMengual.PAMEM:EnricDuran;CAPBarceloneta (Barcelona): Clara Izard, Carmen López; CAP Vila Olímpica

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(Barcelona):JosepManuelBenítez,AlexBassaMassanes,OlgaGon- zalezFerrer.AtencióPrimàriaCostadePonent:JesúsAlmeda,Sònia Sarret; CAP AmadeuTorner (L’Hospitalet de Llobregat): Marifé AlvarezRodriguez;CAPJaumeSoler(Cornellà):AlbertBoadaVal- maseda;CAPMossènCintoVerdaguer(L’HospitaletdeLlobregat):

ManoliLiceran, Dolors Petitbó;CAP17 desetembre(El Pratde Llobregat);BadalonaServeisAssitencials:JordiIbà˜neziNolla;CAP NovaLloreda:SoniaPérez,SusannaMartínez;CAPEixample:Josep M.Vilaseca,LauraSebastián

INSTITUTCATALÀD’ONCOLOGIA(ICO)

ICOCLL: Paloma Quesada, Guillermo Sequera, Eva Gonza- lezBarca, EvaDomingo-Domenech,Ana Oliveira,EstherAlonso, EsmeraldadelaBanda,YasminSabater,MarlenyVergara,Ainara Exposito, Teresa Alonso, Isabel Padrol, Joellen Klaustermeier, Yolanda Florencia,VanesaCamon, AnnaEsteban.Colaboradores Clinic CLL: Elias Campo, Marta Aymerich, Carlos Lopez-Otin, AmparoMu˜noz, YolandaTorralba. DoloresDot, SantiMercadal, JosepSarra.

UnitatBiomarcadorsiSusceptibilitat,ICO:IsabelPadrol,Pilar Medina, Carmen Atienza; Cirurgia Digestiva HUB: Sebastiano Biondo, Javier de Oca, Leandre Ferran; Gastroenterología HUB:

FranciscoRodriguez-Moranta, AntonioSoriano, Jordi Guardiola;

OncologiaMedicaICO:AnderUrruticoechea,MaycaGalan HUELVA

RocíoCapelo,MarianDiazSantos,JuanManuelBanda,Ángela Zumel.BiobancodelSistemaPúblicodeSaluddeAndalucía:Anabel Saez. Jose Antonio Garrido, Marina Lacasaña, JL Gómez Ariza, TamaraGarcía, MiguelÁngelGarcía,MiguelÁngelAlbaHidalgo, Manuel Asuero, Juan Bayo, Valle Coronado Vázquez, Francisco Franco, José Luis Gurucelain, María José Robles Frías, Rudolph VandeHaar,JesúsViñas.H.JuanRamónJiménez,Huelva:Mari- anoAguayo,AntonioPereira,SofíaPérezGutiérrez,RicardoRada, JuanCandón,JuanDomínguez,ManuelRamos,GuillermoPedraza, JuanBraulio,JuanaSalas,DiegoLabrero,DavidMuñoz,FátimaBar- rero,Sonia Delgado,LuísGalisteo, AntonioCamacho. H. Infanta Elena,Huelva:JavierCaballero,MatildeJiménezMuñoz,Francisco Arredondo,RamónLinares,AntonioTejada.H.R.RioTinto,Huelva:

ManuelAsuero,JavierDelgadoAlés,FranciscoFranco,MaríaValle Coronado,MaríaLuisaSánchezBernal.

GRANADA

HospitalUniversitarioSanCecilio.ServiciodeUrología:JoséLuis MijanOrtiz,MercedesNoguerasOca˜na.HospitalUniversitarioVir- gendelasNieves.ServiciodeHematología:PalomaGarcíaMartín.

DepartamentoMedicinaPreventivaySaludPública.Universidadde Granada:AuroraBuenoCavanillas,Miguel,EladioJiménezMejías, ObduliaMoreno Abril,Rocío OlmedoRequena. Centro de Salud ZaidínSur,ServicioAndaluzdeSalud:JoséLuisGastónMorata.Cen- trodeSaludZaidínNorte,ServicioAndaluzdeSalud:EvaGarrido Morales

CANTABRIA

PilarGonzálezEchezarreta,LuisMarianoLópezLópez,M^aMar GonzálezMartínez,PaulaPicónSedano,AlmudenadelaPedraja Pavón

MURCIA

Dirección General Salud Pública, Murcia: María-Dolores Chirlaque, José-María Huerta y Concepción López-Rojo, Jaime Mendiola. Hospital Morales Meseguer: Enrique Pellicer, José Manuel Egea Caparrós, Emilio García Oltra y Javier Martín Martínez.

VALENCIA

FISABIO-SaludPública,Valencia:AnaMolina,VicentVillanueva, Monica,MJoseMiranda,CarolinaAbril,JacoboMartinez,Dolores Salas;HospitalLaFe:AnaSantaballa,JoseLuisRuiz,JuanClofent, MartaPonce,PilarNoos,JoseCervera,AdolfodelVal,AngelSegura, NuriaJiménez,ElenaBellmunt,IsmaelAznar,DavidRamos,Teresa Montón, M^a Cruz Solera; Hospital Dr Peset: Eduardo Moreno,

AntonioMora,NuriaEsta˜n,NataliaCamarasa.;CAPTrinitat:Jose VicenteSolanas;CAPFuentedeSanLuis:JazminRipoll,JuanaCan- tero

ASTURIAS

Instituto Universitario de Oncología de la Universidad de Oviedo:CristinaAriasDíaz,AnaFernándezSomoano,AnaSouto García, SaraMaría ÁlvarezAvellón,Mirko Neumann,MaríaJosé FernándezGonzález,MartaMaríaRodríguezSuárez,GuillermoFer- nández,Bego˜naMartínezArgüelles,EnriqueColado,ManuelRivas delFresno.

GIPUZKOA

Subdirección de Salud Pública de Gipuzkoa: Ander Gómez, UsoaGarín;AmbulatoriodeGros(OSAKIDETZA):EduardoTamayo, M. Angeles Rua; C.S. Lasarte (OSAKIDETZA): M. Luz Jauregi H.

Universitario Donostia (OSAKIDETZA): Javier Recio, Marta Fer- nández,Maite Múgica,Juan Pablo Ciria, Elena Guimón,Cristina Adúriz,AdelaidaLacasta,JoseSanFrancisco,IsabelAlvarez,JoseM.

Enriquez-Navascués,IruneRuiz;Onkologikoa:M.JesúsMichelena, JoséAntonioAlberro

NAVARRA

InstitutoSaludPúblicadeNavarra:AntoniaMartínezAlmansa, LeyreMartínezGo˜ni,MaríaIbarrolaElizagaray;MaríaOsésZubiri ApoyoTécnico:RosanaBurguiPérez;HospitalVirgendelCamino:

Servicio deAnatomíaPatológica: Dra.Ana MaríaPurasGil,Dra.

María Concepción De Miguel Medina, Dra. Mâ BegoñaRepáraz Romero, Dra. Ana Yerani Ruiz de Azúa Ciria, Dra. Marta María deOsquiaMontesDíaz,Dra.MâSocorroRazquinLizárraga,Dra.

YolandaLaplazaJiménez.ServiciodeAparatoDigestivo:Dr.Car- losEnriqueJiménezLópez,Dra.SusanaOqui˜nenaLegaz,Dr.Raúl ArmendárizLezaun.ServiciodeCirugíaGeneral:Dr.HéctorOrtiz Hurtado,Dr.MarioDeMiguelVelasco,Dr.PedroArmendárizRubio, Dr. Fernando Domínguez Cunchillos, Dr. Álvaro Díaz de Lia˜no Arguelles.HospitaldeNavarra:ServiciodeAnatomíaPatológica:

Dr.JoséMaríaMartínezPe˜nuela,Dra.M^aLuisaGómezDorronsoro.

Servicio de Aparato Digestivo: Dr. Fernando Borda Celaya, Dr.

DavidRuiz-ClavijoGarcía,Dra.BelénGonzálezdelaHigueraCar- nicer. Servicio de Cirugía General: Dr. José Miguel Lera Tricas, Dr. Enrique Miguel Balén Rivera, Dr. Francisco Vicente García, Dr.JoséJuan Í˜nigoNoain.Centro deasistenciaextrahospitalaria

“PríncipedeViana”ServiciodeEnfermería:EsperanzaAranguren Erdozain,CarmenIrigarayUlibarrena,JuliaGoñiLopeandía.Unidad deAtenciónalPaciente:MaríaArtiedaCaden.EquipodeAtención Primaria“IIEnsanche”:Dr.FernandoAldanaMoraza.Dr.JesúsJavier AranaDomench; Dra. AliciaArza Arteaga; Dra. Karmele Ayerdi Navarro;Dra.MâMercedesdelBurgoTajadura;Dr.FernandoCalle Irastorza;Dra. Mâ JesúsEsparzaUrrisarri;Dra.BertaFlamarique Zubicoa; Dr. Pablo González Lorente; Dr. Pedro Hualte Sevilla;

Dra. MercedesLázaroEchamendi; Dr.ÁlvaroMartínezDíaz;Dr.

JesúsMaríaMartínezSalaverri;Dr.FranciscoJavierOrozcoGor- richo;Dra.M^aLuisa PérezdelValle;Dr.JosédePradoMarcilla.

Equipo de Atención Primaria “San Juan”: Dra. M^a Luisa Garcés Ducar. Dr. Pablo Aldaz Herce; Dr.José Enrique Ansorena Bara- soain;Dra. IsabelArceizCampos;Dra.ElenaArinaVergara;Dra.

Bego˜naChurioBeraza;Dr.LuisFanloBlasco;Dr.LuisGarcíaDíaz;

Dr.JesúsGarcía-FalcesLarrañeta;Dra.NuriaGoñiRuiz;Dr.Juan GuijarroGarcía;Dra.MâSantosIndurainOrduna;Dr.DavidIturbe Larena;Dra.MaríaPardoFernández;Dr.FranciscoJavierPérezde Ciriza Pejenaute;Dra. Edurne RidruejoEscuin; Dra. Isabel Ruiz Puertas; Dra. Inés Aranzazu Urtasun Samper; Dra. Mâ Eugenia Usúa Sesma;Dra. Mâ JosefaVigataLópez;Dra. CarmenZabalza Apestegui.

MADRID

ISCIII: Cristina Linares, Marta Cervantes, Eva Ferreras, Javier García-Pérez, Pablo Fernández-Navarro, Roberto Pastor, Rebeca Ramis, Ángel González; Entrevistadoras: Tamara Ruiz, Viviana Mu˜noz,RaquelDelgado; Recogidadedatos: MaríaLanza,María

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Marín;Biobanco:ManuelPosada,JuanCosmen,AnaVillanueva;

CentroNacionaldeSanidadAmbiental:ArgeliaCasta˜no,JoséAnto- nioJiménez,CarmenNavarro.

Demométrica:Ana Rin, GemaDíaz, Marta Herreros, Virginia Pedraza,PatriciaLópez,MigueldelaFuente.

HospitalUniversitarioLaPaz: Gerencia, SistemasdeInforma- ción,AdmisiónyArchivo:MercedesFernándezdeCastro, Javier Sobrino,RosaCalvo;Consultasexternas:IsabelCarrascal,Rosario Bernal;Cirugíageneral:AlbertoMateo,DamiánGarcía-Olmo,Anto- nioZarazaga,MiguelÁngelGombau,JoaquínDíaz,TeresaGómez, TeresaSánchez,PalomadelaQuintana;Ginecología:JuanOrdás, PilarCuevas, MargaritaSánchez-Pastor; Urología:Javier J.de la Pe˜na, Ángel Tabernero, Natalia Cámara; Anatomía Patológica:

DavidHardisson,AsunciónSuárez,EmilioBurgos,Fco.JavierAlves, María Miguel; Oncología médica: Jaime Feliú, Cristóbal Belda, PilarZamora,ArgentinaSánchez,AraceliHernández,TeresaBeato, AscensiónArroba, AmparoBallesteros, Soledad Canora,Carmen García, Pilar López, Manuel Romero, Teresa San José, Manuela Espinel;Oncologíaradioterápica:AnaMa˜nas,M.ElenaSánchez.

H.RamónyCajal: Gerencia,SistemasdeInformación,Admisión, ArchivoyAtenciónalPaciente:JoséLuisMorillo,MiguelCuchí,M.

JesúsGarcía,JuanManuelRamos;CirugíaGeneral:RobertoRojo, AlfonsoSanjuanbenito, Augusto García Villanueva,MiguelGras, J.LCaba˜nas,VicentaCollado,IgnacioArano,IsaacCapela,Carmen Mojarrieta, Gastroenterología:Beatriz Pe˜nas, Miguel Rodríguez;

OncologíaRadioterápica:AlfredoRamos,SonsolesSancho,Asun- ciónHervás,PilarMoreno;Ginecología:ConchaSánchez,Dolores Rubio,M.JLópez,LidiaMontoya,PazSancho,LolaRodríguez,Esper- anzaDurán,SilviaMorel;Urología:JavierBurgos,RicardoGarcía, CarmenGómezdelCa˜nizo,Ana Díaz;AnatomíaPatológica:Fer- nando González, Eva Cristóbal, Constantino Barahona, Ricardo García,SilviaVázquez,VirginiaEsteban,MontserratPedrera,Javier Martínez; Oncología Médica: Alfredo Carrato, Carmen Guillén Ponce,AndreaSantos-Olmo.

AtenciónPrimaria:GerenciaÁrea5:RicardoRodríguezBarri- entos;Centro deSaludBarrio delPilar: Gerardo López, Alberto Fernández,Ana B.García, AnaNoriega,M.RosarioCampo,Elisa Varona,FernandoLópez, M.JoséMontero, MaríaTeresaGómez, Pilar Bartibas, Raquel Sanz, Tomasa Montes. Gerencia Área 4:

MiguelÁngelSalinero;CentrodeSaludMarBáltico:MargaritaHer- rero,Mónica Igea, CarmenCalvo, M.LorenaRodríguez,Carmen Pérez-Pellón,Marta Maestre; Centro deSalud LosAlpes: María Ayuso Agora, María García Martín, Dolores Velázquez, Bego˜na Fernández,MiriamCastro,EncarnaciónAyuso,RaquelMasa,Con- chaAntelo,SoledadGarcía, SusanaHerrero,AscensiónDelgado.

Agradecimientogeneraltodoselpersonalinvolucradoenestoscen- trossanitarios,conespecialénfasisalpersonaladministrativode losmismos

GIRONA

Unitatd’EpidemiologiaiRegistredeCancerdeGirona:Loreto Vilardell, Montse Puig-Vives, Gemma Osca-Gelis, Maria Buxo, Angel Izquierdo, M Carme Carmona-Garcia, Rocio Rodriguez Romanos, Carlota Torner Galindo, Patricia Martí Bargalló, Esther Rodriguez Sanchez, Marc Saez, Rafael Marcos-Gragera.

HospitalUniversitarideGirona“Dr.JosepTrueta”: Josep Maria Roncero, David Gallardo, Rosa Coll, Ignacio Blanco, Luis Miguel Alonso Ruano y Elena Alvarez Casta˜no. HospitalSanta Caterina:JoanMelendezRusi˜nol,RocioJuradoPerez,IsauraMarcé Pujol.CAPdeSantaClara:ConxaBou.CAPdeAngles:GabrielColl deTuero,AlbaCollNegre

LEÓN

Juan Pablo de Barrio Lera, José María Cancela Carral, Carlos Ayán Pérez y Marta Elena García Puente, Silvino Pacho Bal- buena, Jose María Canga Presa, Jose Antonio Mari˜no Ramírez, AntonioÁlvarez Martínez,TomásGonzálezdeFrancisco,Tomás GonzálezElosua,EnriquePastorTeso,JesúsFernándezFueyo,Oscar

AndrésSanzGuadarrama,MaríadelAmorTurienzoFrade,Maria Luisa De la Hoz Riesco, Julio Juan Sahagún Fernández, Vicente SimóFernández,RosarioCansecoFernández,MaríaVictoriaDiago Santamaría, Jose Antonio Pedrosa Simón, Ana María González Ganso,AmayaVillafañePacho,SantiagoVivasAlegre,FranciscoJor- queraPlaza,BegoñaÁlvarezCuenllas, EmilianoHonradoFranco, MercedesHernandoMartín,MaríaTeresaRibasAriño,CristinaDíaz Tascón,José AndrésGarcía Palomo,María delCarmenCastañón López,ManuelaPedrazaLorenzo,IsisAtallahGonzález,Florentino GonzálezRivero,ConcepciónHernandoRomán,EusebioÁlvarez Fernández,TomásRoblesBayón,AmaliaGarcíaFernández,Felipe LópezMunicio,MercedesGarcíadeCelis,MaríaJoséBravosGar- cía,Luis ÁngelFernándezIngelmo,Javier García-Norro Herrero, MaríaJoséLópezCarbajo,TeresaRemachaEsteras,BenildeValcarce Baz,ConsueloHonrubiaBaticón,EduardoÁlvarezBaza,Adoración UrdialesUrdiales,JuanIgnacioLópezGil,MaríaAntoniaAbiaLópez, Elena Carriedo Ule, Carmen Bombín Diez, Ana Isabel Barragán Marín,MiguelÁngelPérezBernabeu,SerafíndeAbajoOlea,Carlos VázquezRojo,MaríaÁngelesFernándezFernández,FelisaGonzález González.Entrevistadoras:LidiaGarcíaMartínez,MaríadelHuerto TrancónMoratiel,NuriaCuervoRamos,SaraPrietoFidalgo,Sonia SantaclaraPérez,PatriciaRubioCoque,ÁngelesGarcíaGonzález, AnaBelénDelgadoDíez.

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