Associations of Classic Kaposi Sarcoma with Common Variants in Genes that Modulate Host Immunity Elizabeth E. Brown, 1,2 Daniele Fallin, 2 Ingo Ruczinski, 2 Amy Hutchinson, 3 Brian Staats, 3 Francesco Vitale, 4 Carmela Lauria, 5 Diego Serraino, 6 Giovanni Rezza, 7 Georgina Mbisa, 8 Denise Whitby, 1,8 Angelo Messina, 9 James J. Goedert, 1 Stephen J. Chanock, 1,3,10 and Kaposi Sarcoma Working Group 1 DivisionofCancerEpidemiologyandGenetics,NationalCancerInstitute,NIH,DepartmentofHealthandHumanServices,Rockville, Maryland; 2 JohnsHopkinsBloombergSchoolofPublicHealth,Baltimore,Maryland; 3 CoreGenotypingFacility,AdvancedTechnology Center, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland; 4 DipartimentodiIgieneeMicrobiologiaGiuseppeD’Alessandro,Universita ´ deglistudidiPalermo,Palermo,Italy; 5 LegaItalianaperlalottacontroitumori-sez.Ragusa,Ragusa,Italy; 6 ServiziodiEpidemiologia eBiostatistica,CentrodiRiferimentoOncologico,IstitutidiRicoveroeCuraaCarattereScientifico,Aviano,Italy; 7 RepartodiEpidemiologia, DipartimentodiMalattieInfettive,ParassitarieeImmunomediate,IstitutoSuperiorediSanita `,Rome,Italy; 8 ViralEpidemiologySection,AIDS VaccineProgram,ScienceApplicationsInternationalCorporation-Frederick,NationalCancerInstitute-Frederick,Frederick,Maryland; 9 Universita ´diCatania,Catania,Italy;and 10 PediatricOncologyBranch,CenterforCancerResearch,NationalCancerInstitute,National InstitutesofHealth,DepartmentofHealthandHumanServices,Bethesda,Maryland Abstract Classic Kaposi sarcoma (CKS) is an inflammatory-mediated neoplasm primarily caused by Kaposi sarcoma–associated herpesvirus (KSHV). Kaposi sarcoma lesions are character- ized, in part, by the presence of proinflammatory cytokines and growth factors thought to regulate KSHV replication and CKS pathogenesis. Using genomic DNA extracted from 133 CKS cases and 172 KSHV-latent nuclear antigen- positive, population-based controls in Italy without HIV infection, we examined the risk of CKS associated with 28 common genetic variants in 14 immune-modulating genes. Haplotypes were estimated for IL1A, IL1B, IL4, IL8, IL8RB, IL10, IL12A, IL13 , and TNF . Compared with controls, CKS risk was decreased with 1235T/1010G–containing diplo- types of IL8RB (odds ratio, 0.49; 95% confidence interval, 0.30-0.78; P = 0.003), whereas risk was increased with diplotypes of IL13 containing the promoter region variant 98A (rs20541, alias +130; odds ratio, 1.88; 95% confidence interval, 1.15-3.08; P = 0.01) when considered in multivariate analysis. Risk estimates did not substantially vary by age, sex, incident disease, or disease burden. Our data provide preliminary evidence for variants in immune-modulating genes that could influence the risk of CKS. Among KSHV- seropositive Italians, CKS risk was associated with diplo- types of IL8RB and IL13 , supporting laboratory evidence of immune-mediated pathogenesis. (Cancer Epidemiol Biomarkers Prev 2006;15(5):926–34) Introduction Kaposi sarcoma is an angioproliferative neoplasm caused primarily by infection with Kaposi sarcoma–associated herpesvirus (KSHV; refs. 1, 2). Four distinct clinical forms are described, including classic (3), endemic (4), iatrogenic (5), and AIDS-associated (6) forms, each following an incidence pattern that parallels KSHV seroprevalence (7). Histologically,Kaposisarcomalesionsaresimilarforthefour distinct clinical forms and are characterized by the presence of spindle-shaped tumor cells of vascular endothelial origin in addition to heterogeneous endothelial, fibroblast, and dermal dendritic cell populations and infiltrating inflamma- tory leukocytes (8-10). The inflammatory infiltrate, composed of activated CD8 + T cells, macrophages, and monocytes (11-14), is recruited to early-stage Kaposi sarcoma lesions (15, 16) and is capable of producing a variety of proinflammatory cytokines [IFN-g, tumor necrosis factor-a (TNF-a), interleukin-1 (IL-1), and IL-6; refs. 17-26], chemotactic molecules (IL-8 and IL-8Rh), and growth factors [basic fibroblast growth factor and vascular endothelial growth factor (VEGF); refs. 27, 28]. These inflammatory molecules have been detected in Kaposi sarcoma tissue (29) and have been shown to support the growth of Kaposi sarcoma–derived cells in vitro (30-32). In addition, evidence suggests that high levels of IFN-g induce endothelial cells to acquire the Kaposi sarcoma tumor cell phenotype (33) and that IL-6, IL-8, basic fibroblast growth factor, and VEGF enhance angiogenesis and spindle cell proliferation in culture (22, 34-38). Proinflammatory cyto- kines, chemotactic molecules, and angiogenic factors are tightly regulated and together promote the formation and progression of Kaposi sarcoma lesions by altering inflamma- tion,angiogenesis,andgrowthoftheKaposisarcomaspindle cell phenotype (39). 926 Cancer Epidemiol Biomarkers Prev 2006;15(5). May 2006 Received10/13/05;revised2/14/06;accepted3/13/06. Grant support: IntramuralResearchProgramoftheNIH,NationalCancerInstitute,Division ofCancerEpidemiologyandGeneticsinadditiontocontractsN02-CP-91027withResearch TriangleInstituteandN01-CO-12400withScienceApplicationsInternationalCorporation- Frederick;AssociazioneItalianaRicercasulCancro;ProgrammaRicercheAIDS,Italy-U.S. CollaborativeProject,IstitutoSuperiorediSanita,Italy;ProgettoNazionaleAIDS,Italian MinistryofHealth,IstitutoSuperiorediSanita `,Romagrant20F.13;JohnsHopkinsUniversity SchoolofHygieneandPublicHealthgrantCA-09314-23(E.E.Brown);NationalCancer InstituteOfficeofCancerResearchandTraining(E.E.Brown);MarylandCigaretteRestitution FundResearchGranttotheJohnsHopkinsMedicalInstitutions(I.Ruczinski);andNIH grantCA074841(I.Ruczinski).Thecontentofthispublicationdoesnotnecessarilyreflectthe viewsorpoliciesoftheDepartmentofHealthandHumanServices,nordoesmentionoftrade names,commercialproducts,ororganizationsimplyendorsementbytheU.S.Government. Thecostsofpublicationofthisarticleweredefrayedinpartbythepaymentofpagecharges. Thisarticlemustthereforebeherebymarkedadvertisementinaccordancewith18U.S.C. Section1734solelytoindicatethisfact. Note: SupplementarydataforthisarticleareavailableatCancerEpidemiology,Biomakers, andPreventionOnline(http://cebp.aacrjournals.org/). AdditionalmembersoftheworkinggrouparelistedinAppendix1. Conflict of interest: Studysponsorshadnoroleinstudydesign,datacollection,analysisor interpretation,orwritingthereport.Nofundingwasprovidedbyindustryorcommercial enterprises. Statement of authorship: E.E.Brown,J.J.Goedert,andS.J.Chanickparticipatedinstudy designandresearch.E.E.Brown,D.Fallin,andI.Ruczonskiparticipatedindataanalysesand interpretationoffindings.A.Hutchinson,B.Staats,G.Mbisa,andD.Whitbyconducted genotypingandviraldetectionassays.F.Vitale,C.Lauria,D.Serraino,G.Rezza,andA. Messinaparticipatedinresearch.E.E.Brownwrotethearticle.Allcoauthorscheckedthefinal versionofthearticle. Government statement on copyright: Thepublisherorrecipientacknowledgesrightofthe U.S.governmenttoretainanonexclusive,royalty-freelicenseinandtoanycopyrightcovering thearticle. Requests for reprints: ElizabethE.Brown,NationalCancerInstitute,6120Executive Boulevard,EPS8005/MSC7248Rockville,MD20852.Phone:301-496-8895;Fax:301-402-0817. E-mail: brownbe@mail.nih.gov Copyright D 2006AmericanAssociationforCancerResearch. doi:10.1158/1055-9965.EPI-05-0791 Downloaded from http://aacrjournals.org/cebp/article-pdf/15/5/926/1939535/926.pdf by guest on 14 June 2022