Genome-wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patients

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dc.citation.issue8
dc.citation.volumev. 142
dc.contributor.authorKoster, Roelof
dc.contributor.authorPanagiotou, Orestis A.
dc.contributor.authorWheeler, William A.
dc.contributor.authorKarlins, Eric
dc.contributor.authorGastier-Foster, Julie M.
dc.contributor.authorToledo, Silvia Regina Caminada de [UNIFESP]
dc.contributor.authorPetrilli, Antonio Sergio [UNIFESP]
dc.contributor.authorFlanagan, Adrienne M.
dc.contributor.authorTirabosco, Roberto
dc.contributor.authorAndrulis, Irene L.
dc.contributor.authorWunder, Jay S.
dc.contributor.authorGokgoz, Nalan
dc.contributor.authorPatino-Garcia, Ana
dc.contributor.authorLecanda, Fernando
dc.contributor.authorSerra, Massimo
dc.contributor.authorHattinger, Claudia
dc.contributor.authorPicci, Piero
dc.contributor.authorScotlandi, Katia
dc.contributor.authorThomas, David M.
dc.contributor.authorBallinger, Mandy L.
dc.contributor.authorGorlick, Richard
dc.contributor.authorBarkauskas, Donald A.
dc.contributor.authorSpector, Logan G.
dc.contributor.authorTucker, Margaret
dc.contributor.authorBelynda, D. Hicks
dc.contributor.authorYeager, Meredith
dc.contributor.authorHoover, Robert N.
dc.contributor.authorWacholder, Sholom
dc.contributor.authorChanock, Stephen J.
dc.contributor.authorSavage, Sharon A.
dc.contributor.authorMirabello, Lisa
dc.coverageHoboken
dc.date.accessioned2020-07-20T16:31:00Z
dc.date.available2020-07-20T16:31:00Z
dc.date.issued2018
dc.description.abstractSurvival rates for osteosarcoma, the most common primary bone cancer, have changed little over the past three decades and are particularly low for patients with metastatic disease. We conducted a multi-institutional genome-wide association study (GWAS) to identify germline genetic variants associated with overall survival in 632 patients with osteosarcoma, including 523 patients of European ancestry and 109 from Brazil. We conducted a time-to-event analysis and estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models, with and without adjustment for metastatic disease. The results were combined across the European and Brazilian case sets using a random-effects meta-analysis. The strongest association after meta-analysis was for rs3765555 at 9p24.1, which was inversely associated with overall survival (HR=1.76; 95% CI 1.41-2.18, p=4.84 x 10(-7)). After imputation across this region, the combined analysis identified two SNPs that reached genome-wide significance. The strongest single association was with rs55933544 (HR=1.9; 95% CI 1.5-2.4; p=1.3 x 10(-8)), which localizes to the GLDC gene, adjacent to the IL33 gene and was consistent across both the European and Brazilian case sets. Using publicly available data, the risk allele was associated with lower expression of IL33 and low expression of IL33 was associated with poor survival in an independent set of patients with osteosarcoma. In conclusion, we have identified the GLDC/IL33 locus on chromosome 9p24.1 as associated with overall survival in patients with osteosarcoma. Further studies are needed to confirm this association and shed light on the biological underpinnings of this susceptibility locus. What's new? To date, prognostic factors associated with survival in patients with osteosarcoma are scarce. Here, the authors conducted a multi-institutional genome-wide association study to explore whether germline genetics may contribute to overall survival in osteosarcoma patients. They identified a common single nucleotide polymorphism, rs55933544, located in the GLDC gene on chromosome 9, associated with poor survival. The rs55933544 risk allele was associated with lower expression of the nearby gene, IL33. These findings, if replicated in additional populations, form the foundation for future studies of the molecular basis of the association of the GLDC/IL33 (rs55933544) variant with survival in osteosarcoma.en
dc.description.affiliationNCI, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Room 6E524, Bethesda, MD 20850 USA
dc.description.affiliationInformat Management Serv IMS Inc, Rockville, MD USA
dc.description.affiliationOhio State Univ, Nationwide Childrens Hosp, Dept Pathol & Pediat, Columbus, OH 43210 USA
dc.description.affiliationUniv Fed Sao Paulo, GRAACC, Pediat Oncol Inst, Lab Genet, Sao Paulo, Brazil
dc.description.affiliationUniv Texas MD Anderson Canc Ctr, Dept Pediat, Houston, TX 77030 USA
dc.description.affiliationUCL Canc Inst, Huntley St, London, England|Royal Natl Orthopaed Hosp NHS Trust, Stanmore, Middx, England
dc.description.affiliationUniv Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Litwin Ctr Canc Genet, Toronto, ON, Canada
dc.description.affiliationUniv Navarra, Univ Clin Navarra, Dept Pediat, Pamplona, Spain
dc.description.affiliationOrthopaed Rizzoli Inst, Lab Expt Oncol, Bologna, Italy
dc.description.affiliationUniv Southern Calif, Keck Sch Med, Los Angeles, CA USA
dc.description.affiliationGarvan Inst Med Res, Kinghorn Canc Ctr, Darlinghurst, NSW, Australia
dc.description.affiliationUniv Minnesota, Dept Pediat, Minneapolis, MN 55455 USA
dc.description.affiliationFrederick Natl Lab Canc Res, Leidos Biomed Res, Canc Genom Res Lab, Frederick, MD USA
dc.description.affiliationUnifespUniv Fed Sao Paulo, GRAACC, Pediat Oncol Inst, Lab Genet, Sao Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipIntramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
dc.description.sponsorshipBone Cancer Research Trust UK
dc.description.sponsorshipChair's Grant of the Children's Oncology Group from the National Cancer Institute, National Institutes of Health
dc.description.sponsorshipHuman Specimen Banking of the Children's Oncology Group from the National Cancer Institute, National Institutes of Health
dc.description.sponsorshipWWWW (QuadW) Foundation, Inc.
dc.description.sponsorshipOntario Research Fund
dc.description.sponsorshipCanadian Foundation for Innovation
dc.description.sponsorshipRegione Emilia-Romagna
dc.description.sponsorshipRoyal National Orthopaedic Hospital Musculoskeletal Research Programme and Biobank
dc.description.sponsorshipNational Institute for Health Research UCLH Biomedical Research Centre
dc.description.sponsorshipUCL Experimental Cancer Centre
dc.description.sponsorshipFIS, ISCIII and La Fundacion Bancaria "La Caixa"
dc.description.sponsorshipFundacion Caja Navarra
dc.description.sponsorshipAECC Project
dc.description.sponsorshipRainbows for Kate Foundation
dc.description.sponsorshipLiddy Shriver Sarcoma Initiative
dc.description.sponsorshipVictorian Cancer Agency
dc.description.sponsorshipAustralian National Health and Medical Research Council
dc.description.sponsorshipCancer Australia
dc.description.sponsorshipIDNIH: U10 CA98543
dc.description.sponsorshipIDNIH: U24 CA114766]
dc.description.sponsorshipIDUCL-ECC: PI13/01476
dc.description.sponsorshipIDANHMRC: APP1004017
dc.description.sponsorshipIDCancer Australia: APP1067094
dc.format.extent1594-1601
dc.identifierhttp://dx.doi.org/10.1002/ijc.31195
dc.identifier.citationInternational Journal Of Cancer. Hoboken, v. 142, n. 8, p. 1594-1601, 2018.
dc.identifier.doi10.1002/ijc.31195
dc.identifier.issn0020-7136
dc.identifier.urihttps://repositorio.unifesp.br/handle/11600/55636
dc.identifier.wosWOS:000425184800011
dc.language.isoeng
dc.publisherWiley
dc.relation.ispartofInternational Journal Of Cancer
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectosteosarcomaen
dc.subjectoverall survivalen
dc.subjectgenome-wide association studyen
dc.subjectosteosarcoma-specific survivalen
dc.titleGenome-wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patientsen
dc.typeinfo:eu-repo/semantics/article
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