GenomicProfilingofChondrosarcoma:ChromosomalPatternsin CentralandPeripheralTumors KarolinH.Hallor, 1 JohanStaaf, 2 JudithV.M.G.Bove¤e, 5 PancrasC.W.Hogendoorn, 5 Anne-MarieCleton-Jansen, 5 SakariKnuutila, 6 SuviSavola, 6 TarjaNiini, 6 OtteBrosjo«, 7 HenrikC.F.Bauer, 7 FredrikVultvonSteyern, 3 KjellJonsson, 4 MikaelSkorpil, 8 NilsMandahl, 1 andFredrikMertens 1 Abstract Purpose: Histologicgradeiscurrentlythebestpredictorofclinicalcourseinchondrosarcoma patients.Gradingsuffers,however,fromextensiveinterobservervariabilityandnewobjective markersareneeded.Hence,wehaveinvestigatedDNAcopynumbersinchondrosarcomaswith thepurposeofidentifyingmarkersusefulforprognosisandsubclassification. ExperimentalDesign: Theoverallpatternofgenomicimbalanceswasassessedinaseriesof 67chondrosarcomasusingarraycomparativegenomichybridization.Statisticalanalyseswere appliedtoevaluatethesignificanceofalterationsdetectedinsubgroupsbasedonclinicaldata, morphology,grade,tumorsize,andkaryotypicfeatures.Also,theglobalgeneexpressionprofiles wereobtainedinasubsetofthetumors. Results: Genomicimbalances,inmosttumorsaffectinglargeregionsofthegenome,werefound in90%ofthecases.Severalapparentlydistinctiveaberrationsaffectingconventionalcentraland peripheraltumors,respectively,wereidentified.Althoughrare,recurrentamplificationswere foundat8q24.21-q24.22and11q22.1-q22.3,andhomozygousdeletionsoflocipreviouslyimpli- catedinchondrosarcomadevelopmentaffectedthe CDKN2A,EXT1 ,and EXT2 genes.Thechro- mosomalimbalancesintwodistinctgroupsofpredominantlynear-haploidandnear-triploid tumors,respectively,supportthenotionthatpolyploidizationofaninitiallyhyperhaploid/ hypodiploidcellpopulationisacommonmechanismofchondrosarcomaprogression.Increasing patientageaswellastumorgradewereassociatedwithadverseoutcome,butnocopynumber imbalanceaffectedmetastasisdevelopmentortumor-associateddeath. Conclusion: Despitesimilaritiesintheoverallgenomicpatterns,thepresentfindings suggestthatsomeregionsarespecificallyalteredinconventionalcentralandperipheraltumors, respectively. Chondrosarcoma is the collective term for a biologically and clinically heterogeneous group of malignant cartilage- producing tumors. They may be subdivided according to grade and morphologic features, with the so-called conventional subtype accounting for f85% of the cases; the other variants (dedifferentiated, mesenchymal, clear cell, and myxoid chon- drosarcoma) are individually rare (1). Conventional chondro- sarcoma of bone is further trichotomized according to the location in the bone. Primary conventional central chondro- sarcoma originates from the medullar cavity of the bone, whereas secondary peripheral and periosteal ones develop from the surface of the bone, although with distinct clinical and morphologic characteristics. Finally, chondrosarcomas may either develop de novo or through malignant transforma- tion of a preexisting benign lesion, termed primary and secondary chondrosarcomas, respectively (2). The incidence of chondrosarcoma increases with age, hence primarily affecting adults. It is also known that patients suffering from multiple osteochondromas and enchondroma- tosis are at an elevated risk of developing chondrosarcoma. Multiple osteochondromas is an autosomal dominant dis- order characterized by multiple benign cartilage-capped bony Human Cancer Biology Authors’Affiliations: Departmentsof 1 ClinicalGenetics, 2 Oncology, 3 Orthopedics, and 4 DiagnosticRadiology,LundUniversityHospital,Lund,Sweden; 5 Department ofPathology,LeidenUniversityMedicalCentre,Leiden,theNetherlands; 6 DepartmentofPathology,HaartmanInstituteandHUSLAB,UniversityofHelsinki andHelsinkiUniversityCentralHospital,Finland;andDepartmentsof 7 Orthopedics and 8 Radiology,KarolinskaHospital,Stockholm,Sweden Received 9/15/08; revised 12/2/08; accepted 12/4/08; published OnlineFirst 3/31/09. Grantsupport: Nilsson-EhleFunds,AndersOttoSwa«rdFoundation,Gunnar NilssonCancerFoundation,Siv-Inger&Per-ErikAnderssonMemorialFund,and NetherlandsOrganizationforScientificResearchgrant917-76-315(J.V.M.G. Bove¤e)andSwedishCancerSociety.TheDepartmentofClinicalGenetics,Lund UniversityHospital,theDepartmentofPathology,HaartmanInstitute,Universityof Helsinki,andtheDepartmentofPathology,LeidenUniversityMedicalCentreare partnersoftheEuroBoNeTconsortium,anetworkofexcellencegrantedbythe EuropeanCommissionforstudyingthepathologyandgeneticsofbonetumors. Thecostsofpublicationofthisarticleweredefrayedinpartbythepaymentofpage charges.Thisarticlemustthereforebeherebymarked advertisement inaccordance with18U.S.C.Section1734solelytoindicatethisfact. Note: SupplementarydataforthisarticleareavailableatClinicalCancerResearch Online(http://clincancerres.aacrjournals.org/). Requestsforreprints: KarolinH.Hallor,DepartmentofClinicalGenetics,Lund UniversityHospital,SE-22185Lund,Sweden;Phone:46-46-173398;Fax:46- 46-131061;E-mail:Karolin.Hansen__Hallor@med.lu.se. F 2009AmericanAssociationforCancerResearch. doi:10.1158/1078-0432.CCR-08-2330 www.aacrjournals.org ClinCancerRes2009;15(8)April15,2009 2685