AbstractUndifferentiated pleomorphic sarcoma of bone (UPSb) is a rare tumor often difficult to differentiate from fibrosarcoma of bone (FSb), diagnostically. We applied array comparative genomic hybridization (array CGH) to screen for genes with potential importance in the tumor and compared the results with alterations seen in FSb. Twenty‐two fresh frozen tissue specimens from 20 patients (18 primary tumors and 4 local recurrences) with UPSb were studied. DNA was isolated and hybridized onto Agilent 244K CGH oligoarrays. The hybridization data were analyzed using Agilent DNA Analytics Software. The number of changes ranged from 2 to 168 (average = 66). Losses were most frequently seen at 8p, 9p, 10, 13q, and 18q, and gains at 4q, 5p, 6p, 7p, 8q, 12p, 14q, 17q, 19p, 20q, 22q, and X. Homozygous deletions ofCDKN2A,RB1,TP53, andING1were seen in 8/20, 7/20, 3/20, and 2/20 cases, respectively. Hypermethylation of bothp16INK4aandp14ARFwas found in two cases with loss atCDKN2A. Inactivation either ofCDKN2A,RB1, orTP53was detected in 18/20 cases. One case showed high level gains ofCDK4andMDM2. Frequent gains were seen atMYC,PDGFRA,KIT, andKDR. Immunohistochemical positivity of KIT, PDGFRA, KDR, and PDGFRB was found in 8/14, 5/14, 4/14, and 4/14 cases, respectively. The regions most significantly discriminating between UPSb and FSb includedRB1andMYC. No homozygous deletions ofRB1were found in FSb. In conclusion, our analysis showed the disruption of G1/S checkpoint regulation to be crucial for the oncogenesis of UPSb. © 2011 Wiley‐Liss, Inc.