0165-4608/00/$–see front matter PII S0165-4608(99)00178-8 Cancer Genet Cytogenet 118:89–98 (2000)  Elsevier Science Inc., 2000. All rights reserved. 655 Avenue of the Americas, New York, NY 10010 LEAD ARTICLE Frequent Loss of 9p21 (p16 INK4A ) and Other Genomic Imbalances in Human Malignant Fibrous Histiocytoma Annet Simons, Marga Schepens, Judith Jeuken, Sandra Sprenger, Guillaume van de Zande, Bodil Bjerkehagen, Anne Forus, Vines Weibolt, Ineke Molenaar, Eva van den Berg, Ola Myklebost, Julia Bridge, Ad Geurts van Kessel, and Ron Suijkerbuijk ABSTRACT: To search for new recurrent genetic aberrations in malignant fibrous histiocytoma (MFH), a combination of conventional cytogenetic, comparative genomic hybridization (CGH), and Southern blot analyses was applied to a series of 34 tumors. Cytogenetic analysis revealed the presence of multi- ple structural and numerical aberrations, including marker chromosomes, telomeric associations, dou- ble minutes, and ring chromosomes. The most frequent genomic imbalances in this series of neoplasms as detected by CGH were gains of 1q21–q22 (69%), 17q23–qter (41%), and 20q (66%), and losses of 9p21–pter (55%), 10q (48%), 11q23–qter (55%), and 13q10–q31 (55%). Southern blot analyses with p16 INK4A (CDKN2A; 9p21) and RB1 (13q14) probes provided clear indications for frequent deletions of these tumor suppressor genes, and as such, substantiated the CGH results. Additionally, examination of the TP53 and MDM2 genes showed frequent loss and amplification, respectively. These data indicate that genes involved in the RB1- and TP53-associated cell cycle regulatory pathways may play promi- nent roles in the development of human MFH. © Elsevier Science Inc., 2000. All rights reserved. INTRODUCTION Malignant fibrous histiocytoma (MFH) is the most com- mon malignant soft tissue tumor in adults [1]. Histopatho- logically, MFHs can be subclassified as storiform, pleo- morphic, myxoid, giant cell, and inflammatory [2]. Cytogenetic data on MFHs are scarce; however, most tumors analyzed thus far have exhibited complex karyo- types with multiple numerical and structural abnormali- ties [3–10]. The structural abnormalities have included ring chromosomes, homogeneously-staining regions, dou- ble minutes, telomeric associations, and dicentric chro- mosomes. No specific chromosomal anomaly has been re- ported so far in MFH, but breakpoints in 1p36, 1q11, 1q21, 3p12, 11p11, 17p11, and 19p13 have been recurrently ob- served [4–6]. Moreover, it has been suggested that a 19p + marker may serve as an indicator for high risk of local re- currence and aggressive clinical course [11, 12]. Recently, Walter et al. observed two solitary rearrangements, t(5;7) (q31;q22) and t(13;14)(q10;q10), which were considered as primary changes [9]. In addition to conventional cytogenetic investigations, five comparative genomic hybridization (CGH) studies in- cluding data on MFH have been reported [13–17]. Com- parative genomic hybridization allows for the detection of genomic imbalances (i.e., gains/losses) of whole chromo- somes or chromosomal regions. Accordingly, this tech- nique may reveal the position and/or involvement of genes related to tumor development [18–20]. In the first two studies, the regions 1p31 and 7q32 were found to be frequently gained [13, 14]. In addition, Larramendy et al. reported that gain of 1p was significantly associated with a poor overall survival and gain of 7q32 with a less favor- able metastasis-free/overall survival and an increased risk for local recurrences. As such, gain of 7q32 was proposed by these authors to serve as a novel prognostic marker From the Department of Human Genetics (A. S., M. S., G. v. d. Z., V. W., A. G. v. K, R. S.), and the Department of Neurology (J. J., S. S.), University Hospital, Nijmegen, The Netherlands; the Department of Pathology (B. B., O. M.) and the Department of Tumor Biology (A. F.), The Norwegian Radium Hospital, Oslo, Norway; the Department of Pathology (V. W., I. M.) and the Department of Medical Genetics (E. v. d. B.), University Hospital, Groningen, The Netherlands; and the Department of Pathology and Microbiology (J. B.), University of Nebraska Medical Center, Omaha, Nebraska, USA. Address reprint requests to: Annet Simons, Department of Human Genetics, University Hospital Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Received July 2, 1999; Accepted August 20, 1999.