LEAD ARTICLE Distinct Xp11.2 Breakpoint Regions in Synovial Sarcoma Revealed by Metaphase and Interphase FISH: Relationship to Histologic Subtypes B. de Leeuw, R. F. Suijkerbuijk, D. Olde Weghuis, A. M. Meloni, G. Stenman, L. G. Kindblom, M. Balemans, E. van den Berg, W. M. Molenaar, A. A. Sandberg, and A. Geurts van Kessel ABSTRACt: F/uorescence in situ hybridization (FISH) and molecular analyses ofsynovial sarcomas with cytogenetically similar (X;18)(p11.2;q11.2) translocations have revealed two alternative breakpoint regions in Xp11.2, one residing in the ornithine aminotrunsferase-like I (OATL1) region and the other one in the related but distinct OATL2 region. As these results were obtained by different groups, we set out to evalu- ate an extended series of tumors with special emphasis on the two possible X-related breakpoint regions. Together, seven synovial sarcomas were identified with a break in the OATL1 region and six with a break near OATL2, thereby confirming the actual existence of the two alternative Xp breakpoint regions. We speculate that there seems to be a relationship between the occurrence of these breakpoint regions and the histologic phenotype of the tumors, with a predominance ofOATLl-related breakpoints in the classi- ca• biphasic tumors and of OATL2-related breakpoints in the monophasic fibrous tumors. INTRODUCTION Synovial sarcoma is a soft tissue tumor which occurs mainly in adolescents and young adults. Next to rhabdomyosarcoma, synovial sarcoma is the most common solid tumor in chil- dren under 18 years of age [1, 2]. The patients' ages range from 11 months to 78 years, whereas the mean age at the time of operation is 37 years [3, 4]. About 90% of the primary tumors are found in the extremities, especially the lower limbs [2], whereas 3-10% are found in the head and neck region, heart, and mediastinum [5-7]. In spite of its name, which arose from the light microscopic resemblance of the classic biphasic type to synovial tissue, the exact histogenetic origin of synovial sarcoma is, as yet, unknown. Electron mi- croscopic and immunologic data clearly distinguish the cells from true synovial cells [8, 9]. Also, the tumors may arise at places where normally synovial cells are not present [10]. From the Department of Human Genetics (13. d L., R. F. S., D. O. W.., M. B., A. G. v K.), University Hospital, Nijmegen, The Netherlands; Southwest Biomedical Research Institute of Genetr/x Inc. (,4. M. M., A. A. S.), Scottsdale Arizona; Laboratory of Cyto- genetics (G. S., L. G. K.), Department of Oral Pathology, University of G~teborg, Sweden; Department of Medical Genetics (E. v d B.), University of Groningen, The Netherlands; and Department of Pathology (W. M. M.), University of Groningen, The Netherlands. Address repr/nt requests to: B. de Leeuw, Department of Human Genetics, University Hospital, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Received July 12, 1993; accepted September 3, 1993. For this reason suggestions have been made to change the name to carcinosarcoma [8, 9]. Histologically, synovial sarcomas can be divided into two major groups: the classical biphasic type, containing an epi- thelial and a spindle cell component, and the monophasic type, containing only spindle cells, although some areas may express epithelial markers like EMA, keratin, CEA, $100, and others [8, 9]. The tumors differ in a graded fashion, how- ever, which has led some authors to subdivide the biphasic type into totally biphasic (or glandlike) and focally biphasic [11]. Occasionally, two other types of synovial sarcoma are mentioned, namely the undifferentiated type and the mono- phasic epithelial type. These latter tumors are presumed to represent extreme and rare cases of monophasic and biphasic synovial sarcomas, respectively [1, 11]. The monophasic spin- dle cell and biphasic subtypes are thought to occur with simi- lar frequencies [12], although some authors state that the monophasic type is predominant, comprising about 60% of all cases [9]. A characteristic chromosomal translocation, t(X;18)(p11.2; q11.2], has been found in synovial sarcoma cells [13]. Some- times this translocation is the only cytogenetic abnormality present, which is indicative of a primary causal event in tu- mor development. Recently, we [14, 15] and others [16] have identified yeast artificial chromosomes CYACs) containing hu- man genomic fragments that span the breakpoint region on the X chromosome in different tumors. Both YACs (number 2 and 7) contain ornithine amino transferase (OAT)dike se- quences (OATL1 and OATL2, respectively] that are located © 1994 Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 89 Cancer Genet Cytogenet 73:89-94 (1994) 0165-4608/94/$07.00