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American Journal of Medical Genetics (Semin. Med. Genet.) 115:189 –193 (2002) A R T I C L E Cytogenetics and Molecular Genetics of Bone and Soft-Tissue Tumors AVERY A. SANDBERG* The cytogenetic and molecular findings in bone and soft-tissue sarcomas are summarized. A table presenting all such tumors, with their specific translocations and the genes involved, is included, along with a list of those tumors that most likely result from a stepwise process of numerous genetic changes. ß 2002 Wiley-Liss, Inc. KEY WORDS: soft-tissue sarcomas; bone tumors; chromosome changes; molecular abnormalities For cytogenetic and molecular data on bone and soft-tissue tumors up to 1994, the reader may wish to consult the book by Sandberg and Bridge [1994]. For more recent information, an ongoing series of updates on various bone and soft-tissue tumors are available [Sandberg and Bridge, 2001a,b, in press], as are several comprehensive reviews [Barr et al., 1995; Sorensen and Triche, 1996; Åman, 1999; Ladanyi and Bridge, 2000]. The cytogenetic and molecular aspects of bone and soft-tissue tumors, most of them sarcomas, have received much attention lately. From a cytogenetic viewpoint, these tumors are relatively easy to grow in vitro and hence yield metaphases for chromosome analysis. Most important, a substantial number of these tumors are characterized by specific cytogenetic changes, usually translocations (Table I). In a significant proportion of these tumors (Table I), the translocation is the sole cytogenetic anomaly, indicating the probable causative role of this translocation in the genesis of these tumors. Generally, when there are additional chromosomal changes, the tumor is usually more aggressive than when the translocation is the sole anomaly. At a molecular level, almost all the genes involved in these Avery A. Sandberg, M.D., D.Sc., is Editorin-Chief of Cancer Genetics and Cytogenetics; Clinical Consultant in the Department of DNA Diagnostics at St. Joseph’s Hospital and Medical Center in Phoenix, Arizona; and Clinical Professor in Pathology at the University of Arizona in Tucson. *Correspondence to: Avery A. Sandberg, M.D., D.Sc., Department of DNA Diagnostics, St. Joseph’s Hospital and Medical Center, 350 West Thomas Road, Phoenix, AZ 85013. E-mail: [email protected] DOI 10.1002/ajmg.10691 Inflammatory myofibroblastic tumor ß 2002 Wiley-Liss, Inc. translocations have been identified, leading to their utilization in establishing the diagnosis in confusing tumors, particularly when fresh tissue for cytogenetic analysis is not available. The application of molecular approaches, including TABLE I. Specific Chromosomal Translocations Established Cytogenetically and the Corresponding Gene Changes in Bone and Soft-Tissue Tumors Tumors Alveolar rhabdomyosarcoma Alveolar soft-part sarcoma Clear-cell sarcoma (malignant melanoma of soft parts) Congenital fibrosarcoma and mesoblastic nephroma Dermatofibrosarcoma protuberans (giant-cell fibroblastoma) Desmoplastic round-cell tumor Endometrial stromal sarcoma Ewing sarcoma and peripheral primitive neuroectodermal tumors Myxoid chondrosarcoma, extraskeletal Myxoid liposarcoma Synovial sarcoma Translocation Gene changes t(2;13)(q35;q14) t(1;13)(p36;q14) t(X;17)(p11.2;q25) t(12;22)(q13;q12) PAX3-FKHR PAX7-FKHR ASPL-TFE3 ATF1-EWS t(12;15)(p13;q25) ETV6-NTRK3 t(17;22)(q22;q13) COL1A1-PDGFB t(11;22)(p13;q12) t(7;17)(p15;q21) t(11;22)(q24;q12) WT1-EWS JAZF1-JJAZ1 EWS-FLI1 t(21;22)(q22;q12) t(7;22)(p22;q12) t(17;22)(q12;q12) t(2;22)(q33;q12) t(2;19)(p23;p13.1) t(1;2)(q22-23;p23) t(9;22)(q22;q12) t(9;17)(q22;q11) t(9;15)(q22;q21) t(12;16)(q13;p11) t(12;22)(q13;q12) t(X;18)(p11;q11) EWS-ERG EWS-ETV1 EWS-E1AF FEV-EWS ALK-TPM4 TPM3-ALK EWS-CHN(TEC) RBP56-CHN(TEC) TEC-TCF12 TLS(FUS)-CHOP EWS-CHOP SYT-SSX1 SYT-SSX2 190 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) fluorescence in situ hybridization of various types, to archival tissue has been a major development in the field. In a significant proportion of these tumors . . . the translocation is the sole cytogenetic anomaly, indicating the probable causative role of this translocation in the genesis of these tumors. A revealing advance has been the finding in some sarcomas that the variability in fusion products, due to variability in intragenic breakpoints, may have clinical application, such as in prognosis [Lin et al., 1999]. This has been established in the case of Ewing sarcoma, and similar observations probably also will be made for other types of sarcomas. The figure shown in this article utilizes some of the cytogenetic and molecular findings from Ewing sarcoma and related tumors and serves as an example of the nature of changes that may be encountered in bone and soft-tissue sarcomas and the possible events and the meaning associated with these changes. Figure 1 shows a karyotype from a Ewing sarcoma with the characteristic t(11;22)(q24;q12) (horizontal arrows). The vertical arrows point to additional chromosomal changes (þ 3, þ 7, þ 8, and þ 9) that generally indicate a more aggressive tumor than those containing the translocation as a sole cytogenetic event. The latter is seen not infrequently in Ewing and other sarcomas. Figure 2 is a schematic presentation of the t(11;22) translocation in Ewing sarcoma and a partial karyotype of this translocation. Figure 3 is a schematic presentation of ARTICLE the molecular genetic events resulting from the t(11;22) in Ewing sarcoma, that is, the break in the EWS gene and the break in the FLI gene leading to the for-mation of an abnormal fusion gene EWS-FLI1. The latter is thought to be the direct cause of the development of Ewing sarcoma. Note that the break on the EWS gene may occur in different parts of an alternate splicing area, as it may on the FLI gene, leading to different fusion products (see Fig. 4). The upper part of Figure 3 shows the structure of the EWS and FLI1 genes, with arrowheads indicating the naturally occurring fusion sites in the chimeric transcripts resulting from the t(11;22)q24;q12) and the fusion of the 50 end of the EWS gene and the 30 end of the FLI1 gene, with considerable combinatorial diversity of junctions. The transactivating domain of EWS is retained in EWS-FLI1; the RNA domain is lost. The FLI1 gene encodes Figure 1. Karyotype of a Ewing sarcoma with the characteristic t(11;22)(q24;q12) seen in this tumor. Among the additional changes, trisomy 8 (þ8) is a common secondary abnormality observed in Ewing sarcoma and related tumors [Sandberg and Bridge, 2000]. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) Figure 2. Schematic illustration of the t(11;22) characteristic of Ewing sarcoma (top). Partial G-banded karyotype of the t(11;22)(q24;q12). See text for discussion [Sandberg and Bridge, 2000]. 191 an NH-terminal transactivating region (including a pointed domain encoded largely by exon 4) that is partially retained in some EWS-FLI1 fusions and a COOH-terminal transactivating domain. Exon 9 of the FLI1 gene encodes the highly conserved ETS-type DNA binding domain. The EWS and FLI1 transcripts shown in Figure 4 are presented approximately to scale. Differences in the fusion products have shown clinical significance, in that the prognosis in Ewing sarcoma is different for the type 1 versus the type 2 fusion product of EWS-FLI1. The clinical significance of the other fusion products is unknown, owing to lack of data at this time. Molecular studies shown the involvement and changes in genes not necessarily involved in translocations. An example is the gene KIT in intestinal stromal tumors, whose overexpression or mutation or both is diagnostic of this tumor. Most important, because of its tyrosine kinase content, it is subject to remarkable effects of drugs directed against this kinase, for example, Gleevec, PD17, and, possibly, other similar drugs [Sandberg and Bridge, 2002]. An identical translocation as well as the molecular changes associated with this translocation (Table I) have led to the recognition that infantile fibrosarcoma and congenital mesoblastic nephroma Figure 3. Schematic diagram of the chimeric EWS-FLI1 protein product. NTD ¼ amino terminal domain; BD ¼ binding domain. See text for discussion [Sandberg and Bridge, 2000]. 192 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ARTICLE TABLE II. Bone and Soft-Tissue Tumors Not Associated With Specific Translocations Chondrosarcomas (except extraskeletal) Osteosarcomas Mesothelioma Leiomyosarcomas Fibrosarcoma (adult) Malignant fibrous histiocytoma Malignant peripheral nerve sheath tumor Figure 4. Upper part of the figure shows the structure of the EWS and FLI1 genes with arrowheads indicating the breakpoints and fusion sites in the chimeric transcripts resulting from the t(11;22)(q24;q12) in Ewing sarcoma. See text for discussion [Sandberg and Bridge, 2000]. are tumors of identical genetic origin and pathologic features. Without the unique cytogenetic and molecular findings in these two tumors, it is doubtful whether their common origin would have been recognized. Another example of tumors of quite different anatomic location having the same genetic background is alveolar soft-part sarcoma and some papillary renal cell carcinomas (RCCs), which have an identical translocation, t(X;17)(p11.2;q25). Of significance is the balanced nature of the t(X;17) in RCCs and the unbalanced nature of the translocation in alveolar soft-part sarcomas, leading to a der(17)t(X;17) (p11.2;q25). The abnormal fusion genes in both types of tumors are identical, that is, ASPL(RCC)-TFE3 [Argani et al., 2001; Sandberg and Bridge, in press]. An identical translocation as well as the molecular changes associated with this translocation (Table I) have led to the recognition that infantile fibrosarcoma and congenital mesoblastic nephroma are tumors of identical genetic origin and pathologic features. Both tumors with specific translocations and those without (Table II) have been shown to have numerous cytogenetic and molecular changes. In the case of the former tumors, this may be indicative of biologic tumor progression; in the case of the latter tumors, some of the changes may be primary and causative, whereas others may be of a secondary nature. In most of these tumors (without specific translocations), the primary (causative) genes have not been established. Also, the cytogenetic and molecular changes vary from tumor to tumor as well as in tumors of similar origin. The genetic findings in some of these tumors are not dissimilar from the pattern described in this issue for bladder cancer [Sandberg, in press]. Thus, these tumors are associated with a stepwise process of orchestrated genetic changes starting from excess cellular proliferation, malignant transformation, and ultimately invasiveness and metastases. These changes vary from tumor to tumor, though some of the same genes may be involved in several tumors. Although translocations and other structural chromosome changes affecting oncogenes may be part of this genetic cascade of events in these tumors, most of the genes affected are tumor suppressor genes containing allelic imbalances leading to loss of heterozygosity. It remains to be resolved what constitutes the causative and original genetic event and the order in which the subsequent changes lead to overt cancer and cancerous behavior. Although various ARTICLE chromosomes have been suggested as being responsible for the initiation of some of these tumors, rigorous evidence has not been obtained for any of these tumors. The establishment of the significant role of any genes in the stepwise process of tumorigenesis of the neoplasms shown in Table II may serve important diagnostic and, particularly, prognostic and therapeutic purposes. REFERENCES Åman P. 1999. Fusion genes in solid tumors. Cancer Biol 9:303–318. Argani P, Antonescu CR, Illei PB, Lui MY, Timmons CF, Newbury R, Reuter VE, Garvin AJ, Perez-Atayde AR, Fletcher JA, Beckwith JB, Bridge JA, Ladanyi M. 2001. Primary renal neoplasms with the ASPL- AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol 159:179–192. Barr FG, Chatten J, D’Cruz CM, Wilson AE, Nauta LE, Mycum LM, Biegel JA, Womer RB. 1995. Molecular assays for chromosomal translocations in the diagnosis of pediatric soft tissue sarcomas. JAMA 273:553– 557. Heimann P, El Housni H, Ogur G, Weterman MAJ, Petty EM, Vassart G. 2001. Fusion of a novel gene, RCC17, to the TFE3 gene in t(X;17)(p11.2;q25.3)-bearing papillary renal cell carcinomas. Cancer Res 61:4130–4135. Ladanyi M, Bridge JA. 2000. Contribution of molecular genetic data to the classification of sarcomas. Hum Pathol 31:532–538. Lin PP, Brody RI, Hamelin AC, Bradner JE, Healey JH, Ladany M. 1999. Differential transactivation by alternative EWS-FLI1 proteins correlates with clinical heterogeneity in Ewing’s sarcoma. Cancer Res 59:1428–1432. 193 Sandberg AA. 2002. The cytogenetics and molecular genetics of bladder cancer: a personal view. Am J Med Genet (Semin Med Genet) (in press). Sandberg AA, Bridge JA. 1994. The cytogenetics of bone and soft tissue tumors. Austin: RG Landes Co. Sandberg AA, Bridge JA. 2001a. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: clear cell sarcoma (malignant melanoma of soft parts). Cancer Genet Cytogenet 130:1–7. Sandberg AA, Bridge JA. 2001b. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: mesothelioma. Cancer Genet Cytogenet 127:93– 110. Sandberg AA, Bridge JA. 2002. Updates on the cytogenetics and molecular genetics of bone and soft issue tumors: gastrointestinal stromal tumors. Cancer Genet Cytogenet (in press). Sorensen PHB, Triche TJ. 1996. Gene fusions encoding chimaeric transcription factors in solid tumours. Cancer Biol 7:3–14.