Figure 37.1
Mechanisms of chromosomal DNA rearrangement leading to altered gene expression by either gene fusion (top pathway) or promoter exchange (bottom pathway)
The first mechanism by which chromosomal translocations result in altered gene function is by gene fusion (Fig. 37.1), in which chimeric or fusion genes are the result of joining of two parent genes (one upstream, or 5′, and the other downstream, or 3′, to the breakpoint). Both genes are truncated by the translocation involving the coding portions of the parent genes. In general, translocation breakpoints are located in noncoding introns, and the normal splicing mechanism removes the chimeric intron sequence. The exons are spliced “in frame” for the translational reading frame and can be translated into a novel fusion protein. In rare instances, the breakpoints are located in the exons of the parent genes. This may result in a novel chimeric product if the translational reading frame is maintained, or it may produce a truncated protein (encoded by the 5′ gene sequence) if the reading frame is lost. Transcription of chimeric genes is usually under the control of the upstream parent gene promoter but may be influenced by DNA sequences in or close to the downstream gene.
The second mechanism through which chromosomal translocations result in altered gene function is promoter exchange, in which the breakpoint occurs at the 5′ end of the coding region of the involved gene (Fig. 37.1). This results in the replacement of the gene’s promoter region with enhancer elements or with the promoter from the translocation partner. Promoter exchange leads to transcriptional activation with abnormal gene expression, but the protein is wild-type.
Numerous fusion genes have been identified in malignant tumors of the soft tissues and in mesenchymal tumors in general (Table 37.1). The majority of sarcoma translocations result in in-frame fusion genes, resulting in abnormal chimeric transcription factors [4]. In a few cases, the gene fusion results in an aberrant tyrosine kinase or an autocrine growth factor [8–10]. The der(17) associated with the nonreciprocal t(X;17)(p11.2;q25) of human alveolar soft part sarcoma produces a chimeric transcript between the transcription factor gene TFE3 and ASPL, a novel gene at 17q25 [11]. ASPL encodes a UBX-like domain at the C-terminus of the encoded protein. In alveolar soft part sarcoma, the 5′ end of ASPL is fused to exon 3 or 4 of TFE3, resulting in a fusion protein retaining the C-terminal TFE3 DNA-binding domain, a possible aberrant transcriptional regulator.
Table 37.1
Chromosomal alterations and aberrant gene products in sarcomas and related tumors
Tumor type | Chromosomal change | Fusion gene | Prevalence (%) | Number of fusion transcript variants | Function | Reference |
|---|---|---|---|---|---|---|
Round cell tumors | ||||||
Desmoplastic small round cell tumor (DSRCT) | t(11;22)(p13;q12) | EWSR1–WT1 | 100 | Small (3) | Transcription | Ladanyi. Cancer Res 1994;54:2837 |
Ewing’s sarcoma (ES)/Peripheral | t(11;22)(q24;q12) | EWSR1–FLI1 | >90 | Large (18) | Transcription | Delattre. Nature 1992;359:162 |
Neuroectodermal tumor (PNET) | t(21;22)(q22;q12) | EWSR1–ERG | 5 | Large (4) | Transcription | Sorensen. Nat Genet 1994;6:146 Zucman. EMBO J 1993;12:4481 |
t(7;22)(p22;q12) | EWSR1–ETV1 | <5 | Uncertain | Transcription | Jeon. Oncogene 1995;10:1229 | |
t(17;22)(q12;q12) | EWSR1–E1AF | <5 | Uncertain | Transcription | Urano. Biochem Biophys Res Commun 1996;219:608 | |
t(2;22)(q33;q12) | EWSR1–FEV | <5 | Uncertain | Transcription | Peter. Oncogene 1997; 14:1159 | |
t(16;21)(p11;q22) | FUS–ERG | <5 | Small (2) | Transcription | Shing. Cancer Res 2003;63:4568 | |
Rhabdomyosarcoma, alveolar type (ARMS) | t(2;13)(q35;q14) | PAX3–FOXO1 | 60 | None (1) | Transcription | Galili. Nat Genet 1993;5:230 Shapiro. Cancer Res 1993;53:5108 |
t(1;13)(p36;q14) | PAX7–FOXO1 | 20 | None (1) | Transcription | Davis. Cancer Res 1994;54:2869 | |
t(2;2)(p23;q35) | PAX3–NCOA1 | <5 | Small (2) | Transcription | Sumegi. Genes Chromosomes Cancer 2010;49:224 | |
t(2;8)(q35;q13) | PAX3–NCOA2 | <5 | None (1) | Transcription | Sumegi. Genes Chromosomes Cancer 2010;49:224 | |
t(X;2)(q13;q35) | PAX3–FOXO4 | <5 | None (1) | Transcription | Barr. Cancer Res 2002;62:4704 | |
Spindle cell tumors | ||||||
Dermatofibrosarcoma protuberans/giant cell fibroblastoma | t(17;22)(q22;q13) | COL1A1–PDGFB | 100 | Large (>8) | Dysregulated cell growth (autocrine) | Simon. Nat Genet 1997;15:95 |
Fibrosarcoma, congenital type | t(12;15)(p13;q25) | ETV6–NTRK3 | 100 | None (1) | Signaling (tyrosine kinase receptor) | Knezevich. Nat Genet 1998;18:184 |
Inflammatory myofibroblastic tumora | t(1;2)(q25;p23) | TPM3–ALK | 20 | None (1) | Signaling (TKR) | Griffin. Cancer Res 1999;59:2776 |
Inv(2)(p21;p23.2) | EML4–ALK | 10 | Large (>10) | Signaling (TKR) | Antonescu. Am J Surg Pathol. 2015 | |
t(2;19)(p23;p13) | TPM4–ALK | 10 | None (1) | Signaling (TKR) | Lawrence. Am J Pathol 2000;157:377 | |
6q22 alterations | ROS1 rearrangements (TFG and other genes) | 10 | Uncertain | Signaling (TKR) | Antonescu. Am J Surg Pathol. 2015 | |
t(2;17)(p23;q23) | CLTC–ALK | Uncertain | None (1) | Signaling (TKR) | Bridge. Am J Pathol 2001;159:41 | |
t(2;11)(p23;p15) | CARS–ALK | Uncertain | None (1) | Signaling (TKR) | Cools. Genes Chromosomes Cancer 2002;34:354 | |
t(2;2)(p23;q13) | RANBP2–ALK | Uncertain | None (1) | Signaling (TKR) | Ma. Genes Chromosomes | |
Various loci | Other TK (PDGFRB, RET) | <5 | Uncertain | Signaling (TKR) | Antonescu. Am J Surg Pathol 2015 Cancer 2003;37:98 | |
Low-grade fibromyxoid | t(7;16)(q33;p11) | FUS–CREB3L2 | >75 | Large (>4) | Transcription | Mertens. Lab Invest 2005;85:408 |
Sarcoma/hyalinizing spindle cell tumor with giant rosettes | Reid. Am J Surg Pathol 2003;27:1229 Guillou. Am J Surg Pathol 2007;31:1387 | |||||
t(11;16)(p11;p11) | FUS–CREB3L1 | <10 | Small (2) | Transcription | Mertens. Lab Invest 2005;85,408 | |
Nodular fasciitis | t(17;22)(p13;q13) | MYH9–USP6 | 75 | Uncertain | Signaling | Erickson-Johnson. Lab Invest 2011;91:1427 |
Spindle cell tumors with pericytic differentiation (pericytoma) | t(7;12)(p21-22;q13–15) | ACTB–GLI | Uncertain | Large (6) | Transcription | Dahlén. Am J Pathol 2004;164:1645 |
Synovial sarcoma | t(X;18)(p11;q11) | SS18–SSX1 | 65 | None (1) | Transcription | Clark. Nat Genet 1994;7:502 |
t(X;18)(p11;q11) | SS18–SSX2 | 30 | None (1) | Transcription | Crew. EMBO J 1995;14:2333 De Leeuw. Hum Mol Genet 1995;4:1097 | |
t(X;18)(p11;q11) | SS18–SSX4 | <5 | None (1) | Transcription | Skytting. J Natl Cancer Inst 1999;91:974 | |
Marker chromosome with 20q13.3/Xp11 rearrangement | SS18L1–SSX1 | <5 | None (1) | Transcription | Skytting. J Natl Cancer Inst 1999;91:974 | |
Lipomatous tumors | ||||||
Lipoblastoma | 8q11–13 | HAS2–PLAG1 | >90 | None (1) | Transcription | Hibbard. Cancer Res 2000;60:4869 |
t(7;8)(q22;q12) | COL1A2–PLAG1 | Uncertain | None (1) | Transcription | Hibbard. Cancer Res 2000;60:4869 | |
Lipoma | t(3;12)(q27–28;q14–15) | HMGA2–LPP | 50b | None (1) | Transcription | Ashar. Cell 1995;82:57 |
Other t(12q15) | Other HMGA2 rearrangements | Schoenmakers. Nat Genet 1995;10:436 Petit, Genomics 1996;36:118 | ||||
t(6p21) | HMGA1 rearrangement | 10b | Transcription | Tkachenko. Cancer Res 1997;57:2276 | ||
Liposarcoma, myxoid/round cell type | t(12;16)(q13;p11) | FUS–DDIT3 | >90 | Small (3) | Transcription | Crozat. Nature 1993;363:640 Rabbitts. Nat Genet 1993;4:175 |
t(12;22)(q13;q12) | EWSR1–DDIT3 | 2–5 | Uncertain | Transcription | Panagopoulos. Oncogene 1996;12:489 | |
Liposarcoma, well-differentiated/atypical lipomatous tumor | 12q13–15 amplification | MDM2, CDK4, other genes (HMGA2, GLI, SAS) | >70 | Dysregulated cell growth | Pedeutour. Genes Chromosomes Cancer 1994;10:85 Fletcher. Am J Pathol 1996;148:623 Meza-Zepeda. Cancer 2001;31:264 | |
Other soft tissue tumors | ||||||
Aggressive angiomyxoma | 12q13–15 | HMGA2 rearrangement | Uncertain | Transcription | Nucci. Genes Chromosomes Cancer 2001;32:172 | |
Alveolar soft part sarcoma | der(17)t(X;17)(p11;q25) | ASPL–TFE3 | 100 | Small (2) | Transcription | Ladanyi. Oncogene 2001;20:48 |
Angiomatoid fibrous histiocytoma | t(2;22)(q33;q12) | EWSR1–CREB1 | >50 | None (1) | Transcription | Antonescu. Genes Chromosomes Cancer 2007;46:1051 |
t(12;22)(q13;q12) | EWSR1–ATF1 | 30 | None (1) | Transcription | Hallor. Genes Chromosomes Cancer 2005;44:97 | |
t(12;16)(q13;p11) | FUS–ATF1 | 10 | Uncertain | Transcription | Waters. Cancer Genet Cytogenet 2000;121:109 | |
Clear cell sarcoma (malignant melanoma of soft parts) | t(12;22)(q13;q12) | EWSR1–ATF1 | >80 | Large (4) | Transcription | Zucman. Nat Genet 1993;4:341 Wang. Mod Pathol 2009; 22:1201 |
t(2;22)(q33;q12) | EWSR1–CREB1 | <10 | None (1) | Transcription | Antonescu. Clin Cancer Res 2006;12:5356 | |
Endometrial stromal tumors | t(7;17)(p15;q21) | JAZF1–JJAZ1 | 40–100 | None (1) | Transcription | Koontz. Proc Natl Acad Sci USA 2001;98:6348 |
t(6;7)(p21;p15) | JAZF1–PHF1 | <10 | Small (2) | Transcription | Micci. Cancer Res 2006;66:107 | |
t(6;10;10)(p21;q22;p11) | PHF1–EPC1 | <10 | None (1) | Transcription | Micci. Cancer Res 2006;66:107 | |
Epithelioid sarcoma | del(22q11.2) or 22q11.2 rearrangement | INI1 inactivationc | <10–50c | Loss of tumor suppressor | Kohashi. Hum Pathol 2009;40:349 Modena. Cancer Res 2005;65:4012 | |
Extraskeletal myxoid chondrosarcoma | t(9;22)(q22;q12) | EWSR1–NR4A3 | 70 | Large (>4) | Transcription | Labelle. Hum Mol Genet 1995;4:2219 Clark. Oncogene 1996;12:229 |
t(9;17)(q22;q11) | TAF15–NR4A3 | 25 | None (1) | Transcription | Sjogren. Cancer Res 1999;59:5064 Panagopoulos. Oncogene 1999;18:7594 Attwooll. Oncogene 1999;18:7599 | |
t(9;15)(q22;q21) | TCF12–NR4A3 | <5 | None (1) | Transcription | Sjogren. Cancer Res 2000;60:6832 | |
t(3;9)(q11;q22) | TGF–NR4A3 | <5 | None (1) | Transcription | Hisaoka. Genes Chromosomes Cancer 2004;40:325 | |
Fibrosarcoma, sclerosing epithelioid type | t(7;16)(q33;p11) | FUS–CREB3L2 | 10 | Large (>4) | Signaling | Wang. Mod Pathol 2012;25:846 |
Hemangioendothelioma, epithelioid type | t(1;3)(p36;q25) | WWTR1–CAMTA1 | >90 | Small (2) | Transcription | Errani. Genes Chromosomes Cancer 2011;50:644 |
Hemangioendothelioma, pseudomyogenic | t(7;19)(q22;q13) | SERPINE–FOSB | 15 | Uncertain | Transcription | Walther. J Pathol 2014;232:534 |
Hemangioma, epithelioid with atypia | t(3;19)(q25.1;q13.32) | WWTR1–FOSB | <5 | None (1) | Transcription | Antonescu. Genes Chromosomes Cancer 2014;53:951 |
Hemangioma, epithelioid with atypia | del19(q13.2–q13.32) or t(19;19)(q13.2;q13.32) | ZFP36–FOSB | 15 | Small (2) | Transcription | Antonescu. Genes Chromosomes Cancer 2014;53:951 |
Malignant rhabdoid tumor | del(22q11.2) or 22q11.2 rearrangement | INI1 inactivationc | >90 | Loss of tumor suppressor | Jackson. Clin Cancer Res 2009;15:1923 | |
Myoepithelial tumors of soft tissue and boned | t(6;22)(p21;q12) | EWSR1–POU5F1 | 10 | Uncertain | Transcription | Antonescu. Genes Chromosomes Cancer 2010;49:1114 |
t(1;22)(q23;q12) | EWSR1–PBX1 | 10 | Uncertain | Transcription | Brandal. Genes Chromosomes Cancer 2008;47:558 | |
t(9;22)(q33;q12) | EWSR1–PBX3 | 10 | None (1) | Transcription | Agaram. Genes Chromosomes Cancer 2015;54:63 | |
t(19;22)(q13;q12) | EWSR1–ZNF444 | <5 | Uncertain | Transcription | Brandal. Genes Chromosomes Cancer 2009;48:1051 | |
Myxoinflammatory fibroblastic sarcoma/hemosiderotic fibrolipomatous tumor | t(1;10)(p22;q24) | TGFBR3–MGEA5 | 80 | Uncertain | Transcription | Antonescu. Genes Chromosomes Cancer 2011;50:757 |
3p11–12 amplification | VGLL3, CHMP2B | 80 | Transcription | Hallor. J Pathol 2009;217:716 | ||
Tenosynovial giant cell tumor | t(1;2)(p13;q37) | CSF1–COL6A3 | Uncertain | Large (4) | Transcription | Möller. Genes Chromosomes Cancer 2008;47:21 |
Bone tumors | ||||||
Aneurysmal bone cyst | t(16;17)(q22;p13) | USP6–CDH11 | 20 | None (1) | Signaling | Oliveira. Am J Pathol 2004;5:1773 |
Other t(17p13) | Other USP6 rearrangements (TRAP150, ZNF9, OMD, COL1A1, others) | 40 | Oliveira. Am J Pathol 2004;5:1773 | |||
Chondrosarcoma, mesenchymal type | t(8;8)(q13;q21) | HEY1–NCOA2 | >90 | Small (2) | Transcription | Wang. Genes Chromosomes Cancer 2012;51:127 |
Chondrosarcoma, secondary peripheral type (sporadic) | del(8q24) | EXT1 (homozygous inactivation) | 10e | Biosynthesis of heparan sulfate | de Andrea. Oncogene 2012; 31:1095 | |
Osteochondroma (sporadic) | del(8q24) | EXT1 (homozygous inactivation) | 80e | Biosynthesis of heparan sulfate | Hameetman. J Natl Cancer Inst 2007;99:396 | |
Osteosarcoma, low-grade (central and parosteal) | 12q13–15 amplification | MDM2, CDK4, other genes (HMGA2, GLI, SAS) | >70 | Dysregulated cell growth | Gisselsson. Genes Chromosomes Cancer 2002;33:133 Yoshida. Modern Pathology 2010;23:1279 | |
A recurrent t(7;17)(p15;q21) has been identified in endometrial stromal tumors [12]. Two new zinc finger genes are fused as a result of the translocation: JAZF1 and JJAZ1. Protein products of the zinc finger genes usually function as transcriptional regulators via specific DNA binding through the zinc finger motif. The chimeric protein in endometrial stromal tumors has a tumor-specific mRNA transcript containing 5′ JAZF1 and 3′ JJAZ1 sequences including the zinc finger encoding regions from both parent genes. Since gene expression of wild-type JAZF1 is present in normal endometrial stromal cells, the JAZF1–JJAZ1 fusion gene present in endometrial stromal tumors likely results in aberrant transcriptional regulation in a lineage-specific manner.
Oncogenic Nature of Fusion Transcripts
Sarcomas theoretically develop from mesenchymal stem cells that are present in all compartments of the body. Unlike many epithelial neoplasms, where diverse genetic alterations usually underlie the stepwise progression of precursor lesions leading ultimately to the emergence of malignant clones, soft tissue malignancies have no identifiable precursor lesions and usually have a single genetic alteration typical of a particular type of sarcoma. In addition, chromosomal fusions in soft tissue sarcomas do not seem to represent a form of generalized genomic instability, as occurs with germline TP53 mutations [6] or with microsatellite instability associated with colon carcinoma [13]. Benign tumor counterparts of soft tissue sarcomas usually carry quite different genetic or chromosomal abnormalities or both. For example, the specific sets of chromosomal alterations found in soft tissue lipomas are not among those consistently observed in liposarcoma [14, 15]. Similar to leukemogenesis and lymphomagenesis, the fusion gene in a given sarcoma is speculated to be oncogenic only in a specific cell type at a specific differentiation stage [16] and explains why in some instances the same fusion transcripts can be identified in unrelated tumors. For instance, FUS–ERG is present in both Ewing’s sarcoma (ES)/peripheral neuroectodermal tumor (PNET) and acute myeloid leukemia, while EWSR1–CREB1 is present in both angiomatoid fibrous histiocytoma and clear cell sarcoma, two soft tissue tumors that are clearly distinct both histologically and clinically [17]. In general, the genes involved in sarcoma translocations are transcription factors or cofactors. Many of the chimeric proteins include a strong transcriptional activator N-terminal domain encoded by one partner gene fused with a DNA-binding domain encoded by the other partner gene. In fact, fusion of domains capable of activating transcription with other domains featuring specific DNA-binding function appears to be a common theme shared among neoplasms of mesenchymal derivation, such as soft tissue tumors and leukemia. EWSR1 (and its homologous FUS) is a powerful transcription activator [18] and provides a paradigm for this type of oncogenic mechanism, as also indicated by its “promiscuity” as a fusion partner (Table 37.1).
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