Soft tissue sarcomas, like other cancers, is a genetic disease caused by gene mutations, insertions/deletions, copy number changes, and other alterations. However, the vast majority of STS occur as sporadic tumors in patients with no identified environmental or genetic risk factors.
Radiation is recognized as capable of inducing sarcomas of bone and soft tissue.5 The frequency increases with radiation dose and with the post-radiation observation period and is approximately 0.5% in the adult treated with radiation alone to full dose. Radiation-associated sarcomas generally arise many years following the radiation at the edge of the radiation field, most commonly are high-grade, and the most common histologic subtype is UPS. Following breast irradiation, the most common radiation-induced sarcomas are angiosarcomas.6 Chemotherapeutic agents are likewise associated with risks of sarcoma induction. STS can develop following massive and protracted edema. Stewart–Treves syndrome is the development of a lymphangiosarcoma in a chronically lymphedematous arm following axillary lymphadenectomy.7 Trauma is rarely a factor in the development of STS but can contribute to the development of desmoid tumors.
Certain genetic syndromes are associated with an increased risk of developing sarcomas including neurofibromatosis 1 (NF1, von Recklinghausen’s disease), hereditary retinoblastoma, and Li–Fraumeni syndrome. Patients with NF1 have an approximately 15% risk of developing a malignant peripheral nerve sheath tumor (MPNST) as well as an increased risk of developing GIST.8 Patients with hereditary nonpolyposis colon cancer (HNPCC)/Gardner’s syndrome, resulting from a defect in the APC gene, have an increased risk of developing intra-abdominal/mesenteric desmoid tumors.9 Hereditary retinoblastoma and Li–Fraumeni syndrome are associated with a risk of both bone and STS.10,11
In recent years, it has become evident that the genetics of sarcomas segregate into two major types.12 One type has specific genetic alterations and usually simple karyotypes, including fusion genes due to reciprocal translocations (e.g., PAX3–FKHR in alveolar rhabdomyosarcomas) or specific point mutations (e.g., KIT mutations in GIST) (Table 24-1). The second type has nonspecific genetic alterations and complex, unbalanced karyotypes, reflected by numerous genetic losses and gains (e.g., osteosarcoma, UPS, liposarcomas other than the myxoid type, angiosarcoma, and leiomyosarcoma).
Sarcomas with Specific Genetic Alterations20
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Sarcomas with Specific Genetic Alterations20
|Sarcoma Subtype ||Genetic Alteration ||Affected Gene(s) ||Frequency (%) |
|Alveolar rhabdomyosarcoma ||t(2;13)(q35;q14) || PAX3-FOXO1A ||70 |
| ||t(1;13)(p36;q14) || PAX7-FOXO1A ||15 |
|Alveolar soft part sarcoma ||t(X;17)(p11.2;q25) || ASPSCR1-TFE3 ||>95 |
|Angiomatoid fibrous histiocytoma ||t(2;22)(q34;q12) || EWSR1-CREB1 ||>90 |
| ||t(12;22)(q13;q12) || EWSR1-ATF1 ||<5 |
|Clear-cell sarcoma (melanoma of soft parts) ||t(12;22)(q13;q12) || EWSR1-ATF1 ||>90 |
| ||t(2;22)(q34;q12) || EWSR1-CREB1 ||<5 |
|Atypical Ewing sarcoma ||t(4;19)(q35;q13.1) || CIC-DUX4 ||Unknown |
| ||t(10;19)(q26.3;q13.1) || || |
| ||inv(X)(p11.4;p11.22) || BCOR-CCNB3 ||Unknown |
|Congenital (infantile) fibrosarcoma ||t(12;15)(p13;q25) || ETV6-NTRK3 ||>80 |
|Dermatofibrosarcoma protuberans ||t(17;22)(q22;q13) || COLIA1-PDGFB ||>60 |
|Desmoplastic round cell tumor ||t(11;22)(p13;q12) || WT1-EWSR1 ||>90 |
|Endometrial stromal sarcoma ||t(7;17)(p15;q11) || JAZF1-SUZ12 ||>65 |
| ||t(6;7)(p21;p15) || JAZF1-PHF1 ||Unknown |
| ||t(6;10)(p21;p11) || EPC1-PHF1 ||Unknown |
|Undifferentiated endometrial sarcoma/“high-grade endometrial stromal sarcoma” ||t(10;17)(q22;p13); others || YWHAE-FAM22A/B, other partners ||Unknown |
|Epithelioid hemangioendothelioma ||t(1;3)(p36.3;q25) || WWTR1-CAMTA1 ||>90 |
|Epithelioid sarcoma || INI1 inactivation [22(q11.2)] || hSNF5/INI1 ||>80 |
|Extraskeletal myxoid chondrosarcoma ||t(9;22)(q22;q12) || EWSR1-NR4A3 ||>80 |
| ||t(9;17)(q22;q11) || TAF15-NR4A3 ||Unknown |
| ||t(9;15)(q22;q21) || TCF12-NR4A3 ||Unknown |
|Ewing sarcoma/PNET ||t(11;22)(q24;q12) || EWSR1-FLII ||85 |
| ||t(21;22)(q22;q12) || EWSR1-ERG ||5–10 |
|Fibromyxoid sarcoma (Evans’ tumor) ||t(7;16)(q33;q11) || FUS-CREB3L2 ||>70 |
| ||t(11;16)(p11;p11) || FUS-CREB3L1 ||<20 |
|Gastrointestinal stromal tumor ||4q || KIT exon 11 mut ||65 |
Sarcomas with recurrent chromosome translocations account for approximately one-third of all sarcomas. In many cases, the aberrant protein product of the fused gene acts as an abnormal transcriptional regulator, thus providing the molecular basis for oncogenesis. For example, most synovial sarcomas are characterized by the translocation t(x;18)(p11.2;q11.2). The breakpoint of this translocation fuses the SYT gene (also known as the SS18 gene) from chromosome 18 to one of two homologous genes, SSX1 or SSX2, on the X chromosome. The SYT–SSX gene is thought to function as an aberrant transcriptional regulator. These nonrandom chromosomal aberrations occur in specific types of sarcomas and are being increasingly utilized in the definitive diagnosis of these sarcomas (Table 24-1). Furthermore, these chromosomal abnormalities have been characterized at the molecular level and many of the chimeric genes have been identified, providing clues to the molecular alterations that are fundamental for the development of STS.
Soft tissue sarcomas with nonspecific genetic alterations and complex, unbalanced karyotypes have a high rate of alterations in the p53 and Rb genes. Somatic mutations in the p53 gene are the most frequently detected molecular alteration in sporadic soft tissue sarcoma. These mutations have been detected in a variety of STS including UPS, leiomyosarcoma, liposarcoma, and rhabdomyosarcoma.13 The p53 protein is a transcriptional activator that plays a key role in the integration of signals inducing cell division, arrest of DNA synthesis following DNA damage, and programmed cell death (apoptosis).
In addition to p53 pathway inactivation, mutation or alteration of expression of the retinoblastoma gene Rb frequently occurs in STS.14 The Rb gene is critical for proper entry and transition through the cell cycle because the protein encoded by Rb (pRb) controls the expression of other genes necessary for G1–S cell cycle progression. Normally, this cell cycle progression occurs when cyclin-dependent kinase 4 (cdk4) phosphorylates and inhibits pRb function. As mentioned above, the p53 regulated cyclin-dependent kinase inhibitor, p21, can inhibit cdk4 and prevent cell cycle progression by preventing phosphorylation of pRb. However, when Rb is mutated, the normal cell cycle is perturbed. For well-differentiated/dedifferentiated liposarcomas, 12q is often amplified resulting in overexpression of MDM2 as well as CDK4.
Gene expression profiling by means of DNA microarrays is an important approach to cancer classification and has been applied to STS. Gene chip microarrays are able to give a global snapshot of gene expression in tumors. This technology has been used in sarcomas to differentiate between histological subtypes, better classify equivocal histological subtypes, and determine prognosis and response to chemotherapy.15,16
Advances in next generation sequencing and other genomic analysis platforms have allowed for dramatic advances in our understanding of STS genomics.17Barretina et al18 performed limited sequencing and copy number analysis of 722 genes in over 200 STS. Frequently mutated genes included TP53 (17% of pleomorphic liposarcomas), NF1 (11% of myxofibrosarcomas and 8% of pleomorphic liposarcomas), and PIK3A (18% of myxoid/round cell liposarcomas).