The Clinical Relevance of Molecular Genetics in Soft Tissue Sarcomas

Abstract

Bone and soft tissue sarcomas are an infrequent and heterogeneous group of mesenchymal tumors including more than a hundred different entities attending to histologic patterns. Research into the molecular aspects of sarcomas has increased greatly in the last few years. This enormous amount of knowledge has allowed, for instance, to refine the classification of sarcomas, improve the diagnosis, and increase the number of therapeutical targets available, most of them under preclinical evaluation. However, other important key issues, such as sarcomagenesis and the cell of origin of sarcomas, remain unresolved. From a molecular point of view, these neoplasias are grouped into 2 main types: (a) sarcomas showing relatively simple karyotypes and translocations, which originate gene fusions (eg, EWS-FLI1 in Ewing sarcoma) or point mutations (eg, c-kit in the gastrointestinal tumors) and (b) sarcomas showing unspecific gene alterations, very complex karyotypes, and no translocations. The discovery of the early mechanisms involved in the genesis of sarcomas, the more relevant signaling pathways, and the development of genetically engineered mouse models could also provide a new individualized therapeutic strategy against these tumors. This review describes the clinical application of some of the molecular alterations found in sarcomas, some advances in the field of sarcomagenesis, and the development of animal models.

Cancer of Unknown Primary: The Pathologist’s Approach

“…For further details including the use of new technologies in this context, the reader is referred to the respective literature (e.g., [ 36 ]). A comprehensive list of diagnostically useful specifi c molecular alterations in sarcomas can be found in the current literature as well [ 37 ]. In principle, all issues raised above for sarcomas also apply for melanoma.…”

Novel Approaches to Treatment of Leiomyosarcomas

“…As the authors point out, response rates were lower than cytotoxic chemotherapy but with comparable PFS rates, supporting activity in these patients. Upregulation of HIF1A, a hypoxia-induced gene, has been found in LMS [41] and may represent a potential target in the angiogenesis pathway for the future.…”

Epithelial marker expression does not rule out a diagnosis of Ewing’s sarcoma family of tumours

“…Other gene fusions have been described in ESFT, including FUS/ERG, FUS/FEV, EWSR1/PATZ1, EWSR1/SP3, EWSR1/NFATc2, BRD4/NUT, CIC/DUX4 [5,6], and EWSR1/SMARCA5 [7]. The histopathology includes three larger categories according to their predominant morphological criteria: conventional Ewing's sarcoma (ES), peripheral neuroectodermal tumors (PNET), and atypical ES comprising all subtypes distinct from the other two types [2,3].…”

“…Ewing's sarcoma family of tumors (ESFT) is formed by a group of small round cell tumors (SRCT) genetically defined by specific chromosomal translocations which result in a fusion of the EWSR1 gene, mainly with a member of the ETS family of transcription factors: FLI1 (11q24), ERG (21q22), FEV (2q33), ETV1 (7p22), and ETV4 (17q12) [1][2][3][4][5][6]. Other gene fusions have been described in ESFT, including FUS/ERG, FUS/FEV, EWSR1/PATZ1, EWSR1/SP3, EWSR1/NFATc2, BRD4/NUT, CIC/DUX4 [5,6], and EWSR1/SMARCA5 [7].…”