Abstract
Drug development in sarcoma has been hampered by the rarity and heterogeneity of the disease and lack of predictive biomarkers to therapies. We assessed protein expression and gene alterations in a large number of bone and soft tissue sarcomas in order to categorize the molecular alterations, identify predictive biomarkers and discover new therapeutic targets. Data from sarcoma specimens profiled for protein expression, gene amplification/translocation and DNA sequencing was reviewed. 2539 sarcoma specimens of 22 subtypes were included. TOPO2A was the most overexpressed protein at 52.8%. There was overexpression or loss of other sarcoma relevant proteins such as SPARC, PTEN and MGMT. Approximately 50% of the sarcomas expressed PD-L1 by IHC and presented with PD-1+ TILs, notably the LMS, chondrosarcomas, liposarcomas and UPS. Gene amplification/rearrangement of ALK, cMYC, HER2, PIK3CA, TOPO2A and cMET was relatively uncommon. EGFR gene amplification occurred at a rate of 16.9%. DNA sequencing of 47 genes identified mutations in 47% of the samples. The most commonly mutated genes were TP53 (26.3%) and BRCA2 (17.6%). Overexpression of TOPO2A was associated with TP53 mutation (P = 0.0001). This data provides the landscape of alterations in sarcoma. Future clinical trials are needed to validate these targets.
Highlights
Sarcomas are a rare, heterogeneous group of mesenchymal tumors
Sarcomas can be classified according to the genetic alterations involved in their development: those with oncogenic somatic mutations [e.g. gastrointestinal stromal tumors (GIST)], those with DNA copy number alterations, and those with recurrent chromosomal translocations resulting in abnormal fusion proteins
Of the 77 angiosarcomas, 14 were of breast origin. 862 samples were known to be from a metastatic site
Summary
Heterogeneous group of mesenchymal tumors. With over 100 subtypes, a single therapeutic strategy for this group of cancers is unfeasible. For patients with advanced disease, the selection of therapy is based on the specific sarcoma subtype as well as the patient’s fitness to receive aggressive chemotherapy With this approach, median overall survival for patients with advanced bone and soft tissue sarcomas (STS) remains under two years [1]. Sarcomas can be classified according to the genetic alterations involved in their development: those with oncogenic somatic mutations [e.g. gastrointestinal stromal tumors (GIST)], those with DNA copy number alterations (e.g. dedifferentiated liposarcomas), and those with recurrent chromosomal translocations resulting in abnormal fusion proteins (e.g. synovial sarcomas). We assessed protein expression and gene alterations in a large number of bone and soft tissue sarcomas in order to categorize the molecular alterations, identify predictive biomarkers and discover new therapeutic targets. Methods: Data from sarcoma specimens profiled for protein expression, gene amplification/translocation and DNA sequencing was reviewed.
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