From the Guidelines
Molecular markers, including MDM2 amplification, SS18-SSX fusion, EWSR1 rearrangements, PAX3/7-FOXO1 fusion, and KIT mutations, are crucial for accurate diagnosis and classification of sarcoma types, and their detection through techniques like FISH, RT-PCR, and NGS is essential for determining treatment strategies and predicting prognosis. The identification of these molecular markers is vital for distinguishing between morphologically similar sarcomas and for identifying potential targeted therapy options. For instance, the detection of KIT mutations in gastrointestinal stromal tumors (GISTs) guides the use of tyrosine kinase inhibitors like imatinib, while MDM2 amplification in liposarcomas may indicate potential response to MDM2 inhibitors in clinical trials 1.
Some of the key molecular markers for sarcoma types include:
- MDM2 amplification for well-differentiated/dedifferentiated liposarcoma
- SS18-SSX fusion for synovial sarcoma
- EWSR1 rearrangements for Ewing sarcoma
- PAX3/7-FOXO1 fusion for alveolar rhabdomyosarcoma
- KIT mutations for gastrointestinal stromal tumors (GISTs)
- COL1A1-PDGFB fusion in dermatofibrosarcoma protuberans
- ASPSCR1-TFE3 fusion in alveolar soft part sarcoma
- SYT-SSX fusion genes in synovial sarcoma
These molecular markers can be detected through various techniques, including:
- Fluorescence in situ hybridization (FISH)
- Reverse transcription polymerase chain reaction (RT-PCR)
- Next-generation sequencing (NGS)
The use of these techniques has become increasingly important in the diagnosis and management of sarcomas, as they allow for the identification of specific genetic alterations that can inform treatment decisions and predict patient outcomes 1.
In recent years, there has been a growing recognition of the importance of molecular testing in the diagnosis and management of sarcomas, and guidelines have been developed to provide recommendations for the use of molecular testing in this context 1.
Overall, the identification of molecular markers is a critical step in the diagnosis and management of sarcomas, and their detection through techniques like FISH, RT-PCR, and NGS is essential for determining treatment strategies and predicting prognosis.
From the Research
Molecular Markers for Sarcoma Types
- Sarcoma subtype classification is currently mainly based upon histopathological morphology, but molecular analyses have emerged as an efficient addition to the diagnostic workup and sarcoma care 2.
- Specific fusions are highly supportive or pathognomonic for a diagnostic entity, such as SYT::SSX in synovial sarcoma 2.
- Complex karyotypes also give diagnostic information, for example, supporting dedifferentiation rather than low-grade central osteosarcoma or well-differentiated liposarcoma when detected in combination with MDM2/CDK4 amplification 2.
- Molecular treatment predictive sarcoma markers are available for gastrointestinal stromal tumor (GIST) and locally aggressive benign mesenchymal tumors 2.
- The molecular prognostic markers for sarcomas in clinical practice are few, but the type of NAB2::STAT6 fusion is associated with the outcome in solitary fibrous tumor, and the KIT/PDGFRA pathogenic variant in GISTs can give prognostic information 2.
Specific Sarcoma Types and Their Molecular Markers
- Alveolar rhabdomyosarcoma is associated with the fusion protein PAX3-FOXO1, which is a challenging target for development of small molecule inhibitors 3, 4, 5.
- Biphenotypic sinonasal sarcoma (SNS) is a low-grade spindle cell sarcoma that can have an alternate PAX3-FOXO1 oncogenic fusion, confirming the crucial role of PAX3 in SNS oncogenesis 4.
- The presence of PAX3-FOXO1 in SNS and alveolar rhabdomyosarcoma suggests that these two entities are genetically similar lesions arising from distinct progenitor cell pools 4.
- New markers for sarcoma diagnosis, such as those described in 6, can facilitate accurate diagnosis of soft tissue neoplasms on fine needle aspiration (FNA) and core needle biopsy (CNB) specimens.
Target Genes of PAX3-FOXO1 in Alveolar Rhabdomyosarcoma
- The downstream target genes of PAX3-FOXO1 were identified by analyzing two independent sets of gene expression profiles: primary RMS tumors and RD ERMS cells transduced with inducible P3F constructs 5.
- 34 potential target genes (27 upregulated and 7 downregulated) were significantly and differentially expressed between P3F-positive and P3F-negative categories 5.
- The expression of cell death-related (GREM1, DAPK1) and development-related (MYOD1, HEY1) genes were further investigated, and their differential expression was confirmed in independent tumors and inducible cell culture systems 5.