A Rapid and Cost-Effective Gene Expression Assay for the Diagnosis of Well-Differentiated and Dedifferentiated Liposarcomas

Advances in sarcoma molecular diagnostics

“…In interpreting sequencing results, not all fusions or mutations identified are necessarily functional, pathogenic, or diagnostic. Additionally, sarcoma subtypes characterized by distinctive mutations are often more efficiently diagnosed using more specific lower‐throughput techniques described above than with high‐fidelity mutational sequencing 34 . To improve efficiency, many strategies have been developed to focus MPS sequencing on areas of interest (Table 2).…”

“…Further, Wang et al show that NanoString's use in sarcoma diagnosis is not limited to fusion detection, as its excellent ability to quantify mRNA expression can serve as a proxy for underlying chromosomal amplification, specifically in this case in the chromosome 12q region diagnostic of well‐ and de‐differentiated liposarcomas that together account for approximately 30% of sarcomas 34,89 . From an initial set of 43 genes, they identified a cohort of 20 genes with the highest differentiating power between liposarcomas and lipomas.…”

“…The overall accuracy rate of 98% shows the robustness of this approach. Given its lower cost and shorter turnaround time relative to MPS approaches, NanoString nCounter‐based assays have utility as a replacement for FISH and RT‐PCR as a first‐line method for sarcoma molecular diagnosis 34 …”

“…26 Recent advances include sensitive and specific antibodies for synovial sarcoma (clone E9X9V specific for the SS18-SSX breakpoint, and E5A2C specific for the SSX C-terminus; characteristic of 95% of cases 27 ), alveolar rhabdomyosarcoma (PFM.2 for PAX7-FOXO1 and PAX3-FOXO1; 80% of cases 28 ), chondroblastoma (H3K36M; 96% of cases 29 ), CIC-DUX4 sarcomas (ETV4; >90% of cases 30 ), pseudomyogenic hemangioendothelioma (FOSB; 96% of cases 31 ), osteoblastoma/osteoid osteoma (c-FOS, 83% of cases 32 ), and giant cell tumor of bone (H3F3A p.G34W; 92% of cases 33 ). Another innovative strategy using IHC is to assess antigen overexpression as a consequence of a driver mutation: MDM2 in well-or dedifferentiated liposarcoma as a surrogate for amplification (93% of cases), 34 and STAT6 as the C-terminal partner of a fusion protein product encoded by an otherwise unexpressed gene in solitary fibrous tumors, expressed in the context of NAB2-STAT6 fusion transcripts (98% of cases). 35 Even in cases where entity-specific antibodies are not available, histomorphology and IHC together will inevitably focus the diagnostic possibilities, guiding the need for and choice of molecular ancillary diagnostics.…”

Rare Forms of Lipomatosis: Dercum’s Disease and Roch-Leri Mesosomatous Lipomatosis

“…Nevertheless, histologic examination does not always reliably distinguish benign lipomas from atypical lipomatous tumors/welldifferentiated liposarcomas, nor dedifferentiated liposarcomas from other pleomorphic sarcomas, which are entities with different prognoses and management. Molecular confirmation of pathognomonic 12q13-15 amplifications leading to MDM2 overexpression in sarcomas is a diagnostic gold standard in the case of doubt [61].…”