Identification of a novel, recurrent HEY1‐NCOA2 fusion in mesenchymal chondrosarcoma based on a genome‐wide screen of exon‐level expression data

Abstract

Cancer gene fusions that encode a chimeric protein are often characterized by an intragenic discontinuity in the RNA expression levels of the exons that are 5′ or 3′ to the fusion point in one or both of the fusion partners due to differences in the levels of activation of their respective promoters. Based on this, we developed an unbiased, genome-wide bioinformatic screen for gene fusions using Affymetrix Exon array expression data. Using a training set of 46 samples with different known gene fusions, we developed a data analysis pipeline, the “Fusion Score (FS) model”, to score and rank genes for intragenic changes in expression. In a separate discovery set of 41 tumor samples with possible unknown gene fusions, the FS model generated a list of 552 candidate genes. The transcription factor gene NCOA2 was one of the candidates identified in a mesenchymal chondrosarcoma. A novel HEY1-NCOA2 fusion was identified by 5′ RACE, representing an in-frame fusion of HEY1 exon 4 to NCOA2 exon 13. RT-PCR or FISH evidence of this HEY1-NCOA2 fusion was present in all additional mesenchymal chondrosarcomas tested with a definitive histologic diagnosis and adequate material for analysis (n=9) but was absent in 15 samples of other subtypes of chondrosarcomas. We also identified a NUP107-LGR5 fusion in a dedifferentiated liposarcoma but analysis of 17 additional samples did not confirm it as a recurrent event in this sarcoma type. The novel HEY1-NCOA2 fusion appears to be the defining and diagnostic gene fusion in mesenchymal chondrosarcomas.

Evaluation of NKX2-2 expression in round cell sarcomas and other tumors with EWSR1 rearrangement: imperfect specificity for Ewing sarcoma

“…Given that EWSR1-FLI1 promotes NKX2-2 expression by upregulating GLI1, 30 NKX2-2 positivity in olfactory neuroblastomas may be explained by tumoral activation of sonic hedgehog signaling. 31 Mesenchymal chondrosarcomas, characterized by HEY1-NCOA2 gene fusion, 32 demonstrated immunoreactivity for NKX2-2 in 33% of cases in a prior study 11 and, in this study, …”

NAB2–STAT6 fusion types account for clinicopathological variations in solitary fibrous tumors

“…17,26,28 Notably, few mesenchymal tumor types with specific gene fusions discovered to date do not exhibit typical chromosomal translocations visible at the karyotypic level. 11,13,14,29,30 Instead, this minor subset harbors previously unrecognized intrachromosomal inversion(s), eg, inv(12) (q13q13) in solitary fibrous tumors, 11,13 or interstitial deletion(s), eg del(8) (q13.3q21.1), in mesenchymal chondrosarcomas. 30 In these tumors, the rearranged partner genes have been recently identified by sophisticated profiling or sequencing technology to characterize disease-defining molecular hallmarks.…”

“…11,13,14,29,30 Instead, this minor subset harbors previously unrecognized intrachromosomal inversion(s), eg, inv(12) (q13q13) in solitary fibrous tumors, 11,13 or interstitial deletion(s), eg del(8) (q13.3q21.1), in mesenchymal chondrosarcomas. 30 In these tumors, the rearranged partner genes have been recently identified by sophisticated profiling or sequencing technology to characterize disease-defining molecular hallmarks. 11,13,30 Of these, the NAB2-STAT6 fusion as the main molecular driver of solitary fibrous tumors is unique among currently known gene fusions in mesenchymal tumors for its difficulty in applying FISH to aid in diagnosis.…”

“…30 In these tumors, the rearranged partner genes have been recently identified by sophisticated profiling or sequencing technology to characterize disease-defining molecular hallmarks. 11,13,30 Of these, the NAB2-STAT6 fusion as the main molecular driver of solitary fibrous tumors is unique among currently known gene fusions in mesenchymal tumors for its difficulty in applying FISH to aid in diagnosis. This is ascribed to the close proximity of rearranged NAB2 and STAT6 genes that precludes adequate resolution of florescent signals.…”

RNA‐sequencing identifies novel GREB1‐NCOA2 fusion gene in a uterine sarcoma with the chromosomal translocation t(2;8)(p25;q13)

“…NCOA2 is well known for its involvement in chimeric transcripts in hematologic malignancies and soft tissue tumors. It has been reported to be fused with different partners: KAT6A ‐ NCOA2 (also known as MOZ ‐ TIF2 ) was found in acute myeloid leukemia (AML),20, 21 ETV6 (TEL)‐NCOA2 was reported in childhood acute leukemia, PAX3‐NCOA2 in alveolar rhabdomyosarcoma,22 HEY1‐NCOA2 in mesenchymal chondrosarcomas,23, 24 SRF‐NCOA2 , TEAD1‐NCOA2 , and VGLL2‐NCOA2 in rhabdomyosarcomas,25, 26 and AHRR‐NCOA2 27 and GTF2‐NCOA2 28 in angiofibromas. In all the mentioned fusions, NCOA2 is the 3’‐partner gene, as it was in the present case.…”