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Comprehensive genomic profiling of EWSR1/FUS::CREB translocation-associated tumors uncovers prognostically significant recurrent genetic alterations and methylation-transcriptional correlates

Abstract

To elucidate the mechanisms underlying the divergent clinicopathologic spectrum of EWSR1/FUS::CREB translocation-associated tumors, we performed a comprehensive genomic analysis of fusion transcript variants, recurrent genetic alterations (mutations, copy number alterations), gene expression, and methylation profiles across a large cohort of tumor types. The distribution of the EWSR1/FUS fusion partners—ATF1, CREB1, and CREM—and exon involvement was significantly different across different tumor types. Our targeted sequencing showed that secondary genetic events are associated with tumor type rather than fusion type. Of the 39 cases that underwent targeted NGS testing, 18 (46%) had secondary OncoKB mutations or copy number alterations (29 secondary genetic events in total), of which 15 (52%) were recurrent. Secondary recurrent, but mutually exclusive, TERT promoter and CDKN2A mutations were identified only in clear cell sarcoma (CCS) and associated with worse overall survival. CDKN2A/B homozygous deletions were recurrent in angiomatoid fibrous histiocytoma (AFH) and restricted to metastatic cases. mRNA upregulation of MITF, CDH19, PARVB, and PFKP was found in CCS, compared to AFH, and correlated with a hypomethylated profile. In contrast, S100A4 and XAF1 were differentially upregulated and hypomethylated in AFH but not CCS. Unsupervised clustering of methylation profiles revealed that CREB family translocation-associated tumors form neighboring but tight, distinct clusters. A sarcoma methylation classifier was able to accurately match 100% of CCS cases to the correct methylation class; however, it was suboptimal when applied to other histologies. In conclusion, our comprehensive genomic profiling of EWSR1/FUS::CREB translocation-associated tumors uncovered mostly histotype, rather than fusion-type associated correlations in transcript variants, prognostically significant secondary genetic alterations, and gene expression and methylation patterns.

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Fig. 1: Distribution of tumor types and EWSR1/FUS fusion partners.
Fig. 2: Schematics of predominant fusion transcript variants, for AFH, CCS, GICCS, HCCC, and ME. Exon numbers were based on canonical transcripts for each gene.
Fig. 3: Recurrent genomic alterations in AFH, CCS, GICCS, and HCCC.
Fig. 4: Differential gene upregulation corresponding to hypomethylation on matched CpG sites.
Fig. 5: Comparison of overall survival in 6 AFH, 14 CCS, 9 GICCS, and 5 HCCC.

Data availability

The datasets generated or analyzed during this study are included in this published article [and its Supplementary Information files]. The raw Affymetrix and Illumina 850k methylation array data generated are not publicly available due to lack of access to indefinite hosting capabilities, but are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to acknowledge the Center Core grant (P30 CA008748), the Molecular Diagnostics Service in the Department of Pathology, and the Marie-Josee and Henry R. Kravis Center for Molecular Oncology for use of MSK-IMPACT data.

Funding

This work was supported by P50 CA 140146-01 (SS, WT, CRA), P50 CA217694 (SS, WT, CRA), P30 CA008748 (SS, WT, CRA), Cycle for Survival (CRA, FV), Kristin Ann Carr Foundation (CRA). All other authors report no funding sources related to this study.

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J.K.D. performed study design, data acquisition, data analysis and interpretation, writing and revision of the paper. F.V., L.H., Y.S., L.Z., S.S., W.T., R.B., T.B., J.B., B.D. performed acquisition, analysis, and/or interpretation of data, and review of the paper. C.R.A. performed study design and conception, analysis and interpretation of data, writing, review and revision of paper. All authors read and approved the final manuscript.

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Correspondence to Cristina R. Antonescu.

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Dermawan, J.K., Vanoli, F., Herviou, L. et al. Comprehensive genomic profiling of EWSR1/FUS::CREB translocation-associated tumors uncovers prognostically significant recurrent genetic alterations and methylation-transcriptional correlates. Mod Pathol 35, 1055–1065 (2022). https://doi.org/10.1038/s41379-022-01023-9

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