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A novel ATXN1-DUX4 fusion expands the spectrum of ‘CIC-rearranged sarcoma’ of the CNS to include non-CIC alterations

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Acknowledgements

The University of Michigan Peds-MiOncoSeq study is supported by Grant 1UM1HG006508 from the NIH Clinical Sequencing Exploratory Research Award (principle investigator: Arul Chinnaiyan, coinvestigator: Rajen Mody). We thank the MI-Oncoseq integrative clinical sequencing and bioinformatic analysis team for the genomics and transcriptome data.

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Author notes

  1. Drew Pratt and Chandan Kumar-Sinha contributed equally.

Authors and Affiliations

  1. Department of Pathology, University of Michigan, NCRC Bldg 35, 2800 Plymouth Rd, Ann Arbor, MI, 48104, USA

    Drew Pratt, Chandan Kumar-Sinha, Marcin Cieślik, Rohit Mehra, Hong Xiao, Lina Shao, Arul M. Chinnaiyan & Sandra Camelo-Piragua

  2. Michigan Center for Translational Pathology, Ann Arbor, MI, USA

    Chandan Kumar-Sinha, Rohit Mehra & Arul M. Chinnaiyan

  3. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA

    Marcin Cieślik

  4. Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA

    Andrea Franson, Evan Cantor & Rajen Mody

  5. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    Zied Abdullaev, Kenneth Aldape & Martha Quezado

Authors
  1. Drew Pratt
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  2. Chandan Kumar-Sinha
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  3. Marcin Cieślik
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  14. Sandra Camelo-Piragua
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Contributions

DP conceived the project, wrote the manuscript, and performed the bioinformatic analyses for methylation and copy number data. CK-S contributed to the concept, analyzed the clinical sequencing data, identified the ATXN1-DUX4 fusion, performed gene expression analysis and wrote the manuscript. AF and EC provided a critical review of the manuscript and clinical care of the patient. RM, HX and LX designed and performed the ATXN1 FISH probe assay. MC analyzed the whole genome sequencing data. AMC and RM critically reviewed the manuscript and supervised the MI-ONCOSEQ analyses. KA and MQ supervised and interpreted the methylation array analyses and critically reviewed the manuscript. SCP supervised the project, critically reviewed the manuscript, and provided clinical care for the patient.

Corresponding authors

Correspondence to Drew Pratt or Sandra Camelo-Piragua.

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Supplementary Information

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401_2021_2278_MOESM1_ESM.tif

Supplementary file1Supplemental Fig. 1. Microscopic features were similar to previously reported CIC-rearranged sarcomas and included round cell cytomorphology with a myxoid matrix (a) admixed with more spindled cell regions (b). Immunohistochemical staining for NUTM1 was negative (c) (TIF 823 KB)

401_2021_2278_MOESM2_ESM.tif

Supplementary file2Supplemental Fig. 2. Results of integrative clinical sequencing detailing the discovery of a novel ATXN1-DUX4 gene fusion, subclonal mutations, and copy number alterations of chromosomes 1p, 6p, 9q, 10, and 17q. (TIF 2442 KB)

401_2021_2278_MOESM3_ESM.tif

Supplementary file3Supplemental Fig. 3. Copy number aberrations from exome sequencing data (a) confirmed a breakpoint on chromosome 6p involving ATXN1 (6p22.3) with a relatively stable genome lacking amplifications or focal deletions. The segmented copy number derived from methylation signal intensities (b) also confirmed an ATXN1 breakpoint with an intact CIC gene locus (TIF 4492 KB)

401_2021_2278_MOESM4_ESM.tif

Supplementary file4Supplemental Fig. 4. Whole-genome sequencing data (a). Visualization of chromosomal break localized at ATXN1 on Chromosome 6 (GRCh38) based on samplot of whole-genome sequencing data. The genomic location of ATXN1 is shown below. BAC constructs flanking the breakpoint used to perform the FISH assay for ATXN1 gene rearrangement using dual-color break-apart probes are shown (b). The index case showed 63.5% of tumor cells containing an abnormal probe pattern where the majority were one fused signal and one green signal. Normal (control) cells show fused signals (not shown) (TIF 1990 KB)

401_2021_2278_MOESM5_ESM.tif

Supplementary file5Supplemental Fig. 5. T2-weighted axial image of the basal ganglia mass detected at clinical presentation and before treatment (a). A reduction in the size of the mass can be appreciated after 4 months of treatment as per COG AEWS0031, Regimen B (b) (TIF 1535 KB)

401_2021_2278_MOESM6_ESM.tif

Supplementary file6Supplemental Fig. 6. Transcriptome profiling (RNA-seq) showed overexpression of the PEA3 subclass of the ETS transcription factor gene family members ETV4, ETV5, and ETV1 (a). Shown is percentile ranking of Fragments Per Kilobase of transcript per Million mapped reads (FPKM) among the MI-Oncoseq cohort (see Online Resource Supplemental Material for details). Previously reported CNS EFT-CIC tumor-specific gene expression signatures [18], including CAMK1G, SHC4, MYO1D, FOXN3, ERVH48-1, and CCNE1, were upregulated in the index case (b). NUTM1 gene expression was not increased (c) (TIF 2606 KB)

Supplementary file7 (DOCX 33 KB)

Supplementary file8 (XLSX 46 KB)

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Pratt, D., Kumar-Sinha, C., Cieślik, M. et al. A novel ATXN1-DUX4 fusion expands the spectrum of ‘CIC-rearranged sarcoma’ of the CNS to include non-CIC alterations. Acta Neuropathol 141, 619–622 (2021). https://doi.org/10.1007/s00401-021-02278-3

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