Targeted next-generation sequencing of CIC-DUX4 soft tissue sarcomas demonstrates low mutational burden and recurrent chromosome 1p loss.
Gene fusions between CIC and DUX4 define a rare class of soft tissue sarcomas poorly understood at the molecular level. Previous karyotyping and fluorescence in situ hybridization studies support chromosome 8 trisomy as a recurrent alteration; however, other driving alterations are largely unknown. Thus, we analyzed 11 formalin-fixed, paraffin-embedded CIC-DUX4 sarcoma tissue samples (including 3 sample pairs) using targeted Ion Torrent-based multiplexed polymerase chain reaction next-generation sequencing to characterize potential somatic driver alterations in 409 genes. Although we did not identify recurrent somatic mutations (point mutations or insertions/deletions), copy number analysis showed recurrent, broad copy number alterations, including gain of chromosome 8 and loss of 1p. In one sample pair (untreated primary and local recurrence resections), we identified similar copy number profiles and a somatic ARID1A R963X nonsense mutation exclusively in the local recurrence sample. In another sample pair (pre- and post-radiation treatment specimens), we observed single-copy loss of chromosome 7q exclusively in the posttreatment recurrence sample, supporting it as an acquired event after radiation treatment. In the last sample pair (near-concurrent, postchemotherapy primary and distant metastasis), molecular profiles were highly concordant, consistent with limited intertumoral heterogeneity. In summary, next-generation sequencing identified limited somatic driver mutations in CIC-DUX4 sarcomas. However, we identified novel, recurrent copy number alterations, including chromosome 1p, which is also the locus of ARID1A. Additional functional work and assessment of larger cohorts are needed to determine the biological and clinical significance of the alterations identified herein.
Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.
Lorena
L
Lazo de la Vega
Michigan Center for Translational Pathology, Department of Computational Medicine & Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109.
Daniel H
DH
Hovelson
Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.
Andi K
AK
Cani
Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.
Chia-Jen
CJ
Liu
Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; Michigan Center for Translational Pathology, Department of Oral Surgery, University of Michigan Medical School, Ann Arbor, MI 48109.
Jonathan B
JB
McHugh
Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.
David R
DR
Lucas
Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.
Dafydd G
DG
Thomas
Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109. Electronic address: rajivpat@med.umich.edu.
Rajiv M
RM
Patel
Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; Michigan Center for Translational Pathology, Department of Urology, University of Michigan Medical School, Ann Arbor, MI 48109; Michigan Center for Translational Pathology, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109. Electronic address: tomlinss@umich.edu.
Scott A
SA
Tomlins
D014408:Biomarkers, Tumor / Q000235:genetics*; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1; D004252:DNA Mutational Analysis; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010641:Phenotype; D011237:Predictive Value of Tests; D012509:Sarcoma / Q000235:genetics* / Q000556:secondary / Q000628:therapy; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy
D014408:Biomarkers, Tumor; C574694:CIC-DUX4 fusion protein, human; D015514:Oncogene Proteins, Fusion
ARID1A; CIC-DUX4; FFPE tissue; Next-generation sequencing; Soft tissue sarcoma
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