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 trisomy chromosome 8 as a recurrent alteration, however other driving alterations are largely unknown. Thus, we analyzed eleven formalin fixed paraffin embedded CIC-DUX4 sarcoma tissue samples (including three sample pairs) using targeted Ion Torrent based multiplexed polymerase chain reaction (PCR) next generation sequencing to characterize potential somatic driver alterations in 409 genes. Although we did not identify recurrent somatic mutations (point mutations or indels), 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 post-treatment recurrence sample, supporting it as an acquired event after radiation treatment. In the last sample pair (near concurrent, post-chemotherapy primary and distant metastasis), molecular profiles were highly concordant, consistent with limited inter-tumoral 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 is needed to determine the biological and clinical significance of the alterations identified herein.