Expanding the molecular diversity of CIC-rearranged sarcomas with novel and very rare partners Journal Article
| Authors: | Linos, K.; Dermawan, J. K.; Bale, T.; Rosenblum, M. K.; Singer, S.; Tap, W.; Dickson, M. A.; Hornick, J. L.; Antonescu, C. R. |
| Article Title: | Expanding the molecular diversity of CIC-rearranged sarcomas with novel and very rare partners |
| Abstract: | Capicua transcriptional repressor (CIC)-rearranged sarcoma represents a distinct pathologic entity and constitutes the second most prevalent category of undifferentiated round cell sarcomas (URCSs) after Ewing sarcoma. The 2 most common translocations are t(4;19) and t(10;19), resulting in CIC fusions with either DUX4 and DUX4L paralog, respectively; however, other rare variant fusions have also been reported. In this study, we expand the molecular spectrum of CIC-gene partners, reporting on 5 cases of URCSs showing CIC fusions with AXL, CITED1, SYK, and LEUTX by targeted RNA or DNA sequencing. There were 4 female patients and 1 male patient with a wide age range (12-70 years; median, 36 years). Four cases occurred in the deep soft tissues (lower extremity, 3; neck, 1) and 1 case in the central nervous system (midbrain/thalamus). All cases showed similar histologic findings within the spectrum of URCSs. Immunohistochemistry, showed variable positivity for ETV4 in 4 of the 4 cases and positive results for ERG in 3 of the 4 cases and for WT1 in 1 of the 4 cases. CD31 showed positivity in 2 of the 3 cases, including one coexpressing ERG. Unsupervised clustering of methylation profiles by T-distributed stochastic neighborhood embedding performed in 4 cases showed that all clustered tightly together and along the CIC sarcoma methylation class. RNA-sequencing data showed consistent upregulation of ETV1 and ETV4 mRNA in all cases examined, at similar levels to CIC::DUX4 URCSs. Our study expands the molecular diversity of CIC-rearranged URCSs to include novel and rare partners, providing morphologic, immunohistochemical, gene expression, and methylation evidence supporting their classification within the family of tumors harboring the more common DUX4/DUX4L partner genes. Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved. |
| Keywords: | adolescent; adult; child; aged; middle aged; young adult; genetics; metabolism; pathology; tumor marker; ewing sarcoma; sarcoma; rna; gene rearrangement; oncogene proteins, fusion; small cell sarcoma; sarcoma, small cell; sarcoma, ewing; syk; humans; human; male; female; biomarkers, tumor; cic; axl; undifferentiated round cell sarcoma; cited1; leutx; oncogene fusion protein |
| Journal Title: | Modern Pathology |
| Volume: | 36 |
| Issue: | 5 |
| ISSN: | 0893-3952 |
| Publisher: | Nature Research |
| Date Published: | 2023-05-01 |
| Start Page: | 100103 |
| Language: | English |
| DOI: | 10.1016/j.modpat.2023.100103 |
| PUBMED: | 36788092 |
| PROVIDER: | scopus |
| PMCID: | PMC10324473 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Konstantinos Linos -- Export Date: 1 June 2023 -- Source: Scopus |
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