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Clinicopathologic Features of CIC-NUTM1 Sarcomas, a New Molecular Variant of the Family of CIC-Fused Sarcomas

Le Loarer, François, MD, PhD*,†,‡; Pissaloux, Daniel, PhD§,∥; Watson, Sarah, MD, PhD; Godfraind, Catherine, MD, PhD#; Galmiche-Rolland, Louise, MD**; Silva, Karen, MSc††; Mayeur, Laetitia, MSc*; Italiano, Antoine, MD, PhD†,‡,‡‡; Michot, Audrey, MD§§; Pierron, Gaëlle, PhD∥∥; Vasiljevic, Alexandre, MD, PhD††; Ranchère-Vince, Dominique, MD§; Coindre, Jean Michel, MD*,†,‡; Tirode, Franck, PhD∥,¶¶

The American Journal of Surgical Pathology: February 2019 - Volume 43 - Issue 2 - p 268–276
doi: 10.1097/PAS.0000000000001187
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CIC-fused sarcomas represent an emerging family of tumors, for long connected to the Ewing family group of tumors, but underlined by distinct CIC fusions with different partners. 3′ Fusion partners include DUX4, FOXO4, and, as recently emphasized, NUTM1. In this study, we report the clinicopathologic and molecular features of a series of 6 CIC-NUTM1 sarcomas. Mean age at diagnosis was 6 years (2 to 27 y), and 4 patients were male individuals. Primary tumors were located in the central nervous system (n=3), paravertebral soft tissue and epidural spaces (n=1, each), and lung (n=1). Median overall survival was 17.5 months (7 to 37 mo), and all but one patient died of disease. All tumors displayed classic features of CIC-DUX4 sarcomas with round cell to epithelioid microscopic appearance. Most tumors expressed ETV4 and NUTM1 (n=5/6 and 6/6, respectively), whereas WT1cter was positive in only 2 cases. All tested tumors were positive for break-apart fluorescence in situ hybridization for CIC and NUTM1. Apart from CIC or NUTM1 genomic breakpoints, no other recurrent copy number alteration was seen on genomic profiles. Fusion transcripts were identified by RNA-sequencing on either formalin-fixed paraffin-embedded or frozen material. CIC and NUTM1 breakpoints were located between exons 16 and 20 and exons 2 and 5, respectively. Altogether, CIC-NUTM1 sarcomas represent a new molecular variant of CIC-fused sarcomas with a predilection for the central nervous system and younger pediatric population. Its phenotype may be confused with NUT carcinomas.

Departments of *Pathology

‡‡Medical Oncology

§§Surgery, Institut Bergonié

INSERM U1218 ACTION, Bordeaux

Department of Medical Oncology, University of Bordeaux, Talence

Departments of §Pathology

¶¶Translational Research and Innovation, Centre Leon Berard

Cancer Research Center of Lyon, University of Lyon, Université Claude Bernard Lyon 1, CNRS 5286, INSERM U1052, Lyon

Departments of Oncology

∥∥Biology of Tumors, Institut Curie, Paris

**Département of Pathology, APHP, Hôpital Necker, Paris

#Department of Pathology, CHU Clermont-Ferrand, Clermont Ferrand

††Department of Pathology, CHU Lyon, Groupe Hospitalier Est, Bron, France

Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: François Le Loarer, MD, PhD, Department of Pathology, Institut Bergonié, 276 cours de l'Argonne, Bordeaux 33076, France (e-mail: f.le-loarer@bordeaux.unicancer.fr).

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