DNA Methylation Profiling for Diagnosing Undifferentiated Sarcoma with Capicua Transcriptional Receptor (CIC) Alterations

Abstract

Undifferentiated soft tissue sarcomas are a group of diagnostically challenging tumors in the pediatric population. Molecular techniques are instrumental for the categorization and differential diagnosis of these tumors. A subgroup of recently identified soft tissue sarcomas with undifferentiated round cell morphology was characterized by Capicua transcriptional receptor (CIC) rearrangements. Recently, an array-based DNA methylation analysis of undifferentiated tumors with small blue round cell histology was shown to provide a highly robust and reproducible approach for precisely classifying this diagnostically challenging group of tumors. We describe the case of an undifferentiated sarcoma of the abdominal wall in a 12-year-old girl. The patient presented with a voluminous mass of the abdominal wall, and multiple micro-nodules in the right lung. The tumor was unclassifiable with current immunohistochemical and molecular approaches. However, DNA methylation profiling allowed us to classify this neoplasia as small blue round cell tumor with CIC alterations. The patient was treated with neoadjuvant chemotherapy followed by complete surgical resection and adjuvant chemotherapy. After 22 months, the patient is disease-free and in good clinical condition. To put our experience in context, we conducted a literature review, analyzing current knowledge and state-of-the-art diagnosis, prognosis, and clinical management of CIC rearranged sarcomas. Our findings further support the use of DNA methylation profiling as an important tool to improve diagnosis of non-Ewing small round cell tumors.

Case Report: A Unique Case of Pediatric Central Nervous System Embryonal Tumor Harboring the CIC–LEUTX Fusion, Germline NBN Variant and Somatic TSC2 Mutation: Expanding the Spectrum of CIC-Rearranged Neoplasia

“…It is difficult to administer target therapy for oncogenic gene fusions involve transcription factors due to not readily druggable in the direct pharmacologic manner ( 18 ). Patients with CIC - DUX4 may respond to IGF-1R inhibitor ( 19 ), and epigenetically active drugs are worth to test the efficacy in CIC -rearranged neoplasia due to the hypoacetylation and methylation involvement ( 6 , 20 ). In the further study, the generating and expressing CIC - LEUTX chimera in primary cells could be used for proving the oncogenic mechanism of the fusion.…”

Melanotic Neuroectodermal Tumor of Infancy (MNTI) and Pineal Anlage Tumor (PAT) Harbor A Medulloblastoma Signature by DNA Methylation Profiling

“…Generated methylation data were compared to brain tumor classifier v11b4 [ 14 ], sarcoma classifier v12.2, and medulloblastoma classifier group 3/4 classifier v1.0, developed by Heidelberg University and DKFZ ( (accessed on 5 February 2021)) to assign a subgroup score for the tumors in the recognized methylation classes. EPIC BeadChip data were analyzed as previously reported [ 17 , 85 ] by means of R (V.3.6.1), using ChAMP package (V.2.16.1) for quality checks and filters to calculate methylation levels and functionally annotate probes at the gene level. Multidimensional scaling (MDS) on the cohort samples was performed using the cmdscale function with the Euclidean distance.…”

The spectrum of rare central nervous system (CNS) tumors with EWSR1‐non‐ETS fusions: experience from three pediatric institutions with review of the literature

“…In some instances, identified fusions were then confirmed with Sanger sequencing. DNA methylation profiling was performed on three of the tumors (cases 2, 3 and 4) as previously described (44,51). Tumor areas with highest tumor cell content were selected for analysis.…”