title: Recurrent BCOR Internal Tandem Duplication and YWHAE-NUTM2B Fusions in Soft Tissue Undifferentiated Round Cell Sarcoma of Infancy: Overlapping Genetic Features With Clear Cell Sarcoma of Kidney.
abstract: Soft tissue undifferentiated round cell sarcoma (URCS) occurring in infants is a heterogenous group of tumors, often lacking known genetic abnormalities. On the basis of a t(10;17;14) karyotype in a pelvic URCS of a 4-month-old boy showing similar breakpoints with clear cell sarcoma of kidney (CCSK), we have investigated the possibility of shared genetic abnormalities in CCSK and soft tissue URCS. Most CCSKs are characterized by BCOR exon 16 internal tandem duplications (ITDs), whereas a smaller subset shows YWHAE-NUTM2B/E fusions. Because of overlapping clinicopathologic features, we have also investigated these genetic alterations in the so-called primitive myxoid mesenchymal tumor of infancy (PMMTI). Among the 22 infantile URCSs and 7 PMMTIs selected, RNA sequencing was performed in 5 and 2 cases, with frozen tissue, respectively. The remaining cases with archival material were tested for YWHAE-NUTM2B/E by fluorescence in situ hybridization (FISH) or reverse transcription-polymerase chain reaction (RT-PCR), and BCOR ITD by PCR. A control group of 4 CCSKs and 14 URCSs in older children or adults without known gene fusion and 20 other sarcomas with similar histomorphology or age at presentation were also tested. A YWHAE-NUTM2B fusion was confirmed in the index case by FISH and RT-PCR, whereas BCOR ITD was lacking. An identical YWHAE-NUTM2B fusion was found in another URCS case of a 5-month-old girl with a back lesion. The remaining cases and control group lacked YWHAE gene rearrangements; instead, consistent BCOR ITDs, similar to CCSK, were found in 15/29 (52%) infantile sarcoma cases (9/22 infantile URCS and 6/7 PMMTI). In the control cohort, BCOR ITD was found only in 3 CCSK cases but not in the other sarcomas. Histologically, URCS with both genotypes and PMMTI shared significant histologic overlap, with uniform small blue round cells with fine chromatin and indistinct nucleoli. A prominent capillary network similar to CCSK, rosette structures, and varying degree of myxoid change were occasionally seen. BCOR ITD-positive tumors occurred preferentially in the somatic soft tissue of the trunk, abdomen, and head and neck, sparing the extremities. RNAseq showed high BCOR mRNA levels in BCOR ITD-positive cases, compared with other URCSs. In summary, we report recurrent BCOR exon 16 ITD and YWHAE-NUTM2B fusions in half of infantile soft tissue URCS and most PMMTI cases, but not in other pediatric sarcomas. These findings suggest a significant overlap between infantile URCS and CCSK, such as age at presentation, histologic features, and genetic signature, thus raising the possibility of a soft tissue counterpart to CCSK.
authors.affiliation: *Department of Pathology, Shuang Ho Hospital, Taipei Medical University, Taipei ‡Department of Anatomical Pathology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan †Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY §Departments of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD ∥Department of Paediatric Laboratory Medicine, Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada Departments of ¶Histopathology **Pediatric Oncology, University of Sidney, The Children's Hospital at Westmead #Department of Cytogenetics, Sydney Genome Diagnostics, Sydney, NSW, Australia ††Institute of Pediatric Research Citta'della Speranza ‡‡Pathology Unit, Department of Medical and Diagnostic Sciences and Special Therapies, University of Padua, Padua, Italy.
authors.forename: Yu-Chien
authors.initials: YC
authors.lastname: Kao
authors.forename: Yun-Shao
authors.initials: YS
authors.lastname: Sung
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Shih-Chiang
authors.initials: SC
authors.lastname: Huang
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.forename: Catherine T
authors.initials: CT
authors.lastname: Chung
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Graf
authors.forename: Dale C
authors.initials: DC
authors.lastname: Wright
authors.forename: Stewart J
authors.initials: SJ
authors.lastname: Kellie
authors.forename: Narasimhan P
authors.initials: NP
authors.lastname: Agaram
authors.forename: Kathrin
authors.initials: K
authors.lastname: Ludwig
authors.forename: Angelica
authors.initials: A
authors.lastname: Zin
authors.forename: Rita
authors.initials: R
authors.lastname: Alaggio
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007231:Infant, Newborn; D007680:Kidney Neoplasms / Q000235:genetics; D008297:Male; D050596:Oncogene Fusion / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012509:Sarcoma / Q000235:genetics* / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D048948:14-3-3 Proteins; C411984:BCOR protein, human; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C482983:YWHAE protein, human