Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney

Ueno-Yokohata, Hitomi; Okita, Hajime; Nakasato, Keiko; Akimoto, Shingo; Hata, Jun Ichi; Koshinaga, Tsugumichi; Fukuzawa, Masahiro; Kiyokawa, Nobutaka

doi:10.1038/ng.3338

Cited by 135 publications

(163 citation statements)

References 21 publications

(6 reference statements)

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“…3A). 7,9,18,19 Two of the BCOR ITD-positive CCSKs were diagnosed in adult patients, both 29 year-old male patients, and the third being a 5-year-old boy.…”

Section: Resultsmentioning

confidence: 99%

“…All reads were independently aligned with STAR (ver 2.3) 12 and TopHat2 (ver 2.0.14) 13 against the human reference genome (hg19). Based on the known genetic abnormalities reported in CCSK, 7,8 the reads were also investigated manually for YWHAE - NUTM2B/E fusion and BCOR ITD. The mRNA expression of BCOR and PEA3 family genes, including ETV1, ETV4 and ETV5 , were analyzed and compared to other sarcomas.…”

Section: Methodsmentioning

confidence: 99%

“…However, recent studies have identified recurrent genetic abnormalities in CCSK, characterized by either internal tandem duplication (ITD) in exon 16 of BCOR in the majority of cases or the presence of t(10;17)(q22.3;p13.3) translocation resulting in YWHAE-NUTM2B/E fusions in a smaller subset of cases. 7,8 These two genetic alterations appear to be mutually exclusive. 9 With these recent advances in the genetic signatures of CCSK, molecular studies can be applied to further investigate the relationship between CCSK and infantile soft tissue URCS.…”

Section: Introductionmentioning

confidence: 99%

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Recurrent BCOR Internal Tandem Duplication and YWHAE-NUTM2B Fusions in Soft Tissue Undifferentiated Round Cell Sarcoma of Infancy

Kao

Sung

Zhang

et al. 2016

American Journal of Surgical Pathology

158

207

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Soft tissue undifferentiated round cell sarcoma (URCS) occurring in infants is a heterogeneous group of tumors, often lacking known genetic abnormalities. Based on 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 CCSK are characterized by BCOR exon 16 internal tandem duplications (ITD), while a smaller subset shows YWHAE-NUTM2B/E fusions. Due to 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 URCS and 7 PMMTI selected, RNA sequencing (RNAseq) was performed in 5 and 2 cases, with frozen tissue, respectively. The remaining cases with archival material were tested for YWHAE-NUTM2B/E by FISH or RT-PCR, and BCOR ITD by PCR. A control group of 4 CCSK, 14 URCS 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, while lacking BCOR ITD. An identical YWHAE-NUTM2B fusion was found in another URCS case of a 5-month-old girl from the back. The remaining cases and control group lacked YWHAE gene rearrangements; instead, consistent BCOR ITD, 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 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 trunk, abdomen and head and neck, sparing the extremities. RNAseq showed high BCOR mRNA levels in BCOR ITD-positive cases, compared to 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, 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.

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“…3A). 7,9,18,19 Two of the BCOR ITD-positive CCSKs were diagnosed in adult patients, both 29 year-old male patients, and the third being a 5-year-old boy.…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Recurrent BCOR Internal Tandem Duplication and YWHAE-NUTM2B Fusions in Soft Tissue Undifferentiated Round Cell Sarcoma of Infancy

Kao

Sung

Zhang

et al. 2016

American Journal of Surgical Pathology

158

207

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“…Furthermore, development of targeted therapies, based on specific molecular aberrations of CCSK, is desirable for this group of patients. Potential targets for new treatments for CCSK patients might be BCOR ITDs (identified in about 80-90% of CCSKs), hypermethylation of TCF21 (identified in about 80-90% of CCSKs) or the YWHAE-NUTM2 fusion gene (identified in 5-10% of CCSKs) 9,13,14 . Finally, immunotherapy might be a therapeutic option for patients with CCSK in the future 73 .…”

Section: Future Perspectivesmentioning

confidence: 99%

Rationale for the treatment of children with CCSK in the UMBRELLA SIOP–RTSG 2016 protocol

et al. 2018

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“…Long a mystery, genetic alterations underlying CCSK have been delineated in the past decade. The majority (>90%) of CCSK harbor internal tandem duplications (ITD) in the last exon of the BCOR ( Bcl6 interacting co-repressor) gene, which in CCSK is thought to regulate gene transcription through an epigenetic silencing mechanism 6,7,8 . A smaller subset of CCSK harbor a YWHAE-NUTM2B gene fusion resulting from a t(10;17)(q22.3;p13.3) translocation which is identical to that seen in high grade endometrial stromal sarcoma 9,10 .…”

Section: Introductionmentioning

confidence: 99%

Primary Renal Sarcomas With BCOR-CCNB3 Gene Fusion

Argani¹,

Kao

Zhang

et al. 2017

American Journal of Surgical Pathology

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We report two primary renal sarcomas demonstrating BCOR-CCNB3 gene fusions that have recently been identified in undifferentiated round cell sarcomas of bone and soft tissue. These neoplasms occurred in male children aged 11 and 12, and both were cystic as a result of entrapment and dilatation of native renal tubules. Both cases were composed of variably cellular bland spindle cells with fine chromatin set in myxoid stroma and separated by a branching capillary vasculature. Both neoplasms demonstrated immunoreactivity for BCOR, cyclin D1, TLE1 and SATB2 in the spindle neoplastic cells and negativity in the prominent capillary vasculature. One case was extensively cystic and had hypocellular areas that simulated cystic nephroma; this neoplasm recurred 3 years later as a solid, highly cellular spindle cell sarcoma in the abdominal cavity. The morphology and immunoprofile of these renal neoplasms was compared to a control group of other sarcomas with BCOR genetic abnormalities, including clear cell sarcoma of the kidney (CCSK), infantile undifferentiated round cell sarcomas of soft tissue/primitive myxoid mesenchymal tumor of infancy (URCS/PMMTI), and bone/soft tissue sarcomas with BCOR-CCNB3 gene fusion; along with primary renal synovial sarcoma. Our findings show that the renal sarcomas with BCOR-CCNB3 gene fusion overlap with CCSK. They are in keeping with a “BCOR-alteration family” of renal and extra-renal neoplasms which includes CCSK and URCS/PMMTI (which typically harbor BCOR internal tandem duplication), and BCOR-CCNB3 sarcomas, all of which are primarily driven by BCOR overexpression and have overlapping (but not identical) clinicopathologic features.

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Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney

Cited by 135 publications

References 21 publications

Recurrent BCOR Internal Tandem Duplication and YWHAE-NUTM2B Fusions in Soft Tissue Undifferentiated Round Cell Sarcoma of Infancy

Recurrent BCOR Internal Tandem Duplication and YWHAE-NUTM2B Fusions in Soft Tissue Undifferentiated Round Cell Sarcoma of Infancy

Rationale for the treatment of children with CCSK in the UMBRELLA SIOP–RTSG 2016 protocol

Primary Renal Sarcomas With BCOR-CCNB3 Gene Fusion

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