Recurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney

Roy, Angshumoy; Kumar, Vijetha; Zorman, Barry; Fang, Erica; Haines, Katherine; Doddapaneni, Harshavardhan; Hampton, Oliver A.; White, Simon; Bavle, Abhishek; Patel, Nimesh R.; Eldin, Karen W.; Hicks, M. John; Rakheja, Dinesh; Leavey, Patrick J.; Skapek, Stephen X.; Amatruda, James F.; Nuchtern, Jed G.; Chintagumpala, Murali; Wheeler, David A.; Plon, Sharon E.; Sumazin, Pavel; Parsons, D. Williams

doi:10.1038/ncomms9891

Cited by 127 publications

(156 citation statements)

References 36 publications

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“…The BCOR ITD event occurred most frequently in exon 15, 69.7% (23/33), at the C-terminus of the gene, supporting previous lines of evidence (Fig. 1; other exons, see Table 1) [2, 5-9]. The mean length of the exon 15 duplication events in exon 15 was 31.7 codons in length (range 30–38 codons; Table 1).…”

Section: Resultssupporting

confidence: 83%

“…In addition, BCOR can also be frequently overexpressed in high-grade ESS harboring YWHAE- NUT2B rearrangements via an unknown mechanism [2, 5-7, 9]. In addition, it has been recently demonstrated that BCOR ITD is a notable mechanism for BCOR overexpression in three high-grade uterine sarcoma cases regarded as high-grade ESS that did not harbor a characteristic ESS gene fusion [9].…”

Section: Discussionmentioning

confidence: 99%

“…In addition to uterine sarcomas, previous literature links BCOR ITDs in the pathogenesis of pediatric sarcomas, such as CCSK, PMMTI, and round cell sarcoma of infancy [5-7]. We identified 10 pediatric sarcoma cases, with an average age of 4.4 years, including CNS sarcoma, kidney clear cell, soft tissue clear cell, soft tissue fibrosarcoma, soft tissue sarcoma, and uterus sarcoma.…”

Section: Discussionmentioning

confidence: 99%

“…Most recently, BCOR internal tandem duplications (ITDs) have been identified as key oncogenic events in pediatric clear cell sarcomas of the kidney (CCSK) [5], primitive myxoid mesenchymal tumor of infancy (PMMTI) [6], undifferentiated round cell sarcoma of infancy [7], and recently, in 4 cases of endometrial stromal sarcomas (ESS) [8, 9]. Some genomic variations in these BCOR ITDs exist; however, the landscape of BCOR ITDs in a large series of cancer cases has not been described.…”

Section: Introductionmentioning

confidence: 99%

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A Pan-Cancer Landscape Analysis Reveals a Subset of Endometrial Stromal and Pediatric Tumors Defined by Internal Tandem Duplications of BCOR

Juckett¹,

Lin

Madison³

et al. 2018

Oncology

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Background: The Polycomb Repressive Complex 1 (PRC1) regulates epigenetic silencing and is manifestly linked to rare cancer types. The X-linked BCOR gene (BCL-6 Corepressor) is a member of the PRC1 complex and potentiates transcriptional repression through BCL6 binding of PRC1. Accumulating evidence suggests that internal tandem duplications (ITD) of BCOR are oncogenic drivers in a subset of pediatric sarcomas and rare adult tumors. Objective: We reviewed the genomic profiles of a large series of advanced cancer patients to determine the frequency and genomic spectrum of ITD of BCOR across cancer. Methods: Tissues from 140,411 unique advanced cancers were sequenced by hybrid-capture-NGS-based comprehensive genomic profiling of 186–315 genes plus introns from 14 to 28 genes commonly rearranged in cancer, as well as RNA for 265 genes for a portion of these cases. Results: BCOR-ITDs were present in 0.024% of all cases (33/140,411). Of this dataset, sarcoma cancer types were most frequent, 63.6% (21/33), either of uterine origin 52.4% (11/21), or pediatric (nonuterine) 42.8% (9/21). The identified BCOR-ITDs occurred most frequently in exon 15, near C-terminus, 69.7% (23/33), with a mean insertion length of 31.7 codons (range 30–38). Of uterine cases, an expert gynecologic pathology central review identified all these cases as having a similar high-grade morphology consistent with endometrial stromal sarcomas (ESS), and 90% of cases having a round cell component. Of the uterine sarcoma cases harboring exon 15 BCOR-ITDs, none simultaneously carried gene fusions typically associated with ESS. Conclusion: BCOR-ITDs define a rare subset of pediatric sarcomas and clinically aggressive endometrial stromal sarcoma cases, as defined by NGS for the first time. Our findings help delineate the pan-cancer landscape of this alteration and suggest the need for focused investigation to delineate the pro-oncogenic function of BCOR, along with any sensitivity to targeted therapies.

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Section: Resultssupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Pan-Cancer Landscape Analysis Reveals a Subset of Endometrial Stromal and Pediatric Tumors Defined by Internal Tandem Duplications of BCOR

Juckett¹,

Lin

Madison³

et al. 2018

Oncology

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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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TCF21 hypermethylation regulates renal tumor cell clonogenic proliferation and migration

et al. 2017

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We recently identified hypermethylation at the gene promoter of transcription factor 21 (TCF21) in clear cell sarcoma of the kidney (CCSK), a rare pediatric renal tumor. TCF21 is a transcription factor involved in tubular epithelial development of the kidney and is a candidate tumor suppressor. As there are no in vitro models of CCSK, we employed a well‐established clear cell renal cell carcinoma (ccRCC) cell line, 786‐O, which also manifests high methylation at the TCF21 promoter, with consequent low TCF21 expression. The tumor suppressor function of TCF21 has not been functionally addressed in ccRCC cells; we aimed to explore the functional potential of TCF21 expression in ccRCC cells in vitro. 786‐O clones stably transfected with either pBABE‐TCF21‐HA construct or pBABE vector alone were functionally analyzed. We found that ectopic expression of TCF21 in 786‐O cells results in a trend toward decreased cell proliferation (not significant) and significantly decreased migration compared with mock‐transfected 786‐O cells. Although the number of colonies established in colony formation assays was not different between 786‐O clones, colony size was significantly reduced in 786‐O cells expressing TCF21. To investigate whether the changes in migration were due to epithelial‐to‐mesenchymal transition changes, we interrogated the expression of selected epithelial and mesenchymal markers. Although we observed upregulation of mRNA and protein levels of epithelial marker E‐cadherin in clones overexpressing TCF21, this did not result in surface expression of E‐cadherin as measured by fluorescence‐activated cell sorting and immunofluorescence. Furthermore, mRNA expression of the mesenchymal markers vimentin (VIM) and SNAI1 was not significantly decreased in TCF21‐expressing 786‐O cells, while protein levels of VIM were markedly decreased. We conclude that re‐expression of TCF21 in renal cancer cells that have silenced their endogenous TCF21 locus through hypermethylation results in reduced clonogenic proliferation, reduced migration, and reduced mesenchymal‐like characteristics, suggesting a tumor suppressor function for transcription factor 21.

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Recurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney

Cited by 127 publications

References 36 publications

A Pan-Cancer Landscape Analysis Reveals a Subset of Endometrial Stromal and Pediatric Tumors Defined by Internal Tandem Duplications of BCOR

A Pan-Cancer Landscape Analysis Reveals a Subset of Endometrial Stromal and Pediatric Tumors Defined by Internal Tandem Duplications of BCOR

Primary Renal Sarcomas With BCOR-CCNB3 Gene Fusion

TCF21 hypermethylation regulates renal tumor cell clonogenic proliferation and migration

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