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

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

doi:10.1038/ncomms9891

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

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

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Abstract

The X-linked BCL-6 co-repressor (BCOR) gene encodes a key constituent of a variant polycomb repressive complex (PRC) that is mutated or translocated in human cancers. Here we report on the identification of somatic internal tandem duplications (ITDs) clustering in the C terminus of BCOR in 23 of 27 (85%) pediatric clear cell sarcomas of the kidney (CCSK) from two independent cohorts. We profile CCSK tumours using a combination of whole-exome, transcriptome and targeted sequencing. Identical ITD mutations are found in primary and relapsed tumour pairs but not in adjacent normal kidney or blood. Mutant BCOR transcripts and proteins are markedly upregulated in ITD-positive tumours. Transcriptome analysis of ITD-positive CCSKs reveals enrichment for PRC2-regulated genes and similarity to undifferentiated sarcomas harbouring BCOR-CCNB3 fusions. The discovery of recurrent BCOR ITDs defines a major oncogenic event in this childhood sarcoma with significant implications for diagnostic and therapeutic approaches to this tumour.

Original language	English (US)
Article number	8891
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9891
State	Published - Nov 17 2015

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Roy, A., Kumar, V., Zorman, B., Fang, E., Haines, K. M., Doddapaneni, H., Hampton, O. A., White, S., Bavle, A. A., Patel, N. R., Eldin, K. W., John Hicks, M., Rakheja, D., Leavey, P. J., Skapek, S. X., Amatruda, J. F., Nuchtern, J. G., Chintagumpala, M. M., Wheeler, D. A., ... Parsons, D. W. (2015). Recurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney. Nature communications, 6, [8891]. https://doi.org/10.1038/ncomms9891

Roy, A, Kumar, V, Zorman, B, Fang, E, Haines, KM, Doddapaneni, H, Hampton, OA, White, S, Bavle, AA, Patel, NR, Eldin, KW, John Hicks, M, Rakheja, D , Leavey, PJ , Skapek, SX, Amatruda, JF, Nuchtern, JG, Chintagumpala, MM, Wheeler, DA, Plon, SE, Sumazin, P & Parsons, DW 2015, 'Recurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney', Nature communications, vol. 6, 8891. https://doi.org/10.1038/ncomms9891

@article{ca99d4498b1f41a18a5a6c1855411434,

title = "Recurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney",

abstract = "The X-linked BCL-6 co-repressor (BCOR) gene encodes a key constituent of a variant polycomb repressive complex (PRC) that is mutated or translocated in human cancers. Here we report on the identification of somatic internal tandem duplications (ITDs) clustering in the C terminus of BCOR in 23 of 27 (85%) pediatric clear cell sarcomas of the kidney (CCSK) from two independent cohorts. We profile CCSK tumours using a combination of whole-exome, transcriptome and targeted sequencing. Identical ITD mutations are found in primary and relapsed tumour pairs but not in adjacent normal kidney or blood. Mutant BCOR transcripts and proteins are markedly upregulated in ITD-positive tumours. Transcriptome analysis of ITD-positive CCSKs reveals enrichment for PRC2-regulated genes and similarity to undifferentiated sarcomas harbouring BCOR-CCNB3 fusions. The discovery of recurrent BCOR ITDs defines a major oncogenic event in this childhood sarcoma with significant implications for diagnostic and therapeutic approaches to this tumour.",

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

note = "Funding Information: This work was supported by the National Institutes of Health (NHGRI/NCI 1U01HG006485), the Cancer Prevention and Research Institute of Texas (RP120685-P1, RP120685-AC and RP120685-C1) and a Stand Up To Cancer St Baldrick{\textquoteright}s Pediatric Dream Team Translational Research Grant (SU2CAACR-DT1113; Stand Up To Cancer is a programme of the Entertainment Industry Foundation administered by the American Association for Cancer). The results published here are in part based on data generated by the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative managed by the NCI. Information about TARGET can be found at http://ocg.cancer.gov/programs/target. We acknowledge Pamela Parsons for technical assistance. The BCOR-184 antibody was a kind gift from Dr Vivian Bardwell. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",

year = "2015",

month = nov,

day = "17",

doi = "10.1038/ncomms9891",

language = "English (US)",

volume = "6",

journal = "Nature Communications",

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T1 - Recurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney

AU - Roy, Angshumoy

AU - Kumar, Vijetha

AU - Zorman, Barry

AU - Fang, Erica

AU - Haines, Katherine M.

AU - Doddapaneni, HarshaVardhan

AU - Hampton, Oliver A.

AU - White, Simon

AU - Bavle, Abhishek A.

AU - Patel, Nimesh R.

AU - Eldin, Karen W.

AU - John Hicks, M.

AU - Rakheja, Dinesh

AU - Leavey, Patrick J

AU - Skapek, Stephen X

AU - Amatruda, James F

AU - Nuchtern, Jed G.

AU - Chintagumpala, Murali M.

AU - Wheeler, David A.

AU - Plon, Sharon E.

AU - Sumazin, Pavel

AU - Parsons, D. Williams

N1 - Funding Information: This work was supported by the National Institutes of Health (NHGRI/NCI 1U01HG006485), the Cancer Prevention and Research Institute of Texas (RP120685-P1, RP120685-AC and RP120685-C1) and a Stand Up To Cancer St Baldrick’s Pediatric Dream Team Translational Research Grant (SU2CAACR-DT1113; Stand Up To Cancer is a programme of the Entertainment Industry Foundation administered by the American Association for Cancer). The results published here are in part based on data generated by the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative managed by the NCI. Information about TARGET can be found at http://ocg.cancer.gov/programs/target. We acknowledge Pamela Parsons for technical assistance. The BCOR-184 antibody was a kind gift from Dr Vivian Bardwell. Publisher Copyright: © 2015 Macmillan Publishers Limited. All rights reserved.

PY - 2015/11/17

Y1 - 2015/11/17

N2 - The X-linked BCL-6 co-repressor (BCOR) gene encodes a key constituent of a variant polycomb repressive complex (PRC) that is mutated or translocated in human cancers. Here we report on the identification of somatic internal tandem duplications (ITDs) clustering in the C terminus of BCOR in 23 of 27 (85%) pediatric clear cell sarcomas of the kidney (CCSK) from two independent cohorts. We profile CCSK tumours using a combination of whole-exome, transcriptome and targeted sequencing. Identical ITD mutations are found in primary and relapsed tumour pairs but not in adjacent normal kidney or blood. Mutant BCOR transcripts and proteins are markedly upregulated in ITD-positive tumours. Transcriptome analysis of ITD-positive CCSKs reveals enrichment for PRC2-regulated genes and similarity to undifferentiated sarcomas harbouring BCOR-CCNB3 fusions. The discovery of recurrent BCOR ITDs defines a major oncogenic event in this childhood sarcoma with significant implications for diagnostic and therapeutic approaches to this tumour.

AB - The X-linked BCL-6 co-repressor (BCOR) gene encodes a key constituent of a variant polycomb repressive complex (PRC) that is mutated or translocated in human cancers. Here we report on the identification of somatic internal tandem duplications (ITDs) clustering in the C terminus of BCOR in 23 of 27 (85%) pediatric clear cell sarcomas of the kidney (CCSK) from two independent cohorts. We profile CCSK tumours using a combination of whole-exome, transcriptome and targeted sequencing. Identical ITD mutations are found in primary and relapsed tumour pairs but not in adjacent normal kidney or blood. Mutant BCOR transcripts and proteins are markedly upregulated in ITD-positive tumours. Transcriptome analysis of ITD-positive CCSKs reveals enrichment for PRC2-regulated genes and similarity to undifferentiated sarcomas harbouring BCOR-CCNB3 fusions. The discovery of recurrent BCOR ITDs defines a major oncogenic event in this childhood sarcoma with significant implications for diagnostic and therapeutic approaches to this tumour.

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DO - 10.1038/ncomms9891

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VL - 6

JO - Nature Communications

JF - Nature Communications

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ER -

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

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