Oncotarget

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TCF21 hypermethylation in genetically quiescent clear cell sarcoma of the kidney

Saskia L. Gooskens, Samantha Gadd, Jaime M. Guidry Auvil, Daniela S. Gerhard, Javed Khan, Rajesh Patidar, Daoud Meerzaman, Qing-Rong Chen, Chih Hao Hsu, Chunhua Yan, Cu Nguyen, Ying Hu, Charles G. Mullighan, Jing Ma, Lawrence J. Jennings, Ronald R. de Krijge, Marry M. van den Heuvel-Eibrink, Malcolm A. Smith, Nicole Ross, Julie M. Gastier-Foster and Elizabeth J. Perlman _

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Oncotarget. 2015; 6:15828-15841. https://doi.org/10.18632/oncotarget.4682

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Abstract

Saskia L. Gooskens1,2, Samantha Gadd3, Jaime M. Guidry Auvil4, Daniela S. Gerhard4, Javed Khan5, Rajesh Patidar5, Daoud Meerzaman6, Qing-Rong Chen6, Chih Hao Hsu6, Chunhua Yan6, Cu Nguyen6, Ying Hu6, Charles G. Mullighan7, Jing Ma7, Lawrence J. Jennings3, Ronald R. de Krijger8,9, Marry M. van den Heuvel-Eibrink2, Malcolm A. Smith10, Nicole Ross11, Julie M. Gastier-Foster11 and Elizabeth J. Perlman3

1 Department of Pediatric Hematology and Oncology, Erasmus MC - Sophia Children’s Hospital, Rotterdam, The Netherlands

2 Department of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

3 Department of Pathology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University’s Feinberg School of Medicine and Robert H. Lurie Cancer Center, Chicago, IL, USA

4 Office of Cancer Genomics, National Cancer Institute, Bethesda, MD, USA

5 Genetics Branch, Oncogenomics section, National Cancer Institute, Bethesda, MD, USA

6 Computational Genomics Research Group, Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

7 Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA

8 Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands

9 Department of Pathology, Reinier de Graaf Hospital, Delft, The Netherlands

10 Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA

11 Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Ohio State University College of Medicine, Columbus, OH, USA

Correspondence to:

Elizabeth J. Perlman, email:

Keywords: clear cell sarcoma of the kidney, whole genome sequencing, methylation, TCF21, TARID

Received: April 10, 2015 Accepted: June 07, 2015 Published: June 28, 2015

Abstract

Clear Cell Sarcoma of the Kidney (CCSK) is a rare childhood tumor whose molecular pathogenesis remains poorly understood. We analyzed a discovery set of 13 CCSKs for changes in chromosome copy number, mutations, rearrangements, global gene expression and global DNA methylation. No recurrent segmental chromosomal copy number changes or somatic variants (single nucleotide or small insertion/deletion) were identified. One tumor with t(10;17)(q22;p13) involving fusion of YHWAE with NUTM2B was identified. Integrated analysis of expression and methylation data identified promoter hypermethylation and low expression of the tumor suppressor gene TCF21 (Pod-1/capsulin/epicardin) in all CCSKs except the case with t(10;17)(q22;p13). TARID, the long noncoding RNA responsible for demethylating TCF21, was virtually undetectable in most CCSKs. TCF21 hypermethylation and decreased TARID expression were validated in an independent set of CCSK tumor samples. The presence of significant hypermethylation of TCF21, a transcription factor known to be active early in renal development, supports the hypothesis that hypermethylation of TCF21 and/or decreased TARID expression lies within the pathogenic pathway of most CCSKs. Future studies are needed to functionally verify a tumorigenic role of TCF21 down-regulation and to tie this to the unique gene expression pattern of CCSK.


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