TCF21 hypermethylation in genetically quiescent clear cell sarcoma of the kidney

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Oncotarget. Volume 6, Issue 18: p.15828-15841, 30 June 2015, 10.18632/oncotarget.4682

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 regulatory CpGs around the TCF21 locus, was virtually undetectable in most CCSKs. TCF21 hypermethylation and decreased TARID expression were validated in an independent set of 19 CCSK tumor samples (data not submitted). 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.

This study characterized TARGET cases as described below:

13 Discovery Cases
13 cases had GE
13 cases had mRNA-Seq
13 cases had CN
11 cases had methylation
13 cases had WGS

GE=gene expression; CN=copy number

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