title: TCF21 hypermethylation in genetically quiescent clear cell sarcoma of the kidney.
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.
authors.affiliation: Department of Pediatric Hematology and Oncology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands.|Department of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
authors.forename: Saskia L
authors.initials: SL
authors.lastname: Gooskens
authors.affiliation: 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.
authors.forename: Samantha
authors.initials: S
authors.lastname: Gadd
authors.affiliation: Office of Cancer Genomics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Jaime M
authors.initials: JM
authors.lastname: Guidry Auvil
authors.affiliation: Office of Cancer Genomics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Gerhard
authors.affiliation: Genetics Branch, Oncogenomics section, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Javed
authors.initials: J
authors.lastname: Khan
authors.affiliation: Genetics Branch, Oncogenomics section, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Patidar
authors.affiliation: Computational Genomics Research Group, Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Daoud
authors.initials: D
authors.lastname: Meerzaman
authors.affiliation: Computational Genomics Research Group, Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Qing-Rong
authors.initials: QR
authors.lastname: Chen
authors.affiliation: Computational Genomics Research Group, Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Chih Hao
authors.initials: CH
authors.lastname: Hsu
authors.affiliation: Computational Genomics Research Group, Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Yan
authors.affiliation: Computational Genomics Research Group, Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Cu
authors.initials: C
authors.lastname: Nguyen
authors.affiliation: Computational Genomics Research Group, Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Jennings
authors.affiliation: Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands.|Department of Pathology, Reinier de Graaf Hospital, Delft, The Netherlands.
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.affiliation: Department of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
authors.forename: Marry M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
authors.affiliation: Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Ross
authors.affiliation: Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Gastier-Foster
authors.affiliation: 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.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Perlman
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D015870:Gene Expression; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D018227:Sarcoma, Clear Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C491825:TCF21 protein, human
keywords: TARID; TCF21; clear cell sarcoma of the kidney; methylation; whole genome sequencing