A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor

Samantha Gadd, Vicki Huff, Amy L Walz, Ariadne H A G Ooms, Amy E Armstrong, Daniela S Gerhard, Malcolm A Smith, Jaime M Guidry Auvil, Daoud Meerzaman, Qing-Rong Chen, Chih Hao Hsu, Chunhua YAN, Cu Nguyen, Ying Hu, Leandro C Hermida, Tanja Davidsen, Patee Gesuwan, Yussanne Ma, Zusheng Zong, Andrew J MungallRichard A Moore, Marco A Marra, Jeffrey S Dome, Charles G Mullighan, Jing Ma, David A Wheeler, Oliver A Hampton, Nicole Ross, Julie M Gastier-Foster, Stefan T. Arold, Elizabeth J Perlman

Research output: Contribution to journalArticlepeer-review

220 Scopus citations

Abstract

We performed genome-wide sequencing and analyzed mRNA and miRNA expression, DNA copy number, and DNA methylation in 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to genes previously implicated in Wilms tumors (WT1, CTNNB1, AMER1, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MLLT1, MYCN, and TP53), we identified mutations in genes not previously recognized as recurrently involved in Wilms tumors, the most frequent being BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, and ARID1A. DNA copy number changes resulted in recurrent 1q gain, MYCN amplification, LIN28B gain, and MIRLET7A loss. Unexpected germline variants involved PALB2 and CHEK2. Integrated analyses support two major classes of genetic changes that preserve the progenitor state and/or interrupt normal development.
Original languageEnglish (US)
Pages (from-to)1487-1494
Number of pages8
JournalNature Genetics
Volume49
Issue number10
DOIs
StatePublished - Aug 21 2017

Bibliographical note

KAUST Repository Item: Exported on 2020-10-01
Acknowledgements: The authors thank the Clinical Applications of Core Technology Laboratory of the Hartwell Center for Bioinformatics and Biotechnology of St. Jude Children's Research Hospital for performing the copy number analysis, and the Northwestern University Genomic Core facility for performing the methylation analysis. The authors are grateful for the expertise of K. Novik, L. Monovich, P. Beezhold, D. Kersey, D. Turner, M. McNulty, and Y. Moyer. This work would not be possible without the dedication of the experts within the many clinical disciplines at local institutions and within the Children's Oncology Group and National Wilms Tumor Study Group, the patients, and their families. The TARGET initiative is supported by US National Cancer Institute (NCI) grant U10 CA98543. Work performed under contracts from the NCI within HHSN261200800001E includes specimen processing (the COG Biopathology Center), WGS (CGI, Inc.), whole-exome sequencing (Baylor College of Medicine), miRNA-seq, RNA-seq, and target capture sequencing (BCCA Genome Sciences Center). Financial support was provided by TARGET U10 CA98543 contract HHSN261200800001E and National Institutes of Health (NIH) grants U10CA180886, NIH U10CA180899, NIH U10CA098413, and NIH U10CA42326 (E.J.P.); U10CA98543 (J.S.D., E.J.P.); U24 CA114766 and UO1CA88131 (E.J.P.), and NCI T32 CA079447 (A.L.W., A.E.A.). This work is also supported by the American and Lebanese Syrian Associated Charities of St. Jude (J.M., C.G.M.), the King Abdullah University of Science and Technology (S.T.A.), and the Dutch Cancer Society (A.H.A.G.O.). The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the US Government.

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