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

Nature Genetics volume 49, pages 1487–1494 (2017)Cite this article

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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.

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Figure 1: Genetic landscape of FHWT.
Figure 2: 11p15 ICR1 and ICR2 methylation and select miRNA expression patterns.

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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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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine and Robert H. Lurie Cancer Center, Chicago, Illinois, USA

    Samantha Gadd, Ariadne H A G Ooms & Elizabeth J Perlman

  2. Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Vicki Huff

  3. Division of Hematology-Oncology and Transplantation, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

    Amy L Walz & Amy E Armstrong

  4. Department of Pathology, Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands

    Ariadne H A G Ooms

  5. Office of Cancer Genomics, National Cancer Institute, Bethesda, Maryland, USA

    Daniela S Gerhard, Jaime M Guidry Auvil, Leandro C Hermida & Patee Gesuwan

  6. Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA

    Malcolm A Smith

  7. Center for Biomedical Informatics and Information Technology, National Cancer Institute, Bethesda, Maryland, USA

    Daoud Meerzaman, Qing-Rong Chen, Chih Hao Hsu, Chunhua Yan, Cu Nguyen, Ying Hu & Tanja Davidsen

  8. Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency (BCCA), Vancouver, British Columbia, Canada

    Yussanne Ma, Zusheng Zong, Andrew J Mungall, Richard A Moore & Marco A Marra

  9. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada

    Marco A Marra

  10. Division of Pediatric Hematology/Oncology, Children's National Medical Center, Washington, DC, USA

    Jeffrey S Dome

  11. Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Charles G Mullighan & Jing Ma

  12. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA

    David A Wheeler & Oliver A Hampton

  13. Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, Ohio, USA

    Nicole Ross & Julie M Gastier-Foster

  14. Division of Biological and Environmental Sciences and Engineering, Computational Bioscience Research Center, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia

    Stefan T Arold

Authors
  1. Samantha Gadd
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  2. Vicki Huff
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  3. Amy L Walz
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  31. Elizabeth J Perlman
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Contributions

D.S.G., J.M.G.A., M.A.S., P.G., L.C.H., and T.D. oversaw the administrative and data management aspects of the TARGET project. D.M., C.H.H., C.N., C.Y., Q.-R.C., and Y.H. performed the bioinformatic analysis. S.T.A. performed the in silico protein structure analysis. J.M.G.-F. and N.R. performed the specimen processing and quality control. J.S.D. and V.H. provided the samples and clinical data. C.G.M. and J.M. performed the copy number analysis through level 1. S.G. performed the level 4 analyses of all platforms and wrote the paper with contributions from all other authors. A.L.W. performed the miRNA analysis. A.E.A. performed the level 3 and 4 copy number analysis. A.H.A.G.O. performed the TP53 analysis. Y.M., Z.Z., A.J.M., R.A.M., and M.A.M. performed the target capture sequencing and mRNA sequencing. D.A.W. and O.A.H. performed the whole-exome sequencing. E.J.P. designed and oversaw all aspects of the study.

Corresponding author

Correspondence to Elizabeth J Perlman.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 (PDF 1400 kb)

Life Sciences Reporting Summary (PDF 130 kb)

Supplementary Table 1

Discovery set verified COSMIC mutations, nonsense, and frameshift mutations and verified somatic missense and in-frame variants predicted to be damaging and not identified in 1000 Genomes series 3. (XLSX 212 kb)

Supplementary Table 2

Verified high-quality somatic structural variants identified in 80 samples anaylzed by whole-genome sequencing. (XLSX 24 kb)

Supplementary Table 3

Details of variants detected by target capture sequencing and predicted to be damaging within the validation set. (XLSX 241 kb)

Supplementary Table 4

Distribution by histology and concurrent mutations identified in validation set. (XLSX 14 kb)

Supplementary Table 5

Segmental DNA copy changes (>8 probes with segment log2 mean below –0.5 or above 0.5). (XLSX 1403 kb)

Supplementary Table 6

GSEA Hallmark and positional gene sets significantly enriched (FDR < 20%, and P < 5% in each NMF gene expression cluster). (XLSX 12 kb)

Supplementary Table 7

Genes with >5 localized, coordinately differentially methylated probes (q < 0.05 and FC either >1.5 or <0.5). (XLSX 19 kb)

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Gadd, S., Huff, V., Walz, A. et al. A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor. Nat Genet 49, 1487–1494 (2017). https://doi.org/10.1038/ng.3940

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