Genetic changes associated with relapse in favorable histology Wilms tumor: A Children's Oncology Group AREN03B2 study

Samantha Gadd, Vicki Huff, Andrew D. Skol, Lindsay A. Renfro, Conrad V. Fernandez, Elizabeth A. Mullen, Corbin D. Jones, Katherine A. Hoadley, Kai Lee Yap, Nilsa C. Ramirez, Sheena Aris, Quy H. Phung, Elizabeth J. Perlman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Over the last decade, sequencing of primary tumors has clarified the genetic underpinnings of Wilms tumor but has not affected therapy, outcome, or toxicity. We now sharpen our focus on relapse samples from the umbrella AREN03B2 study. We show that over 40% of relapse samples contain mutations in SIX1 or genes of the MYCN network, drivers of progenitor proliferation. Not previously seen in large studies of primary Wilms tumors, DIS3 and TERT are now identified as recurrently mutated. The analysis of primary-relapse tumor pairs suggests that 11p15 loss of heterozygosity (and other copy number changes) and mutations in WT1 and MLLT1 typically occur early, but mutations in SIX1, MYCN, and WTX are late developments in some individuals. Most strikingly, 75% of relapse samples had gain of 1q, providing strong conceptual support for studying circulating tumor DNA in clinical trials to better detect 1q gain earlier and monitor response.

Original languageEnglish (US)
Article number100644
JournalCell Reports Medicine
Volume3
Issue number6
DOIs
StatePublished - Jun 21 2022

Funding

This project was funded by the NCI Molecular Profiling to Predict Response to Treatment (MP2PRT) Program: Retrospective Characterization and Analysis of Biospecimens Collected from NCI-Sponsored Trials of the NCTN and NCORP. The project was also supported by the COG Chair's Grant (U10CA098543), NCTN Network Group Operations Center Grant (U10CA180886), Statistics & Data Center Grant (U10CA098413), NCTN Statistics & Data Center (U10CA180899), Human Specimen Banking in NCI-Sponsored Clinical Trials (U24CA114766), Human Specimen Banking in NCI-Sponsored Clinical Trials (1U24-CA196173), and supported by St. Baldrick's Foundation. This clinical study was supported in whole or in part by funding from the National Cancer Institute (NCI) under the Cancer MoonshotSM Initiative. This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261201500003I. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank the Children's Oncology Group (COG) protocol coordinators, research coordinators, clinical research assistants, and other health professionals who contributed to acquiring samples used in this study. The authors in particular wish to thank the extended AREN03B2 team, who contributed to the central review and clinical annotation of these samples, as well as Jeff Dome, chair of the COG renal tumor disease committee during acquisition of some of the samples utilized in this study. We also acknowledge the excellent efforts of project managers from the BPC (Yvonne Moyer and Kae Tegtmeier), as well as support from Kristina Tracy from the Genomics Platform of the Broad Institute of MIT and Harvard. Most importantly, we are very grateful to the individuals and their families for consenting to sample deposition through AREN03B2 to the BPC. Conceptualization: E.J.P. C.V.F. E.A.M. V.H. and N.R.; methodology, software, formal analysis, and investigation: S.G. A.D.S. C.D.J. K.A.H. E.J.P. and K.L.Y.; resources: C.V.F. E.A.M. V.H. and N.C.R.; data curation: L.A.R.; writing – original draft: E.J.P. and S.G.; writing – reviewing & editing: V.H. C.V.F. K.A.H. L.A.R. A.D.S. and K.L.Y; visualization: K.A.H. and E.J.P.; supervision and project management: Q.H.P. and S.A.; funding acquisition: E.J.P. The authors declare no competing interests. This project was funded by the NCI Molecular Profiling to Predict Response to Treatment (MP2PRT) Program: Retrospective Characterization and Analysis of Biospecimens Collected from NCI -Sponsored Trials of the NCTN and NCORP . The project was also supported by the COG Chair's Grant (U10CA098543), NCTN Network Group Operations Center Grant ( U10CA180886 ), Statistics & Data Center Grant ( U10CA098413 ), NCTN Statistics & Data Center ( U10CA180899 ), Human Specimen Banking in NCI -Sponsored Clinical Trials ( U24CA114766 ), Human Specimen Banking in NCI -Sponsored Clinical Trials ( 1U24-CA196173 ), and supported by St. Baldrick's Foundation . This clinical study was supported in whole or in part by funding from the National Cancer Institute ( NCI ) under the Cancer Moonshot SM Initiative. This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health , under contract HHSN261201500003I . The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank the Children’s Oncology Group (COG) protocol coordinators, research coordinators, clinical research assistants, and other health professionals who contributed to acquiring samples used in this study. The authors in particular wish to thank the extended AREN03B2 team, who contributed to the central review and clinical annotation of these samples, as well as Jeff Dome, chair of the COG renal tumor disease committee during acquisition of some of the samples utilized in this study. We also acknowledge the excellent efforts of project managers from the BPC (Yvonne Moyer and Kae Tegtmeier), as well as support from Kristina Tracy from the Genomics Platform of the Broad Institute of MIT and Harvard. Most importantly, we are very grateful to the individuals and their families for consenting to sample deposition through AREN03B2 to the BPC.

Keywords

  • 1q gain
  • : Wilms tumor
  • DIS3
  • MYCN
  • SIX1
  • TERT
  • relapse

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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