Significance of TP53 mutation in Wilms tumors with diffuse anaplasia: A report from the Children's Oncology Group

Ariadne H.A.G. Ooms, Samantha Gadd, Daniela S. Gerhard, Malcolm A. Smith, Jaime M. Guidry Auvil, Daoud Meerzaman, Qing Rong Chen, Chih Hao Hsu, Chunhua Yan, Cu Nguyen, Ying Hu, Yussanne Ma, Zusheng Zong, Andrew J. Mungall, Richard A. Moore, Marco A. Marra, Vicki Huff, Jeffrey S. Dome, Yueh Yun Chi, Jing TianJames I. Geller, Charles G. Mullighan, Jing Ma, David A. Wheeler, Oliver A. Hampton, Amy L. Walz, Marry M. Van Den Heuvel-Eibrink, Ronald R. De Krijger, Nicole Ross, Julie M. Gastier-Foster, Elizabeth J. Perlman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Purpose: To investigate the role and significance of TP53 mutation in diffusely anaplastic Wilms tumors (DAWTs). Experimental Design: All DAWTs registered on National Wilms Tumor Study-5 (n = 118) with available samples were analyzed for TP53 mutations and copy loss. Integrative genomic analysis was performed on 39 selected DAWTs. Results: Following analysis of a single random sample, 57 DAWTs (48%) demonstrated TP53 mutations, 13 (11%) copy loss without mutation, and 48 (41%) lacked both [defined as TP53-wild-type (wt)]. Patients with stage III/IV TP53-wt DAWTs (but not those with stage I/II disease) had significantly lower relapse and death rates than those with TP53 abnormalities. Indepth analysis of a subset of 39 DAWTs showed seven (18%) to be TP53-wt: These demonstrated gene expression evidence of an active p53 pathway. Retrospective pathology review of TP53-wt DAWT revealed no or very low volume of anaplasia in six of seven tumors. When samples from TP53-wt tumors known to contain anaplasia histologically were available, abnormal p53 protein accumulation was observed by immunohistochemistry. Conclusions: These data support the key role of TP53 loss in the development of anaplasia in WT, and support its significant clinical impact in patients with residual anaplastic tumor following surgery. These data also suggest that most DAWTs will show evidence of TP53 mutation when samples selected for the presence of anaplasia are analyzed. This suggests that modifications of the current criteria to also consider volume of anaplasia and documentation of TP53 aberrations may better reflect the risk of relapse and death and enable optimization of therapeutic stratification.

Original languageEnglish (US)
Pages (from-to)5582-5591
Number of pages10
JournalClinical Cancer Research
Volume22
Issue number22
DOIs
StatePublished - Nov 15 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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