Genetic changes associated with relapse in favorable histology Wilms tumor: A Children's Oncology Group AREN03B2 study - PubMed (original) (raw)

. 2022 Jun 21;3(6):100644.

doi: 10.1016/j.xcrm.2022.100644. Epub 2022 May 25.

Vicki Huff 2, Andrew D Skol 1, Lindsay A Renfro 3, Conrad V Fernandez 4, Elizabeth A Mullen 5, Corbin D Jones 6, Katherine A Hoadley 7, Kai Lee Yap 1, Nilsa C Ramirez 8, Sheena Aris 9, Quy H Phung 9, Elizabeth J Perlman 10

Affiliations

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

Samantha Gadd et al. Cell Rep Med. 2022.

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.

Keywords: 1q gain; : Wilms tumor; DIS3; MYCN; SIX1; TERT; relapse.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Figures

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Graphical abstract

Figure 1

Figure 1

Recurrent alterations in WT discovery set individuals Genetic alterations identified in at least 3 individuals within the primary (P) and relapse (R) tumors are illustrated in this OncoPrint. The numbers on the right provide the percentage of P or R samples that have alterations in the relevant gene. These data are also expanded in Figure S1, which provides all genes recurrently involved in each designated individual.

Figure 2

Figure 2

TERT gene expression by mutation or copy number status RNA-seq data, normalized using variance-stabilizing transformation, was used to generate boxplots with the ggplot2 R package (v.3.6.3). The top, middle, and lower lines of the box represent the 25th, 50th, and 75th percentiles, respectively. The upper whisker extends to the largest value no greater than 1.5 times the interquartile range from the box and the lower whisker extends to the smallest value no lower than 1.5 times the interquartile range from the box. Filled black circles represent individual samples. Gray circles represent outliers (outside 1.5 times the interquartile range). Comparison of TERT gene expression in the 64 R and P tumor samples with available RNA-seq data reveals significantly higher TERT gene expression in the 5 samples with promoter mutations compared with the 59 samples lacking promoter mutations (p = 0.0067, Student’s t test).

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References

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