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A Gradual Transition Toward Anaplasia in Wilms Tumor Through Tolerance to Genetic Damage

Uno, Kaname LU orcid ; Rastegar, Bahar LU ; Jansson, Caroline LU ; Durand, Geoffroy LU ; Valind, Anders LU orcid ; Chattopadhyay, Subhayan LU orcid ; Bertolotti, Alessia ; Ciceri, Sara ; Spreafico, Filippo and Collini, Paola , et al. (2024) In Modern Pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 37(1). p.100382-100382
Abstract

Patients with Wilms tumor (WT) in general have excellent survival, but the prognosis of patients belonging to the subgroup of WT with diffuse anaplasia (DA) is poor due to frequent resistance to chemotherapy. We hypothesized that DA WT cells might undergo changes, such as acquiring a persistent tolerance to DNA damage and copy number aberrations (CNAs), which could eventually lead to their resistance to chemotherapy treatment. Tissue sections from chemotherapy-treated DA WTs (n = 12) were compared with chemotherapy-treated nonanaplastic WTs (n = 15) in a tissue microarray system, enabling analysis of 769 tumor regions. All regions were scored for anaplastic features and immunohistochemistry was used to quantify p53 expression,... (More)

Patients with Wilms tumor (WT) in general have excellent survival, but the prognosis of patients belonging to the subgroup of WT with diffuse anaplasia (DA) is poor due to frequent resistance to chemotherapy. We hypothesized that DA WT cells might undergo changes, such as acquiring a persistent tolerance to DNA damage and copy number aberrations (CNAs), which could eventually lead to their resistance to chemotherapy treatment. Tissue sections from chemotherapy-treated DA WTs (n = 12) were compared with chemotherapy-treated nonanaplastic WTs (n = 15) in a tissue microarray system, enabling analysis of 769 tumor regions. All regions were scored for anaplastic features and immunohistochemistry was used to quantify p53 expression, proliferation index (Ki67), and DNA double-strand breaks (γH2AX). CNAs were assessed by array-based genotyping and TP53 mutations using targeted sequencing. Proliferation index and the frequency of DNA double-strand breaks (γH2AX dot expression) increased with higher anaplasia scores. Almost all (95.6%) areas with full-scale anaplasia had TP53 mutations or loss of heterozygosity, along with an increased amount of CNAs. Interestingly, areas with wild-type TP53 with loss of heterozygosity and only one feature of anaplasia (anaplasia score 1) also had significantly higher proliferation indices, more DNA double-strand breaks, and more CNAs than regions without any anaplastic features (score 0); such areas may be preanaplastic cell populations under selective pressure for TP53 mutations. In conclusion, we suggest that chemoresistance of DA WTs may be partly explained by a high proliferative capability of anaplastic cells, which also have a high burden of double-stranded DNA breaks and CNAs, and that there is a gradual emergence of anaplasia in WT.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
anaplasia, copy number aberrations, double-stranded DNA breaks, TP53 mutation/loss of heterozygosity (LOH), Wilms tumor
in
Modern Pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
volume
37
issue
1
pages
1 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:37951357
  • scopus:85182957040
ISSN
1530-0285
DOI
10.1016/j.modpat.2023.100382
language
English
LU publication?
yes
id
b1462214-470e-4add-b28e-0bbc8b82bf96
date added to LUP
2024-02-26 11:30:36
date last changed
2024-04-25 19:20:36
@article{b1462214-470e-4add-b28e-0bbc8b82bf96,
  abstract     = {{<p>Patients with Wilms tumor (WT) in general have excellent survival, but the prognosis of patients belonging to the subgroup of WT with diffuse anaplasia (DA) is poor due to frequent resistance to chemotherapy. We hypothesized that DA WT cells might undergo changes, such as acquiring a persistent tolerance to DNA damage and copy number aberrations (CNAs), which could eventually lead to their resistance to chemotherapy treatment. Tissue sections from chemotherapy-treated DA WTs (n = 12) were compared with chemotherapy-treated nonanaplastic WTs (n = 15) in a tissue microarray system, enabling analysis of 769 tumor regions. All regions were scored for anaplastic features and immunohistochemistry was used to quantify p53 expression, proliferation index (Ki67), and DNA double-strand breaks (γH2AX). CNAs were assessed by array-based genotyping and TP53 mutations using targeted sequencing. Proliferation index and the frequency of DNA double-strand breaks (γH2AX dot expression) increased with higher anaplasia scores. Almost all (95.6%) areas with full-scale anaplasia had TP53 mutations or loss of heterozygosity, along with an increased amount of CNAs. Interestingly, areas with wild-type TP53 with loss of heterozygosity and only one feature of anaplasia (anaplasia score 1) also had significantly higher proliferation indices, more DNA double-strand breaks, and more CNAs than regions without any anaplastic features (score 0); such areas may be preanaplastic cell populations under selective pressure for TP53 mutations. In conclusion, we suggest that chemoresistance of DA WTs may be partly explained by a high proliferative capability of anaplastic cells, which also have a high burden of double-stranded DNA breaks and CNAs, and that there is a gradual emergence of anaplasia in WT.</p>}},
  author       = {{Uno, Kaname and Rastegar, Bahar and Jansson, Caroline and Durand, Geoffroy and Valind, Anders and Chattopadhyay, Subhayan and Bertolotti, Alessia and Ciceri, Sara and Spreafico, Filippo and Collini, Paola and Perotti, Daniela and Holmquist Mengelbier, Linda and Gisselsson, David}},
  issn         = {{1530-0285}},
  keywords     = {{anaplasia; copy number aberrations; double-stranded DNA breaks; TP53 mutation/loss of heterozygosity (LOH); Wilms tumor}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{100382--100382}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Modern Pathology : an official journal of the United States and Canadian Academy of Pathology, Inc}},
  title        = {{A Gradual Transition Toward Anaplasia in Wilms Tumor Through Tolerance to Genetic Damage}},
  url          = {{http://dx.doi.org/10.1016/j.modpat.2023.100382}},
  doi          = {{10.1016/j.modpat.2023.100382}},
  volume       = {{37}},
  year         = {{2024}},
}