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Resolving the Pathogenesis of Anaplastic Wilms Tumors through Spatial Mapping of Cancer Cell Evolution

Rastegar, Bahar LU ; Andersson, Natalie LU orcid ; Petersson, Alexandra LU ; Karlsson, Jenny LU ; Chattopadhyay, Subhayan LU orcid ; Valind, Anders LU orcid ; Jansson, Caroline LU ; Durand, Geoffroy LU ; Romerius, Patrik LU and Jirström, Karin LU orcid , et al. (2023) In Clinical Cancer Research 29(14). p.2668-2677
Abstract

PURPOSE: While patients with intermediate-risk (IR) Wilms tumors now have an overall survival (OS) rate of almost 90%, those affected by high-stage tumors with diffuse anaplasia have an OS of only around 50%. We here identify key events in the pathogenesis of diffuse anaplasia by mapping cancer cell evolution over anatomic space in Wilms tumors.

EXPERIMENTAL DESIGN: We spatially mapped subclonal landscapes in a retrospective cohort of 20 Wilms tumors using high-resolution copy-number profiling and TP53 mutation analysis followed by clonal deconvolution and phylogenetic reconstruction. Tumor whole-mount sections (WMS) were utilized to characterize the distribution of subclones across anatomically distinct tumor... (More)

PURPOSE: While patients with intermediate-risk (IR) Wilms tumors now have an overall survival (OS) rate of almost 90%, those affected by high-stage tumors with diffuse anaplasia have an OS of only around 50%. We here identify key events in the pathogenesis of diffuse anaplasia by mapping cancer cell evolution over anatomic space in Wilms tumors.

EXPERIMENTAL DESIGN: We spatially mapped subclonal landscapes in a retrospective cohort of 20 Wilms tumors using high-resolution copy-number profiling and TP53 mutation analysis followed by clonal deconvolution and phylogenetic reconstruction. Tumor whole-mount sections (WMS) were utilized to characterize the distribution of subclones across anatomically distinct tumor compartments.

RESULTS: Compared with non-diffuse anaplasia Wilms tumors, tumors with diffuse anaplasia showed a significantly higher number of genetically distinct tumor cell subpopulations and more complex phylogenetic trees, including high levels of phylogenetic species richness, divergence, and irregularity. All regions with classical anaplasia showed TP53 alterations. TP53 mutations were frequently followed by saltatory evolution and parallel loss of the remaining wild-type (WT) allele in different regions. Morphologic features of anaplasia increased with copy-number aberration (CNA) burden and regressive features. Compartments demarcated by fibrous septae or necrosis/regression were frequently (73%) associated with the emergence of new clonal CNAs, although clonal sweeps were rare within these compartments.

CONCLUSIONS: Wilms tumors with diffuse anaplasia display significantly more complex phylogenies compared with non-diffuse anaplasia Wilms tumors, including features of saltatory and parallel evolution. The subclonal landscape of individual tumors was constrained by anatomic compartments, which should be considered when sampling tissue for precision diagnostics.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Kidney Neoplasms/pathology, Anaplasia/genetics, Retrospective Studies, Phylogeny, Wilms Tumor/genetics
in
Clinical Cancer Research
volume
29
issue
14
pages
2668 - 2677
publisher
American Association for Cancer Research
external identifiers
  • scopus:85164845553
  • pmid:37140929
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-23-0311
language
English
LU publication?
yes
id
10d066e6-4673-4275-abc4-bdcc882e3129
date added to LUP
2023-07-17 14:40:04
date last changed
2024-04-19 23:36:27
@article{10d066e6-4673-4275-abc4-bdcc882e3129,
  abstract     = {{<p>PURPOSE: While patients with intermediate-risk (IR) Wilms tumors now have an overall survival (OS) rate of almost 90%, those affected by high-stage tumors with diffuse anaplasia have an OS of only around 50%. We here identify key events in the pathogenesis of diffuse anaplasia by mapping cancer cell evolution over anatomic space in Wilms tumors.</p><p>EXPERIMENTAL DESIGN: We spatially mapped subclonal landscapes in a retrospective cohort of 20 Wilms tumors using high-resolution copy-number profiling and TP53 mutation analysis followed by clonal deconvolution and phylogenetic reconstruction. Tumor whole-mount sections (WMS) were utilized to characterize the distribution of subclones across anatomically distinct tumor compartments.</p><p>RESULTS: Compared with non-diffuse anaplasia Wilms tumors, tumors with diffuse anaplasia showed a significantly higher number of genetically distinct tumor cell subpopulations and more complex phylogenetic trees, including high levels of phylogenetic species richness, divergence, and irregularity. All regions with classical anaplasia showed TP53 alterations. TP53 mutations were frequently followed by saltatory evolution and parallel loss of the remaining wild-type (WT) allele in different regions. Morphologic features of anaplasia increased with copy-number aberration (CNA) burden and regressive features. Compartments demarcated by fibrous septae or necrosis/regression were frequently (73%) associated with the emergence of new clonal CNAs, although clonal sweeps were rare within these compartments.</p><p>CONCLUSIONS: Wilms tumors with diffuse anaplasia display significantly more complex phylogenies compared with non-diffuse anaplasia Wilms tumors, including features of saltatory and parallel evolution. The subclonal landscape of individual tumors was constrained by anatomic compartments, which should be considered when sampling tissue for precision diagnostics.</p>}},
  author       = {{Rastegar, Bahar and Andersson, Natalie and Petersson, Alexandra and Karlsson, Jenny and Chattopadhyay, Subhayan and Valind, Anders and Jansson, Caroline and Durand, Geoffroy and Romerius, Patrik and Jirström, Karin and Holmquist Mengelbier, Linda and Gisselsson, David}},
  issn         = {{1078-0432}},
  keywords     = {{Humans; Kidney Neoplasms/pathology; Anaplasia/genetics; Retrospective Studies; Phylogeny; Wilms Tumor/genetics}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{14}},
  pages        = {{2668--2677}},
  publisher    = {{American Association for Cancer Research}},
  series       = {{Clinical Cancer Research}},
  title        = {{Resolving the Pathogenesis of Anaplastic Wilms Tumors through Spatial Mapping of Cancer Cell Evolution}},
  url          = {{http://dx.doi.org/10.1158/1078-0432.CCR-23-0311}},
  doi          = {{10.1158/1078-0432.CCR-23-0311}},
  volume       = {{29}},
  year         = {{2023}},
}