Resolving the pathogenesis of anaplastic Wilms tumors through spatial mapping of cancer cell evolution

Autor: Bahar Rastegar, Natalie Andersson, Alexandra Petersson, Jenny Karlsson, Subhayan Chattopadhyay, Anders Valind, Caroline Jansson, Geoffroy Durand, Patrik Romerius, Karin Jirstrom, Linda Holmquist Mengelbier, David Gisselsson
Rok vydání: 2023
Předmět:
Zdroj: Clinical Cancer Research.
ISSN: 1557-3265
1078-0432
DOI: 10.1158/1078-0432.ccr-23-0311
Popis: Purpose: While patients with intermediate-risk Wilms tumors (WT) now have an overall survival rate of almost 90%, those affected by high-stage tumors with diffuse anaplasia (DA) have an overall survival of only around 50%. We here identify key events in the pathogenesis of DA by mapping cancer cell evolution over anatomic space in WTs. Experimental Design: We spatially mapped subclonal landscapes in a retrospective cohort of 20 WTs using high-resolution copy number profiling and TP53 mutation analysis followed by clonal deconvolution and phylogenetic reconstruction. Tumor whole mount sections were utilized to characterize the distribution of subclones across anatomically distinct tumor compartments. Results: Compared to non-DA WTs, tumors with DA 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 allele in different regions. Morphological 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, while clonal sweeps were rare within these compartments. Conclusions: WTs with DA display significantly more complex phylogenies compared to non-DA WTs, 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.
Databáze: OpenAIRE
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