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

Abstract

<div>Abstract<p>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 <i>TP53</i> 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 <i>TP53</i> alterations. <i>TP53 </i>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.</p></div>