Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Department of Pediatrics, Skåne University Hospital, Lund, Sweden.
Clin Cancer Res. 2023 Jul 14;29(14):2668-2677. doi: 10.1158/1078-0432.CCR-23-0311.
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.
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.
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.
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.
虽然中危（IR）Wilms 肿瘤患者的总体生存率（OS）几乎达到 90%，但那些患有弥漫性间变的高危期肿瘤的患者 OS 仅约为 50%。我们通过在 Wilms 肿瘤中对肿瘤细胞的解剖空间进行进化作图，来鉴定弥漫性间变发病机制中的关键事件。
我们使用高分辨率拷贝数谱分析和 TP53 突变分析，对 20 例 Wilms 肿瘤的回顾性队列进行了亚克隆景观的空间作图，随后进行克隆去卷积和系统发生重建。肿瘤整体切片（WMS）用于描述解剖上不同的肿瘤隔室中克隆亚群的分布。
与非弥漫性间变 Wilms 肿瘤相比，弥漫性间变肿瘤具有明显更多的遗传上不同的肿瘤细胞亚群和更复杂的系统发生树，包括高的系统发生物种丰富度、分化和不规则性。所有具有经典间变的区域均显示 TP53 改变。TP53 突变后常伴有跳跃进化，不同区域中剩余的野生型（WT）等位基因也同时丢失。间变的形态特征随着拷贝数异常（CNA）负担和退行特征的增加而增加。由纤维隔或坏死/退行区分的隔室常与新的克隆 CNA 的出现有关（73%），尽管这些隔室中克隆清扫很少见。
与非弥漫性间变 Wilms 肿瘤相比，弥漫性间变 Wilms 肿瘤显示出明显更复杂的系统发生树，包括跳跃和并行进化的特征。个体肿瘤的亚克隆景观受到解剖隔室的限制，在进行精确诊断时应考虑组织采样。
