Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
Department of Pediatrics, Division of Hematology and Oncology, Hospital for Sick Children, Toronto, ON, Canada.
Br J Cancer. 2021 Jan;124(2):437-446. doi: 10.1038/s41416-020-01102-1. Epub 2020 Oct 5.
Although cure rates for Wilms tumours (WT) are high, many patients receive therapy with attendant long-term complications. Our goal was to stratify WT using genome-wide analyses to identify candidate molecular features for patients who would benefit from a reduction in therapy.
We generated DNA methylation and exome sequencing data on WT-kidney pairs (n = 57) and unpaired tumours (n = 27) collected either at our centre or by the Children's Oncology Group. Samples were divided into a discovery set (n = 32) and validation set (n = 52).
Analysis of DNA methylation revealed two subgroups of WT with distinct features. Subgroup A has a similar DNA methylation profile to mature kidney, while Subgroup B has genome-wide dysregulation of DNA methylation. The rate of non-synonymous missense mutations and segmental chromosomal aberrations was higher in Subgroup B tumours, suggesting that this group has genome instability related to its epigenetic state. Subgroup A had a higher proportion of cases of bilateral disease. Tumours with high-risk histology or from patients who relapsed were only found in Subgroup B.
We have identified subgroup-specific molecular events that could inform future work supporting more targeted therapeutic approaches and patient stratification. We propose a novel developmental tumour model based on these findings.
尽管威尔姆斯瘤（WT）的治愈率很高，但许多患者仍接受治疗，伴随长期并发症。我们的目标是通过全基因组分析对 WT 进行分层，以确定那些受益于减少治疗的患者的候选分子特征。
我们在本中心或儿童肿瘤组收集的 WT-肾脏对（n=57）和未配对肿瘤（n=27）上生成了 DNA 甲基化和外显子测序数据。样本分为发现集（n=32）和验证集（n=52）。
DNA 甲基化分析显示，WT 有两个具有不同特征的亚组。亚组 A 的 DNA 甲基化谱与成熟肾脏相似，而亚组 B 则存在全基因组的 DNA 甲基化失调。亚组 B 肿瘤中的非同义错义突变和片段性染色体异常率较高，表明该组与表观遗传状态相关的基因组不稳定性。亚组 A 中有更高比例的双侧疾病病例。高危组织学或复发患者的肿瘤仅在亚组 B 中发现。
我们已经确定了亚组特异性的分子事件，这可能为未来支持更有针对性的治疗方法和患者分层的工作提供信息。我们根据这些发现提出了一种新的发育性肿瘤模型。
