Ten percent of children with cancer harbour a mutation in a predisposition gene. In children with the kidney cancer, Wilms tumour, the prevalence is as high as 30%. Certain predispositions are associated with defined histological and clinical features, suggesting differences in tumourigenesis. To investigate this, we assembled a cohort of 137 children with Wilms tumour, of whom 71 had a pathogenic germline or mosaic variant. We examined 237 neoplasms (including two secondary leukaemias), utilising WGS, RNA sequencing and genome wide methylation, validating our findings in an independent cohort. Tumour development differed in children harbouring a predisposition, depending on the variant gene and its developmental timing. Differences pervaded the repertoire of driver events, including high risk mutations, the clonal architecture of normal kidneys, and the relatedness of neoplasms from the same individual. Our findings indicate that predisposition may preordain Wilms tumourigenesis, suggesting a variant specific approach to managing children merits consideration.

中文翻译：

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肾母细胞瘤体细胞基因组中的易感性足迹


10% 的癌症儿童携带易感基因突变。在患有肾癌、肾母细胞瘤的儿童中，患病率高达 30%。某些易感性与明确的组织学和临床特征相关，表明肿瘤发生的差异。为了调查这一点，我们收集了一组 137 名肾母细胞瘤儿童，其中 71 名具有致病性种系或嵌合变异。我们利用 WGS、RNA 测序和全基因组甲基化检查了 237 例肿瘤（包括两种继发性白血病），在一个独立的队列中验证了我们的发现。携带易感性的儿童的肿瘤发展不同，具体取决于变异基因及其发育时间。差异普遍存在于驱动事件的曲目中，包括高风险突变、正常肾脏的克隆结构以及来自同一个体的肿瘤的相关性。我们的研究结果表明，易感性可能预示了肾母细胞瘤的发生，这表明值得考虑采用一种变异特异性方法来管理儿童。