Wellcome Sanger Institute, Hinxton CB10 1SA, UK.
Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.
Science. 2019 Dec 6;366(6470):1247-1251. doi: 10.1126/science.aax1323.
Adult cancers often arise from premalignant clonal expansions. Whether the same is true of childhood tumors has been unclear. To investigate whether Wilms tumor (nephroblastoma; a childhood kidney cancer) develops from a premalignant background, we examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 cases studied (61%), we found premalignant clonal expansions in morphologically normal kidney tissues that preceded tumor development. These clonal expansions were defined by somatic mutations shared between tumor and normal tissues but absent from blood cells. We also found hypermethylation of the locus, a known driver of Wilms tumor development, in 58% of the expansions. Phylogenetic analyses of bilateral tumors indicated that clonal expansions can evolve before the divergence of left and right kidney primordia. These findings reveal embryonal precursors from which unilateral and multifocal cancers develop.
成人癌症通常起源于癌前克隆扩增。儿童肿瘤是否也是如此尚不清楚。为了研究Wilms 瘤(肾母细胞瘤;一种儿童肾癌)是否起源于癌前背景,我们研究了肿瘤与其相应正常组织之间的系统发生关系。在 23 例研究病例中的 14 例(61%)中,我们发现了在肿瘤发生之前存在于形态正常肾组织中的癌前克隆扩增。这些克隆扩增是由肿瘤和正常组织之间共享但不存在于血细胞中的体细胞突变定义的。我们还发现,在 58%的扩增中, 基因座的甲基化呈超甲基化状态,这是 Wilms 瘤发展的已知驱动因素。双侧肿瘤的系统发生分析表明,克隆扩增可以在左右肾原基分化之前发生进化。这些发现揭示了单侧和多灶性癌症的胚胎前体。