Darwinian evolution of tumor cells remains underexplored in childhood cancer. We here reconstruct the evolutionary histories of 56 pediatric primary tumors, including 24 neuroblastomas, 24 Wilms tumors and 8 rhabdomyosarcomas. Whole genome copy number and whole exome mutational profiling of multiple regions per tumor was performed followed by clonal deconvolution to reconstruct a phylogenetic tree for each tumor. Overall, 88% of the tumors exhibited genetic variation among primary tumor regions. This variability typically emerged through collateral phylogenetic branching, leading to spatial variability in the distribution of more than 50% (96/173) of detected diagnostically informative genetic aberrations. Single cell sequencing of 547 individual cancer cells from eight solid pediatric tumors confirmed branching evolution to be a fundamental underlying principle of genetic variation in all cases. Strikingly, cell-to-cell genetic diversity was almost twice as high in aggressive compared to clinically favorable tumors (median Simpson index of diversity 0.45 vs. 0.88; p=0.029). Similarly, a comparison of multiregional sampling data from a total of 274 tumor regions showed that new phylogenetic branches emerge at a higher frequency per sample and carry a higher mutational load in high-risk than in low-risk tumors. Timelines based on spatial genetic variation showed that the mutations most influencing relapse risk occur at initiation of clonal expansion in neuroblastoma and rhabdomyosarcoma, while in Wilms tumor they are late events. Thus, from an evolutionary standpoint, some high-risk childhood cancers are born bad, while others grow worse over time.

中文翻译：

---

广泛的克隆分支决定了高危儿科癌症的进化史。

在儿童期癌症中，肿瘤细胞的达尔文进化仍未得到充分研究。我们在这里重建了56例小儿原发性肿瘤的进化历史，包括24例神经母细胞瘤，24例Wilms肿瘤和8例横纹肌肉瘤。进行每个肿瘤多个区域的全基因组拷贝数和整个外显子组突变谱分析，然后进行克隆解卷积，为每个肿瘤重建系统发育树。总体而言，88％的肿瘤在原发性肿瘤区域之间表现出遗传变异。这种可变性通常是通过附带的系统发育分支出现的，从而导致超过50％（96/173）的检测到的诊断性遗传异常的分布具有空间可变性。对来自8种实体小儿肿瘤的547个癌细胞进行单细胞测序，证实分支进化是所有情况下遗传变异的基本基本原理。令人惊讶的是，与临床上有利的肿瘤相比，侵袭性细胞间遗传多样性几乎高出一倍（中位辛普森指数多样性指数为0.45 vs. 0.88； p = 0.029）。同样，对来自总共274个肿瘤区域的多区域采样数据进行的比较显示，新的系统发育分支以每个样本的频率更高，并且在高风险的情况下比在低风险的肿瘤中承担更高的突变负荷。基于空间遗传变异的时间轴表明，影响复发风险最大的突变发生在神经母细胞瘤和横纹肌肉瘤的克隆扩张开始时，而在威尔姆斯瘤中则是晚期事件。从而，