Tumors frequently display high chromosomal instability and contain multiple copies of genomic regions. Here, we describe GRITIC, a generic method for timing genomic gains leading to complex copy number states, using single-sample bulk whole-genome sequencing data. By applying GRITIC to 6,091 tumors, we found that non-parsimonious evolution is frequent in the formation of complex copy number states in genome-doubled tumors. We measured chromosomal instability before and after genome duplication in human tumors and found that late genome doubling was followed by an increase in the rate of copy number gain. Copy number gains often accumulate as punctuated bursts, commonly after genome doubling. We infer that genome duplications typically affect the landscape of copy number losses, while only minimally impacting copy number gains. In summary, GRITIC is a novel copy number gain timing framework that permits the analysis of copy number evolution in chromosomally unstable tumors.

中文翻译：

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基因组加倍肿瘤中染色体不稳定性的历史


肿瘤经常表现出高度的染色体不稳定性并包含基因组区域的多个拷贝。在这里，我们描述了 GRITIC，一种使用单样本批量全基因组测序数据计时基因组增益导致复杂拷贝数状态的通用方法。通过将 GRITIC 应用于 6,091 个肿瘤，我们发现在基因组加倍肿瘤中复杂拷贝数状态的形成中经常出现非简约进化。我们测量了人类肿瘤基因组复制前后的染色体不稳定性，发现基因组加倍后期伴随着拷贝数增益率的增加。拷贝数的增加通常以间断爆发的形式累积，通常发生在基因组加倍之后。我们推断，基因组重复通常会影响拷贝数丢失的情况，而对拷贝数增加的影响却很小。总之，GRITIC 是一种新颖的拷贝数获得计时框架，可以分析染色体不稳定肿瘤中的拷贝数进化。