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海星推断了人类癌症中复杂的基因组重排的特征

原文发布日期：2022-07-14

英文摘要：

摘要翻译：

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海星推断了人类癌症中复杂的基因组重排的特征

Starfish infers signatures of complex genomic rearrangements across human cancers

原文发布日期：2022-07-14

英文摘要：

Complex genomic rearrangements (CGRs) are common in cancer and are known to form via two aberrant cellular structures—micronuclei and chromatin bridges. However, which of these mechanisms is more relevant to CGR formation in cancer and whether there are other undiscovered mechanisms remain unknown. Here we developed a computational algorithm, ‘Starfish’, to analyze 2,014 CGRs from 2,428 whole-genome-sequenced (WGS) tumors and discovered six CGR signatures based on their copy number and breakpoint patterns. Extensive benchmarking showed that our CGR signatures are highly accurate and biologically meaningful. Three signatures can be attributed to known biological processes—micronuclei- and chromatin-bridge-induced chromothripsis and circular extrachromosomal DNA. Over half of the CGRs belong to the remaining three signatures, not reported previously. A unique signature, which we named ‘hourglass chromothripsis’, with localized breakpoints and a low amount of DNA loss, is abundant in prostate cancer. Hourglass chromothripsis is associated with mutant SPOP, which may induce genome instability.

摘要翻译：

染色体组重排列（CGRs）在癌症中较为常见，已知其形成机制涉及两种异常细胞结构：微核和染色质桥。然而，在癌症中哪种机制更相关于CGRs的形成，以及是否存在其他尚待发现的机制仍有待探究。本研究开发了一种计算算法“星鱼”（Starfish），分析了来自2428例完整基因组 sequencing (WGS) 的肿瘤的2014个CGRs，并根据其拷贝数和断裂模式发现了六种CGR 标志。通过大规模验证实验，我们发现我们的 CGR 标志具有极高的准确性及其生物学意义。其中三种标志可归因于已知的生物过程——微核或染色质桥导致的染色体切碎和圆环状超出染色体的DNA。其余三分之一以上的CGR属于三种尚未报道过的标志。一种独特的标志，我们称之为“小时glass型染色体切碎”，具有局部化断裂模式和少量 DNA 丢失特征，在前列腺癌中非常普遍。该标志与突变性SPOP相关联，可能与基因组不稳定性有关。