Zhang Xiaoxiao, Kschischo Maik
Department of Mathematics and Technology, University of Applied Sciences Koblenz, 53424 Remagen, Germany.
Department of Informatics, Technical University of Munich, 81675 Munich, Germany.
Cancers (Basel). 2022 Mar 10;14(6):1424. doi: 10.3390/cancers14061424.
A large proportion of tumours is characterised by numerical or structural chromosomal instability (CIN), defined as an increased rate of gaining or losing whole chromosomes (W-CIN) or of accumulating structural aberrations (S-CIN). Both W-CIN and S-CIN are associated with tumourigenesis, cancer progression, treatment resistance and clinical outcome. Although W-CIN and S-CIN can co-occur, they are initiated by different molecular events. By analysing tumour genomic data from 33 cancer types, we show that the majority of tumours with high levels of W-CIN underwent whole genome doubling, whereas S-CIN levels are strongly associated with homologous recombination deficiency. Both CIN phenotypes are prognostic in several cancer types. Most drugs are less efficient in high-CIN cell lines, but we also report compounds and drugs which should be investigated as targets for W-CIN or S-CIN. By analysing associations between CIN and bio-molecular entities with pathway and gene expression levels, we complement gene signatures of CIN and report that the drug resistance gene is strongly associated with S-CIN. Finally, we propose a potential copy number-dependent mechanism to activate the pathway in high-S-CIN tumours.
很大一部分肿瘤的特征是染色体数目或结构不稳定（CIN），其定义为获得或丢失整条染色体（W-CIN）的速率增加或积累结构畸变（S-CIN）的速率增加。W-CIN和S-CIN均与肿瘤发生、癌症进展、治疗耐药性及临床结果相关。虽然W-CIN和S-CIN可能同时出现，但它们由不同的分子事件引发。通过分析来自33种癌症类型的肿瘤基因组数据，我们发现大多数W-CIN水平高的肿瘤经历了全基因组加倍，而S-CIN水平与同源重组缺陷密切相关。两种CIN表型在几种癌症类型中都具有预后价值。大多数药物在高CIN细胞系中的效率较低，但我们也报告了一些化合物和药物，应将其作为W-CIN或S-CIN的靶点进行研究。通过分析CIN与具有通路和基因表达水平的生物分子实体之间的关联，我们补充了CIN的基因特征，并报告耐药基因与S-CIN密切相关。最后，我们提出了一种潜在的拷贝数依赖性机制，以在高S-CIN肿瘤中激活该通路。
