The consequences of chromosomal aneuploidy on the transcriptome of cancer cells

Abstract

Chromosomal aneuploidies are a defining feature of carcinomas, i.e., tumors of epithelial origin. Such aneuploidies result in tumor specific genomic copy number alterations. The patterns of genomic imbalances are tumor specific, and to a certain extent specific for defined stages of tumor development. Genomic imbalances occur already in premalignant precursor lesions, i.e., before the transition to invasive disease, and their distribution is maintained in metastases, and in cell lines derived from primary tumors. These observations are consistent with the interpretation that tumor specific genomic imbalances are drivers of malignant transformation. Naturally, this precipitates the question of how such imbalances influence the expression of resident genes. A number of laboratories have systematically integrated copy number alterations with gene expression changes in primary tumors and metastases, cell lines, and experimental models of aneuploidy to address the question as to whether genomic imbalances deregulate the expression of one or few key genes, or rather affect the cancer transcriptome more globally. The majority of these studies showed that gene expression levels follow genomic copy number. Therefore, gross genomic copy number changes, including aneuploidies of entire chromosome arms and chromosomes, result in a massive deregulation of the transcriptome of cancer cells. This article is part of a Special Issue entitled: Chromatin in time and space.

Never in Neutral: A Systems Biology and Evolutionary Perspective on how Aneuploidy Contributes to Human Diseases

“…Similar findings have been obtained in more systematic analyses of aneuploidy in budding yeast, in which S. cerevisiae strains were engineered to carry either specific or random chromosome copy number imbalances [Torres et al, 2007;Pavelka et al, 2010b]. In general, there is a consensus across all these studies that the average expression level of genes harbored on aneuploid chromosomes directly follows chromosome copy number [Ried et al, 2012].…”

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“…The reason is that chromosome changes alter system inheritance (the order of genes along the chromosomes and within the genome) and lead to the diverse and wide-spread changes in gene expression at both transcriptional and translational levels. The higher degree and rate of CIN correlate with the more dramatic and dynamic changes of gene expression Liu et al, 2014;Stevens et al, 2013Stevens et al, , 2014Donnelly and Storchová, 2014;Duesberg et al, 2011;Gao et al, 2007;Ried et al, 2012;Stepanenko and Kavsan, 2012). An altered distribution of chromatin (changes in genome topology) and aberrant expression of transcription factors may intensify changes in gene expression and favor further deregulation of cellular functions.…”

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“…Cancer cells often show complicated karyotypes, but the link between certain karyotypic patterns and certain types of cancer has also been pointed out [36]. Individuals with Down syndrome exhibit an increased risk of leukemia, but, enigmatically, incidence of solid tumors is lower than that of euploid individuals [37].…”