Chromosome-wide gene dosage rebalance may benefit tumor progression

The high-risk of tumor initiation in patients with Turner syndrome (TS) characterized by X chromosome monosomy in women has been well established and aneuploidy, defined as an abnormal number of chromosomes, is a common feature in human cancer. However, the underlying mechanisms of X chromosome aneuploidy promoting tumorigenesis remain obscure. We propose that chromosome-wide gene dosage imbalance (CDI) may serve as an important mechanism. Here, we assess the relative expression ratios of X chromosome and autosomes (expression ratios of X:AA) between tumor samples and adjacent normal samples across 16 tumor types using expression datasets from The Cancer Genome Atlas (TCGA) project. Our results show that the expression ratios of X:AA in tumor samples are frequently rebalanced to a lower level compared to those in adjacent normal samples, which is termed chromosome-wide gene dosage rebalance (CDR) thereafter. Gene ontology (GO) analysis of differentially expression genes from X chromosome reveals that downregulation of multicellularity-related genes and upregulation of unicellularity-related genes in tumors form a distinctive feature and enrichment analysis shows that downregulated genes are enriched in tumor suppressor genes, which indicate that CDR benefits tumor progression. Further experimental results prove that disturbance of X chromosome expression by knocking down of XIST in breast cancer cells, which functions in initiation phase of X chromosome inactivation (XCI), inhibits tumor progression. Our results demonstrate that the prevalent CDRs across tumor types serve as an important mechanism in promoting tumor progression, which partially explains the high risk of tumor in patients with TS and also provides a new cancer therapy from the CDR perspective.