The high-risk of tumor initiation in patients with Turner syndrome (TS) characterized by X chromosome monosomy inwomen has been well established and aneuploidy, defined as an abnormal number of chromosomes, is a common feature inhuman 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 assessthe relative expression ratios of X chromosome and autosomes (expression ratios of X:AA) between tumor samples andadjacent 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 tothose 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-relatedgenes and upregulation of unicellularity-related genes in tumors form a distinctive feature and enrichment analysis shows thatdownregulated genes are enriched in tumor suppressor genes, which indicate that CDR benefits tumor progression. Furtherexperimental 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 demonstratethat the prevalent CDRs across tumor types serve as an important mechanism in promoting tumor progression, which par-tially explains the high risk of tumor in patients with TS and also provides a new cancer therapy from the CDR perspective.