The landscape of X chromosome copy number alterations in cancer

Copy number alterations are frequent, early events in cancer evolution. Previous pan-cancer analyses have not characterized recurrent copy number alterations on the actively and inactively transcribed X chromosome. The monoallelic expression of the active X chromosome predicts a higher sensitivity of cell fitness to copy number alterations on the active X chromosome than expected from autosomal copy number alterations. Large deletions on the active X chromosome are likely intolerable due to loss of expression of essential genes; a duplication of the active X chromosome will increase chromosome X expression by 100% instead of 50%,which is the expected increase of gene expression from duplication of a single autosome homolog. Recurrent copy number alterations on the X chromosomes could lead to the discovery of new, therapeutically actionable drivers of tumor evolution. We have developed a new method to accurately determine the copy number alterations on the active and inactive X from combined whole genome sequencing and RNA-seq of >8,000 TCGA tumors. We found recurrent copy number gains on the active X chromosome q-arm spanning the telomere. The active X chromosome copy number gains overlapped previously identified cancer genes in the Cancer Gene Census from other tumors such as ATP2B3, FLNA, MTCP1, RPL10, PHF6 and GPC3. These segmental and arm-level gains were not significantly more frequent in patients with whole genome doubling or TP53 mutations. These results suggested that recurrent gains of the q-arm of the active X chromosome were not a result of genomic instability, suggesting that these gains were putative driver events that could be truncal in tumor evolution. Telomere-spanning segmental copy number gains on the q-arm were less common in female glioblastoma or uveal melanoma tumors, which are cancer types that affect both male and female patients. This work shows that copy number gains on the active X chromosome are a new source of cancer driver mutations. The sensitivity of the active X chromosome to selection suggests that genes in recurrent X chromosome amplifications could be new genetic dependencies or therapeutic targets in treating female cancers. The results of this study may identify previously unknown drivers of cancer on the active X chromosome that could be new, effective therapeutic targets in cancer.