The Inactive X Chromosome Is Hypermutated in Cancer

The mutation rate of cancer cells can vary across the genome based on sequence features and processes such as transcription and replication. In an analysis of the genome-wide distribution of somatic single-nucleotide variants in primary medulloblastomas, Jäger and colleagues made the unexpected observation that the X chromosome accumulated more than twice the number of mutations than autosomes in the majority of female samples regardless of copy number or patient age. Male medulloblastoma genomes and female medulloblastoma genomes missing an X chromosome generally did not have X chromosome hypermutation, suggesting that hypermutation may specifically affect the inactive X chromosome. Indeed, haplotyping of the X chromosome based on allele frequencies in cancers with a second inactive X chromosome or on occupancy of macroH2A1, a histone variant enriched on the inactive X chromosome, revealed that hypermutation was restricted to the inactive X chromosome. Hypermutation occurred in both genic and intergenic regions of the inactive X chromosome, suggesting it was not attributable to a lack of transcription-coupled repair, and was not observed in normal female cells, suggesting that the unique heterochromatin structure of the inactive X chromosome did not affect hypermutation. The mutation spectrum of the inactive X chromosome and autosomes was similar within individual tumors, providing further evidence against a specific process targeting the inactive X chromosome. Instead, late replication may subject the inactive X chromosome to increased replication stress, as late-replicating autosomal regions also had an increased mutation rate. Overall, inactive X chromosome hypermutation was observed in 56 of 191 (29%) female genomes across nine different pediatric and adult cancer types, and was not seen in genomes of nonmalignant cells. Future studies are needed to determine the effect on inactive X chromosome hypermutation on X chromosome gene expression and whether these findings have clinical significance.

Jäger N, Schlesner M, Jones DT, Raffel S, Mallm JP, Junge KM, et al. Hypermutation of the inactive X chromosome is a frequent event in cancer. Cell 2013 Oct 17 [Epub ahead of print].