Common Fragile Site Profiling in Epithelial and Erythroid Cells Reveals that Most Recurrent Cancer Deletions Lie in Fragile Sites Hosting Large Genes

Cancer genomes exhibit numerous deletions, some of which inactivate tumor suppressor genes and/or correspond to unstable genomic regions, notably common fragile sites (CFSs). However, 70%–80% of recurrent deletions cataloged in tumors remain unexplained. Recent findings that CFS setting is cell-type dependent prompted us to reevaluate the contribution of CFS to cancer deletions. By combining extensive CFS molecular mapping and a comprehensive analysis of CFS features, we show that the pool of CFSs for all human cell types consists of chromosome regions with genes over 300 kb long, and different subsets of these loci are committed to fragility in different cell types. Interestingly, we find that transcription of large genes does not dictate CFS fragility. We further demonstrate that, like CFSs, cancer deletions are significantly enriched in genes over 300 kb long. We now provide evidence that over 50% of recurrent cancer deletions originate from CFSs associated with large genes. [Display omitted] •A limited number of loci constitute the pool of CFSs for all human cell types•The CFS pool consists of chromosome regions with genes over 300 kb long•Transcription of large genes does not dictate the fragility of cognate CFSs•The majority of cancer deletions correlate with large-gene-associated CFSs Common fragile sites (CFSs) are loci prone to breakage upon replication stress and are hot spots for chromosomal rearrangements in tumors. The number of CFSs present in the human genome remains unknown. In this study, Debatisse and colleagues now show that the pool of CFSs for human cells is made up of chromosome regions with genes over 300 kb long and that the majority of recurrent cancer deletions originate from CFSs.