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Abstract Human cancers are characterized by the presence of genomic instability. Recently, two studies have catalogued the presence of a specific class of genomic aberrations, large deletions and insertions, in a few thousand human cancers and reported that most of the prevalent recurrent focal deletions targeted common fragile sites and large genes. In various experimental systems, deletions in common fragile sites and large genes have been linked to the presence of DNA replication stress. Thus, taken together, these results suggest the presence of DNA replication stress in human cancers, consistent with the recently proposed oncogene‐induced DNA damage model for cancer development.