Gross chromosomal rearrangements (including translocations, deletions, 
insertions and duplications) are a hallmark of cancer genomes and often create 
oncogenic fusion genes. An obligate step in the generation of such gross 
rearrangements is the formation of DNA double-strand breaks (DSBs). Since the 
genomic distribution of rearrangement breakpoints is non-random, intrinsic 
cellular factors may predispose certain genomic regions to breakage. Notably, 
certain DNA sequences with the potential to fold into secondary structures 
[potential non-B DNA structures (PONDS); e.g. triplexes, quadruplexes, 
hairpin/cruciforms, Z-DNA and single-stranded looped-out structures with 
implications in DNA replication and transcription] can stimulate the formation 
of DNA DSBs. Here, we tested the postulate that these DNA sequences might be 
found at, or in close proximity to, rearrangement breakpoints. By analyzing the 
distribution of PONDS-forming sequences within ±500 bases of 19 947 
translocation and 46 365 sequence-characterized deletion breakpoints in cancer 
genomes, we find significant association between PONDS-forming repeats and 
cancer breakpoints. Specifically, (AT)n, (GAA)n and (GAAA)n constitute the most 
frequent repeats at translocation breakpoints, whereas A-tracts occur 
preferentially at deletion breakpoints. Translocation breakpoints near 
PONDS-forming repeats also recur in different individuals and patient tumor 
samples. Hence, PONDS-forming sequences represent an intrinsic risk factor for 
genomic rearrangements in cancer genomes.