Abstract
BackgroundChromosomal breakage followed by faulty DNA repair leads to gene amplifications and deletions in cancers. However, the mere assessment of the extent of genomic changes, amplifications and deletions may reduce the complexity of genomic data observed by array comparative genomic hybridization (array CGH). We present here a novel approach to array CGH data analysis, which focuses on putative breakpoints responsible for rearrangements within the genome.ResultsWe performed array comparative genomic hybridization in 29 primary tumors from high risk patients with breast cancer. The specimens were flow sorted according to ploidy to increase tumor cell purity prior to array CGH. We describe the number of chromosomal breaks as well as the patterns of breaks on individual chromosomes in each tumor. There were differences in chromosomal breakage patterns between the 3 clinical subtypes of breast cancers, although the highest density of breaks occurred at chromosome 17 in all subtypes, suggesting a particular proclivity of this chromosome for breaks. We also observed chromothripsis affecting various chromosomes in 41% of high risk breast cancers.ConclusionsOur results provide a new insight into the genomic complexity of breast cancer. Genomic instability dependent on chromosomal breakage events is not stochastic, targeting some chromosomes clearly more than others. We report a much higher percentage of chromothripsis than described previously in other cancers and this suggests that massive genomic rearrangements occurring in a single catastrophic event may shape many breast cancer genomes.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-579) contains supplementary material, which is available to authorized users.
Highlights
Chromosomal breakage followed by faulty DNA repair leads to gene amplifications and deletions in cancers
Flow sorting for fractions with different ploidy values was performed on 48 frozen tumor samples of high risk breast tumors. 27 tumor samples (56.3% of the total) showed clear aneuploid cell cycle profiles (Figure 1A)
All of these DNA samples carried genomic alterations, while 2N subpopulations from these tumors either did not carry any genomic aberrations or carried few aberrations, which localized in all cases to sites of common copy number variations (CNVs) as per the Toronto CNV database
Summary
Chromosomal breakage followed by faulty DNA repair leads to gene amplifications and deletions in cancers. We present here a novel approach to array CGH data analysis, which focuses on putative breakpoints responsible for rearrangements within the genome. Most studies of DNA copy number changes in breast tumors report on the potential clinical value of altered genes within these changes, while few have focused on the breakage events leading to the rearrangements themselves. Genomic instability is usually measured as the proportion of the genome that is altered rather than the number or patterns of those changes. This complexity has not been properly addressed before
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