Abstract
BackgroundGenomic DNA copy number aberrations are frequent in solid tumors, although the underlying causes of chromosomal instability in tumors remain obscure. Genes likely to have genomic instability phenotypes when mutated (e.g. those involved in mitosis, replication, repair, and telomeres) are rarely mutated in chromosomally unstable sporadic tumors, even though such mutations are associated with some heritable cancer prone syndromes.MethodsWe applied array comparative genomic hybridization (CGH) to the analysis of breast tumors. The variation in the levels of genomic instability amongst tumors prompted us to investigate whether alterations in processes/genes involved in maintenance and/or manipulation of the genome were associated with particular types of genomic instability.ResultsWe discriminated three breast tumor subtypes based on genomic DNA copy number alterations. The subtypes varied with respect to level of genomic instability. We find that shorter telomeres and altered telomere related gene expression are associated with amplification, implicating telomere attrition as a promoter of this type of aberration in breast cancer. On the other hand, the numbers of chromosomal alterations, particularly low level changes, are associated with altered expression of genes in other functional classes (mitosis, cell cycle, DNA replication and repair). Further, although loss of function instability phenotypes have been demonstrated for many of the genes in model systems, we observed enhanced expression of most genes in tumors, indicating that over expression, rather than deficiency underlies instability.ConclusionMany of the genes associated with higher frequency of copy number aberrations are direct targets of E2F, supporting the hypothesis that deregulation of the Rb pathway is a major contributor to chromosomal instability in breast tumors. These observations are consistent with failure to find mutations in sporadic tumors in genes that have roles in maintenance or manipulation of the genome.
Highlights
Genomic DNA copy number aberrations are frequent in solid tumors, the underlying causes of chromosomal instability in tumors remain obscure
We found that tumors with mutations in exons 5–8 of TP53 showed a higher frequency of alterations, as well as significant differences in the frequency of alteration of certain regions of the genome compared to tumors without mutations as indicated by the t-statistic for each clone (Figure 2)
The same three clusters were observed in an independent set of breast tumors (Chin et al, submitted), confirming our initial observation
Summary
Genomic DNA copy number aberrations are frequent in solid tumors, the underlying causes of chromosomal instability in tumors remain obscure. The interplay between selection and genetic instability in shaping tumor genomes is currently most clearly established in tumors with defects in mismatch repair These tumors have a high frequency of nucleotide sequence level aberrations, fewer DNA copy number alterations and characteristic histological phenotype [1]. The foregoing discussion suggests that failures in a number of different processes that maintain genome integrity could contribute to the wide variety of genomic alterations in solid tumors Often these aberrations include net gain or loss of whole chromosomes (aneuploidy) or parts of chromosomes. The number of lower magnitude gains and losses of chromosomal segments was associated with differential expression of genes involved in processes maintaining or manipulating the genome These genes are significantly enriched for the known targets of E2F. These observations support the hypothesis that deregulation of the Rb/E2F pathway is a major contributor to chromosomal instability in breast tumors
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