Breast tumor copy number aberration phenotypes and genomic instability
- Equal contributors
1 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, San Francisco, CA 94143, USA
2 University of California San Francisco Comprehensive Cancer Center, San Francisco, CA 94143, USA
3 Cancer Research Institute, University of California San Francisco, San Francisco, CA 94143-0808, USA
4 Micro Array Core Facility, VUMC University Medical Center, 1081BT Amsterdam, The Netherlands
5 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York 20021, USA
6 Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143-0808, USA
7 Geraldine Brush Cancer Research Institute, California Pacific Medical Center, San Francisco, California 94115, USA
8 Department of Pathology, University of California San Francisco, San Francisco, California, USA
9 Division of Life Sciences, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
BMC Cancer 2006, 6:96 doi:10.1186/1471-2407-6-96Published: 18 April 2006
Genomic 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.
We 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.
We 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.
Many 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.