Breast tumor copy number aberration phenotypes and genomic instability
Open Access
- 18 April 2006
- journal article
- research article
- Published by Springer Science and Business Media LLC in BMC Cancer
- Vol. 6 (1), 96
- https://doi.org/10.1186/1471-2407-6-96
Abstract
Background 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. Methods 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. Results 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. Conclusion 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.Keywords
This publication has 48 references indexed in Scilit:
- Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic controlNature, 2004
- Geminin Is Targeted for Repression by the Retinoblastoma Tumor Suppressor Pathway through Intragenic E2F SitesOnline Journal of Public Health Informatics, 2004
- Expression of E2F-4 in invasive breast carcinomas is associated with poor prognosisThe Journal of Pathology, 2004
- Distinct expression patterns of the transcription factor E2F-1 in relation to tumour growth parameters in common human carcinomasThe Journal of Pathology, 2004
- Whole genome scanning identifies genotypes associated with recurrence and metastasis in prostate tumorsHuman Molecular Genetics, 2004
- ATR and ATRIP: Partners in Checkpoint SignalingScience, 2001
- Assembly of microarrays for genome-wide measurement of DNA copy numberNature Genetics, 2001
- Role for E2F in Control of Both DNA Replication and Mitotic Functions as Revealed from DNA Microarray AnalysisMolecular and Cellular Biology, 2001
- Computer-assisted identification of cell cycle-related genes: new targets for E2F transcription factorsJournal of Molecular Biology, 2001
- E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosisGenes & Development, 2001