tumoral chromosomal imbalances
Definition: Chromosomal imbalances can range from alterations spanning entire chromosomes to intragenic duplications or deletions. Gains of genetic material are tumoral genomic gains. Losses of genetic material are tumoral genomic losses.
Unlike rearrangements, in which the genes that become deregulated and the functional consequences of the rearrangements can be readily identified through analysis of the breakpoint regions, most chromosomal imbalances have functional consequences that are unknown.
Determining the implications of some chromosomal gains or losses involving single genes has been relatively straightforward, but most imbalances affect large genomic regions containing multiple genes, and many tumors have numerous unbalanced chromosomal abnormalities.
Although this degree of genetic complexity has hampered the delineation of the roles of individual chromosomal gains or losses in cancer, recent studies suggest that integration of genomewide analysis of gene dosage, global gene-expression profiling, and functional genomic techniques could identify functionally relevant genes within genomic regions that are affected by chromosomal imbalances.
Large-scale chromosomal imbalances
Chromosomal imbalances such as deletions and amplifications are common chromosomal anomalies in most tumors.
Specific anomalies are consistently associated with specific tumor types or stages, implicating the role of the genes in a region of chromosomal imbalance in tumor initiation and progression.
Tumor-specific patterns of large-scale chromosomal imbalances characterize most forms of cancer.
Large-scale chromosomal imbalances are crucial for tumor pathogenesis and have an impact on the global transcriptional profile of cancer cells, and that some imbalances even initiate cancer.
The genes and genetic pathways that have been dysregulated by such imbalances remain surprisingly elusive.
Many genes are affected by the regions of gain and loss, and there are complex interactions and relationships that occur between these genes, hindering their identification.
The study of untranslated RNA sequences, such as microRNAs, is in its infancy, and it is likely that such sequences are also dysregulated by chromosomal imbalance, contributing to pathogenesis.
Comparative genomic hybridization (CGH)
The development of comparative genomic hybridization (CGH) has obviated the need to obtain metaphase spreads from tumors, so that the chromosomal imbalances in many solid tumors may be revealed using an extracted genomic DNA sample.
However, the resolution of the cytogenetic method remains and the extreme technical difficulty of CGH has restricted its use.
Conceptually, DNA microarray-based CGH is an obvious solution to all of the limitations of conventional CGH. Although arrays have been used for CGH studies, their success has been limited by poor specific signal-to-noise ratios.
See also
Oncobase
tumoral genomic gains
tumoral genomic losses
References
Fröhling S, Döhner H.Chromosomal abnormalities in cancer.N Engl J Med. 2008 Aug 14;359(7):722-34. PMID: 18703475
Stallings RL. Are chromosomal imbalances important in cancer? Trends Genet. 2007 Mar 30; PMID: 17400327
Cai WW, Mao JH, Chow CW, Damani S, Balmain A, Bradley A. Genome-wide detection of chromosomal imbalances in tumors using BAC microarrays. Nat Biotechnol. 2002 Apr;20(4):393-6. PMID: 11923847