Genomic profiling of human tumors: moving from cytogenetics to DNA arrays

Genetic instability results, in a large majority of solid tumors, in deep c hromosomal rearrangements. However, because chromosomal instability produce s highly complex caryotypes, rarely showing stereotypic aberrations, it has not been possible to characterize solid cancers according to specific patt erns of chromosomal rearrangements. This contracts with the situation in he matological malignancies, where cytogenetics has allowed to lay out the bas is of a renewed classification. New insights have been brought by the devel opment of comparative genomic hybridization (CGH). This molecular cytogenet ics approach was originally devised to detect regions in the genome of tumo r cells undergoing quantitative changes, i.e. gains or losses of copy numbe rs. The large body of studies based on CGH show that solid tumors undergo f requent gains and losses and that every chromosomes shaw at least one regio n of anomaly. Furthermore, different tumor types present distinct CGH patte rns of gains and losses. These observations favor the idea that it may be p ossible to type human solid cancers according to their patterns of genomic aberrations. However; despite the fact that a number of CGH based studies p resent data suggesting that different tumor types or cancers at different s tages of evolution show distinct patterns of gains and losses, it has prove n difficult to be conclusive. This can be mainly attributed to the lack of spatial resolution of CGH. indeed CGH uses metaphase chromosomes as hybridi zation targets and therefore its resolution is at the level of chromosomal banding. The recent adaptation of DNA array technology to CGH will allow to pass this limitation. In DNA array based CGH (array-CGH) metaphase chromos omes have been replaced by spots of cloned DNA. These DNA clones may either be genomic (BACs, YACs or cosmids) or coding (cDNAs). The resolution of ar ray-CGH is therefore determined by the size of the cloned DNA insert (100 K b for BACs, 1-2 kb for cDNAs). Data corresponding to each of these clones i s or will be in a near future linked to DNA sequence data. Hence, in a near future, array-CGH will allow to increase the resolution from a cytogenetic level to a molecular level. Finally, because array technology is highly ad aptable to automation, going am classical CGH to array-CGH will produce a q uantum leap in throughput.