From cytogenetics to cytogenomics of tumors

Cytogenetics of malignancy developed over the last thirty years have clearl y demonstrated that cancers are an acquired genetic, in fact genomic, disea se of the cell, thus validating the old Boveri hypothesis. Nearly all tumor s clearly show genomic abnormalities with a monoclonal expansion in most ca ses. Formation of fusion genes is the first type, the prototype being the F LI1-EWS fusion due to the t(11;22)(q24;q12) translocation from Ewing sarcom a. These are most often observed in sarcomas or in neuroectodermal tumors. The fusion gene can be amplified, for example the PAX3/FKHR fusion of t(2;1 3) (q35;q14) characteristic of alveolar rhabdomyosarcoma. The second type i s loss of genetic information either following chromosomal rear rearrangeme nts (deletions, unbalanced translocations) or other genetic events (mutatio n, loss of function) detected by a loss of heterozygosity. Tumor suppressor genes are generally involved in these frequent rearrangements. The third t ype of genomic event are gains of genetic material, ranging from moderate o ver-representation of a chromosomal segment to amplified sequences of oncog enes taking on the appearance of double minute or HSR during metaphases, Sm all gains are more difficult to study than amplified regions, and are less well known, but recent results clearly show that the dosage effect of oncog enes is also probably involved in their selection. The multistep process le ading to malignancy is demonstrated by the presence of acquired multiple ch romosomal abnormalities in solid tumors, and their increasing complexity du ring metastasis or relapse. Several of the genomic rearrangements are tumor -specific and can be used for diagnosis, and in some situations for prognos is. For example in neuroblastoma, one of the most frequent solid tumor of c hildren, deletion of 1p36, amplification of MYCN and over-representation of 17q in tumor cells, are important prognostic factors. Cytogenomics of mali gnant cells ranges from chromosome banding morphology to DNA-DNA micro-arra ys through FISH, CGH, DNA fibers, microdissection and careful determination of the phenotype of studied cells. This will allow individual genotyping o f the malignant tumor which is a prerequisite to highly targeted and theref ore specific treatments.