Array based genetic profiling of bone and soft tissue tumors

In this thesis, genetic alterations in bone and soft tissue tumors have been investigated with the purpose of identifying regions of importance for tumor development, diagnosis and prognosis. This has primarily been performed by array comparative genomic hybridization analysis and gene expression profiling of cytogenetically analyzed tumors. In Article I, the content of ring chromosomes in a subset of tumors with few or no other chromosomal aberrations were disclosed. Most frequently encountered were amplifications in 12q13.3-14.1 and 12q15.1, involving CDK4 and MDM2, respectively. The simultaneous amplification of 12q and 1p32 or 6q23-25 sequences suggested molecular mechanisms for dedifferentiation of liposarcoma. In Article IV, inflammatory/myxoinflammatory soft tissue sarcomas, primarily located distally in the extremities, with a t(1;10) and/or ring chromosomes with 3p11.1-12.1 amplification were investigated. Potential target genes of these aberrations were FGF8 in 10q24 and VGLL3 in 3p12. Irrespective of the morphologic diagnosis, tumors with a t(1;10) displayed similar gene expression patterns and clinical features. In Articles II and III, the spectra of genomic imbalances occurring in chordomas and chondrosarcomas were studied. Several regions of importance for tumor development were identified. For instance, both tumor types showed recurrent homozygous deletion of the CDKN2A locus and in peripheral chondrosarcoma homozygous loss of EXT1 and EXT2 was demonstrated. Clinicopathologic features did not correlate with any pattern of genomic imbalances, but these studies may have included too few tumors to detect clinically relevant subgroups.