Deregulation of the G1 to S-Phase Cell Cycle Checkpoint Is Involved in the Pathogenesis of Human Osteosarcoma

Osteosarcoma (OS) displays complex karyotypes with numerical changes as well as structural abnormalities suggesting that several oncogenes and tumor suppressor genes may be implicated in the biology of OS. The aim of our study was to investigate the possible implication of the molecular alterations of the G1to S-phase checkpoint genes in the pathogenesis of OS. We analyzed samples from 29 patients and found molecular alterations of the RBand TP53genes in 6 (21) and 3 (10) cases, respectively. Homozygous deletion of the INK4A/ARFlocus and methylation of INK4Awas detected in 3 (10) and 2 (7) cases, respectively. CDK4and MDM2co-amplification was observed in 1 case (3). Cyclin D3 is differentially expressed in a greater proportion than D1- and D2-type cyclins. Cytogenetically, all cases had complex karyotypes being especially significant the losses of the chromosomes 4, 13, and 17. As a whole, 11 of 29 (38) analyzed OS presented alterations in some of the analyzed G1to S-phase checkpoint genes. These alterations were more frequently present in adults (P0.032). All patients with genetic alterations in the G1/S-phase checkpoint died during their clinical follow-up, whereas more than 53 of the remaining cases were alive in this period (P0.007). Hence, in the pathogenesis of human OS, deregulation of the G1/S checkpoint genes, especially RB, TP53,and INK4/ARFlocus, plays an important role and defines a subgroup of patients with a poor outcome.