Genome instability in secondary solid tumors developing after radiotherapyof bilateral retinoblastoma

Genome alterations of seven secondary tumors (five osteosarcomas, one malig nant peripheral sheath nerve tumor, one leiomyosarcoma) occurring in the fi eld of irradiation of patients treated for bilateral retinoblastoma have be en studied. These patients were predisposed to develop radiation-induced tu mors because of the presence of a germ line mutation in the retinoblastoma gene (RB1). Tumor cells were characterized by a high chromosome instability whereas microsatellites and minisatellites were found to be stable. In all tumors, the normal RBI allele was lost with the corresponding chromosome 1 3, whereas the germ line mutated allele was retained. The two alleles of TP 53 were inactivated, one by deletion of the short arm of chromosome 17, the other by mutation. As compared with non-radiation induced tumors, the obse rved panel of TP53 mutations was uncommon with sites not recurrently found otherwise and a high rate of deletions (3/7). In these predisposed patients , the loss of the single normal allele of RB1 is rather due to the radiatio n-induced chromosome instability than a direct effect of ionizing radiation .