Genome instability in secondary solid tumors developing after radiotherapy of bilateral retinoblastoma

Abstract

Genome alterations of seven secondary tumors (®ve osteosarcomas, one malignant peripheral sheath nerve tumor, one leiomyosarcoma) occurring in the ®eld of irradiation of patients treated for bilateral retinoblastoma have been studied. These patients were predisposed to develop radiation-induced tumors 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 RB1 allele was lost with the corresponding chromosome 13, whereas the germ line mutated allele was retained. The two alleles of TP53 were inactivated, one by deletion of the short arm of chromosome 17, the other by mutation. As compared with non-radiationinduced tumors, the observed 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 radiation-induced chromosome instability than a direct eect of ionizing radiation. Oncogene (2001) 20, 8092 ± 8099.

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

“…Highdose radiation induces multiple double-strand breaks in chromosomes and breakage-fusion-bridge cycles, resulting in a gain of oncogenes, loss of tumor suppressor genes, and activation of DNA damage responses. 27 Telomerase expression can be activated during this process. 28 Therefore, ATRX loss and alternative lengthening of telomeres might not be needed for immortalization of radiation-associated tumors.…”

Radiation-induced genomic instability and bystander effects: inter-related nontargeted effects of exposure to ionizing radiation

“…Although there is evidence of genetic instability in radiogenic tumours, it may not be possible to distinguish between instability that may be a consequence of malignant changes in cells and instability that might reflect the delayed effects of exposure to ionizing radiation, that is, is such instability a cause or a consequence of malignancy. However, it has been suggested that instability-generated p53 point mutations are important in the genesis of thorotrastinduced tumours (Iwamoto et al, 1999;Ishikawa et al, 2001) and that the high level of genome instability in secondary solid tumours developing after radiotherapy of bilateral retinoblastoma, including uncommon p53 mutations, is attributable to instability rather than a direct effect of ionizing radiation (Lefevre et al, 2001). Clearly, any process that increases the frequency with which genetic changes arise will increase the probability of relevant genetic changes in potential target cells and the correlation between the genotype-dependent expression of chromosomal instability in mouse mammary epithelial and susceptibility to mammary tumours supports a role for radiation-induced instability in the process of tumorigenesis (Ponnaiya et al, 1997;Ullrich and Ponnaiya, 1998).…”

Second cancers after radiotherapy: any evidence for radiation-induced genomic instability?

“…Several studies were performed on sarcomas that developed within tissue irradiated for a previous malignancy and were diagnosed many years after treatment ( Table 2). Most of the sarcomas occurred after varying types of first tumors, except for one study among patients treated for retinoblastoma (Lefevre et al, 2001). Among the second tumor studies that Shoshan, 2000 (Lefevre et al, 2001).…”

“…Most of the sarcomas occurred after varying types of first tumors, except for one study among patients treated for retinoblastoma (Lefevre et al, 2001). Among the second tumor studies that Shoshan, 2000 (Lefevre et al, 2001). In the study by Gafanovich et al (1999), all the tumors showed evidence of MIN.…”

“…Very few studies included patients treated only with radiation (Shoshan et al, 2000;Lefevre et al, 2001) and it is virtually impossible to divorce radiation-related effects from chemotherapy (CT)-related effects (see Table 2, comments column). Karyotypic patterns unique to radiation-associated second tumors compared to de novo tumors (BenYehuda et al, 1996;Mertens et al, 2000;Shoshan et al, 2000;Lefevre et al, 2001;Tarkkanen et al, 2001) suggest that events in radiation-induced carcinogenesis do differ from spontaneous cancers. Unfortunately, more specific details related to the hypothesized order of these events are difficult to evaluate, even when taking advantage of karyotypic clues (Chauveinc et al, 1999).…”