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Genome Instability in Secondary Solid Tumors Developing After Radiotherapy of Bilateral Retinoblastoma

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Genome Instability in Secondary Solid Tumors Developing After Radiotherapy of Bilateral Retinoblastoma Oncogene (2001) 20, 8092 ± 8099 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc Genome instability in secondary solid tumors developing after radiotherapy of bilateral retinoblastoma Sandrine-He leÁ ne LefeÁ vre1, Nicolas Vogt1, Anne-Marie Dutrillaux1, Laurent Chauveinc2, Dominique Stoppa-Lyonnet3, FrancËois Doz4, Laurence Desjardins5, Bernard Dutrillaux1,6, Sylvie Chevillard6 and Bernard Malfoy*,1 1Institut Curie ± CNRS UMR 147, 26 rue d'Ulm 75248 Paris Cedex 05, France; 2Institut Curie, Service de RadiotheÂrapie, 26 rue d'Ulm 75248 Paris Cedex 05, France; 3Institut Curie, Service de GeÂneÂtique Oncologique, 26 rue d'Ulm 75248 Paris Cedex 05, France; 4Institut Curie, Service de PeÂdiatrie, 26 rue d'Ulm 75248 Paris Cedex 05, France; 5Institut Curie, Service d'Ophtalmologie, 26 rue d'Ulm 75248 Paris Cedex 05, France; 6CEA, DSV DRR, 60 avenue du GeÂneÂral Leclerc 92265 Fontenay-aux-Roses, France Genome alterations of seven secondary tumors (®ve these cancers and the diculty in collecting a series of osteosarcomas, one malignant peripheral sheath nerve cases in clearly de®ned context. tumor, one leiomyosarcoma) occurring in the ®eld of It is well established that therapeutic irradiation can irradiation of patients treated for bilateral retinoblasto- induce secondary malignancies within or at the margin ma have been studied. These patients were predisposed to of the radiation ®eld after a long latent period. These develop radiation-induced tumors because of the presence tumors have dierent histology from the primary of a germ line mutation in the retinoblastoma gene lesions, with sarcomas being common (Robinson et (RB1). Tumor cells were characterized by a high al., 1988). Well documented data are available on chromosome instability whereas microsatellites and radiation-induced thyroid tumors developing after minisatellites were found to be stable. In all tumors, radiotherapy or accidental irradiation. A key role of the normal RB1 allele was lost with the corresponding the RET protooncogene was demonstrated in radia- chromosome 13, whereas the germ line mutated allele tion-induced as well as in spontaneous thyroid tumors, was retained. The two alleles of TP53 were inactivated, but both the frequency and the speci®city of RET one by deletion of the short arm of chromosome 17, the rearrangements seemed to be higher in radiation- other by mutation. As compared with non-radiation- induced tumors (Bongarzone et al., 1997; Bounacer et induced tumors, the observed panel of TP53 mutations al., 1997; Klugbauer et al., 1995; Nikiforov et al., 1997, was uncommon with sites not recurrently found otherwise 1999). Data is also available for other cancers and a high rate of deletions (3/7). In these predisposed developing after radiotherapy. Cytogenetic data in- patients, the loss of the single normal allele of RB1 is dicated that these radiation-induced cancers generally rather due to the radiation-induced chromosome in- had complex karyotypes with multiple deletions and stability than a direct eect of ionizing radiation. chromosome losses (Chauveinc et al., 1999; Mertens et Oncogene (2001) 20, 8092 ± 8099. al., 2000). This suggests that complex oncogenic processes are involved. The molecular analysis of two Keywords: ionizing radiation; secondary cancers; reti- series of radiation-induced tumors of the central noblastoma; chromosome instability; TP53; predisposi- nervous system has been published. No signi®cant tion dierence in the pattern of gene alterations was observed between radiation-induced and spontaneous astrocytomas (Brat et al., 1999). In contrast, for Introduction meningioma, it was concluded that radiation-induced forms displayed a distinct pattern of molecular genetic Despite extensive epidemiological studies and numer- alterations from that observed in spontaneous tumors ous case reports of ionizing radiation-induced human (Shoshan et al., 2000). De®nitive conclusions cannot be solid tumors, little data is available on the genetic drawn about secondary lung and breast cancers alterations present in these cancers. In particular, it is developing after radiotherapy for Hodgkin's disease. not currently known if speci®c pathways of cancer- In a series of lung cancers (De Benedetti et al., 1996), ogenesis are involved compared to spontaneous cancers radiation-induced characteristic mutations of TP53 of identical histological origin. Such studies are dicult gene were assumed to be present, whereas this was to carry out because of the heterogeneous origin of not con®rmed in more recent work (Behrens et al., 2000). In the latter study, an increase of microsatellite instability was noticed, as compared with sporadic cases, in therapy-related tumors post-Hodgkin's dis- *Correspondence: B Malfoy; E-mail: [email protected] Received 5 July 2001; revised 17 September 2001; accepted 1 ease. However, the role of smoking in pulmonary October 2001 neoplasia and the recurrent combination of chemother- Genome instability in radiation-induced tumors S-H LefeÁvre et al 8093 apy and radiotherapy complicates the interpretation of Radiotherapy was administered by photon or by these data. electron. The total radiation dose was 45 Gy. After a The paucity of available data does not allow an latent period of 7 ± 22 years, a secondary tumor overview of the speci®c eects of ionizing radiation in developed in the radiation ®eld. These tumors (®ve the induction of human tumors. In particular, the role osteosarcomas, one malignant peripheral sheath nerve and the consequences of genetic predispositions are tumor, one leiomyosarcoma) were considered to be poorly understood. Data on second cancers occurring radiation-induced according to the Cahan criteria after childhood cancers indicate that genetic predis- (Cahan et al., 1948). positions may also predispose to radiotherapy-related cancers (de Vathaire et al., 1992). Patients carrying a RB1 and TP53 analysis germ line mutation of the retinoblastoma gene (RB1) usually develop bilateral retinoblastoma (Draper et al., LOH analyses were performed on the seven radiation- 1992; Vogel, 1979). In addition to having a high risk of induced tumors (Table 1), using microsatellite se- developing other spontaneous cancers, these patients quences distributed along the whole of chromosomes also have a high frequency of secondary tumors, in 13 and 17 where the RB1 and TP53 genes are localized particular, osteosarcomas, in the ®eld of irradiation. on bands 13q14.1 and 17p13.1, respectively. Twenty- Cumulative incidence of a secondary cancer at 50 years one loci were analysed on chromosome 13, including after diagnosis was 51% for patients with predisposi- three in the RB1 gene, and 16 on chromosome 17, tion and 5% for patients which developed non- including one in the TP53 gene (Figure 1). For the hereditary retinoblastoma (Wong et al., 1997). three intragenic loci of RB1, LOH were observed in all These radiation-induced cancers, developing in a informative microsatellites indicating the loss of one known genetic context, may provide an opportunity to allele in the seven studied cases. For cases 1, 3, 4, 5 and determine the pathways underlying the radiation- 7, data were in favor of a whole chromosome 13 loss. induced eects. We have studied seven secondary For case 2, several loci in the distal and proximal parts tumors developing in the ®eld of irradiation in patients of the chromosome 13 were not informative and it was treated for bilateral retinoblastoma. We show that, in not possible to establish the boundaries of the deletion. these tumors characterized by high chromosome Heterozygosity was maintained only in the distal part instability, the normal allele of RB1 was lost with of chromosome 13 for case 6, suggesting that a large deletion of the chromosome 13 (where the RB1 gene is deletion occurred. The TP53 intragenic microsatellite localized) and not by inactivation due to an intragenic indicated a LOH in all of the six informative cases. In mutation attributable to the ionizing radiation. More- case 1, the loss of one copy of TP53 could be expected over, the uncommon panel of mutations observed on since TP53 was surrounded by loci which underwent TP53 suggests the presence of mutational mechanisms LOH (see also below). For cases 2, 3 and 4, a whole which could be speci®c to, or particularly active in, chromosome 17 short arm was deleted. In contrast, for radiation-induced tumors. cases 1, 5 and 6, the proximal part of the arm was not lost. All chromosome 17 was lost in case 7, no LOH being observed in the six other cases on the 17q arm. Results Patients Seven children with bilateral retinoblastoma underwent therapeutic irradiation between 4 ± 14 months of age (Table 1). Case 2 was a low penetrancy familial case. No retinoblastoma was reported in other families. Table 1 Localizations and histological types of the radiation- induced tumors Case Delaya Localization Type Xenograftb 1 7 Maxilla bone right osteosarcoma 7 2 9 Maxilla bone left osteosarcoma 7 3 22 Orbital bone right Malignant peripheral + sheath nerve tumor 4 20 Nasal fossa left Leiomyosarcoma + 5 11 Temporal bone left osteosarcoma + 6 20 Nasal fossa left osteosarcoma 7 7 13 Maxilla bone right osteosarcoma 7 Figure 1 LOH pattern of radiation-induced tumors on chromo- aDelay in years between the irradiation of the retinoblastoma and the somes 13 (a) and 17 (b). Filled sequences: LOH; Empty sequence: development of the secondary tumor. bGrown (+) or not grown (7) no LOH; point: non-informative. In case 3, identical
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