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Carcinogenesis Advance Access originally published online on February 20, 2006
Carcinogenesis 2006 27(6):1266-1272; doi:10.1093/carcin/bgi356
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Specific TP53 mutation pattern in radiation-induced sarcomas

Nathalie Gonin-Laurent, Anne Gibaud, Mathilde Huygue, Sandrine H. Lefèvre, Morgane Le Bras 1, Laurent Chauveinc 2, Xavier Sastre-Garau 3, François Doz 4, Livia Lumbroso 5, Sylvie Chevillard 6 and Bernard Malfoy *

UMR7147 Institut Curie-CNRS-UPMC, CEA LRC38, 1 Génotoxicologie des Tumeurs, 2 Service de Radiothérapie, 3 Service de Pathologie, 4 Departement de Pédiatrie, 5 Service d'Ophtalmologie, Institut Curie, Paris and 6 CEA, DSV DRR, Fontenay-aux-Roses, France

* To whom correspondence should be addressed at: Institut Curie-CNRS, UMR7147. 26, rue d'Ulm, 75248 Paris Cedex 05, France. Tel: +33 1 42346685, Fax: +33 1 42346674; Email: bernard.malfoy{at}curie.fr


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
The mutagenic properties of ionizing radiation are well known, but the presence of specific mutations in human radiation-induced tumours is not established. We have studied a series of 36 secondary sarcomas arising in the irradiation field of a primary tumour following radiotherapy. The allelic status and the presence of mutations of the TP53 gene were investigated. The mutation pattern was compared with data from sporadic sarcomas recorded in the IARC TP53 somatic mutations database. A high proportion (58%) of the radiation-induced sarcomas exhibited a somatic inactivating mutation for one allele of TP53, systematically associated with a loss of the other allele. The high frequency (52%) of short deletions observed in the mutation pattern of radiation-induced sarcomas may be related to the induction of DNA breaks by ionizing radiation. The lack of hyper-reactivity of CpG dinucleotides and the presence of recurrent sites of mutation at codons 135 and 237 seem also to be specific for radiation tumorigenesis.

Abbreviations: LOH, loss of heterozygocity


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
It is now well established that cancer can occur after ionizing radiation exposure to accidental, occupational or medical sources. Extensive epidemiological studies have been performed to determine the nature of the radiation-induced cancers and the risk run by irradiated individuals (1–5). Ionizing radiation effects have also been investigated in numerous experimental systems (6). While DNA damage in the genome has been extensively described, the nature of the subsequent mutations in radiation-induced tumours remains largely unknown. The molecular characterization of human radiation-induced tumours is limited by their rare occurrence. In addition, the lack of pathological specificities increases the difficulty of confidently establishing the radiation-induced origin of the tumours. Nevertheless, in case of sarcomas occurring in the irradiation field after radiotherapy for a primary neoplasm, stringent criteria have allowed the radiation-induced aetiology to be established with a high level of confidence (7,8). In adults, radiation-induced sarcomas have been observed after radiotherapy for breast, prostate or cervical cancer but remain rare (8–10). In contrast, they are among the most frequent secondary cancers for patients treated with radiotherapy during childhood (11). The risk of radiation-induced sarcomas is especially high for predisposed patients treated for bilateral retinoblastoma, a rare childhood cancer, linked to a germline mutation in the tumour suppressor gene RB1 (12–14).

The tumour suppressor gene TP53 is recurrently mutated in all kinds of human cancers and has been used to investigate the relationships between a given mutagen and the type of mutations induced in the genome (15). In a few cancers, these relationships are well documented: for example, tobacco smoke compounds induce a high rate of G>T transversions at codons 157, 158, 248 and 273 in lung cancers, aflatoxin B1 leads to a predominance of G>T transversions at codon 249 in hepatocellular carcinomas and, in non-melanoma skin cancers, CC to TT double transitions are associated with UV exposure (16–18). In human radiation-induced tumours, published data are not informative regarding the presence of a signature for the ionizing radiation effects in the TP53 mutation spectrum (19–24). In contrast, in murine radiation-induced tumours, a high percentage of deletions was found in the Trp53 sequence (25,26).

The aim of our work was to investigate the presence of a signature for ionizing radiation in sarcomas developing in the field of irradiation after radiotherapy. A specific mutation pattern was identified in TP53, characterized by a high level of deletions, the lack of hyper-reactivity of the CpG dinucleotides and the presence of recurrent mutation sites at codons 135 and 237.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Biological material
Thirty-six secondary tumours developing in the field of irradiation of a primary cancer were collected at the Institut Curie (Table I). Radiotherapy was administrated by photon or by electron beam therapy. Informed consent from patients or parents was obtained for all cases. These tumours were diagnosed as radiation-induced according to the Cahan criteria (7). In the series, the two preponderant primary cancers were breast cancers (17 cases) and bilateral retinoblastoma (12 cases) corresponding to the core recruitment of the Institut Curie hospital. All patients treated for a bilateral retinoblastoma were predisposed to radiation-induced tumours because of the presence of a germline mutation on RB1 [(27) and unpublished data]. No Li-Fraumeni Syndrome was diagnosed for the patients of the series. Patients treated for retinoblastoma were irradiated in their early childhood (range 4–24 months, mean 10.6 months, median 11.5 months), whereas all other radiotherapies were performed during adulthood (range 19–74 years, mean 47.2 years, median 49 years) (Table I). The latency periods of tumour occurrence ranged from 7 to 36 years with a mean of 17.5 years and a median of 19 years. In 26 cases, peripheral lymphocytes were available. Fourteen tumours were grown as xenografts in athymic mice and recovered for molecular analysis at passage 1 or 2 (Table I). Animal care and housing were in accordance with institutional guidelines as stipulated by the Ministère de l'Agriculture, Direction de la Santé et de la Protection animale. DNA and RNA were extracted from frozen samples using Qiagen kits (Qiagen Courtaboeuf, France). Reverse transcription was performed using Superscript II (Invitrogen, Cergy-Pontoise, France) and oligo(dT)12-18 (Roche, Meylan, France).


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  		Table I. Radiation-induced sarcomas characterization

 
Allelic status
Loss of heterozygosity (LOH) at the TP53 locus was analysed after PCR amplification of microsatellite DNA in standard conditions (28). DNA fragments were run on an ABI PRISM 3100 Genetic Analyser (Applied Biosystems Courtaboeuf, France). Allelic size and intensities were determined using the Genescan analysis program. The list of the analysed microsatellites and detailed data are available on request.

TP53 mutation analysis
Overlapping PCR fragments covering the full-length cDNAs were sequenced in both directions by the dideoxyribonucleotide method using the BigDye Cycle Sequencing V3.1 or 1.1 Ready Reaction kit and an ABI PRISM 3100 Genetic Analyser (Applied Biosystem). In some cases, exons and parts of neighbouring introns of genomic DNA were sequenced. When normal DNA was available, it was checked that sequence changes were not constitutive. Primer sequences are available on request. The IARC TP53 somatic mutations database R10 (29) was used for comparison of mutation rates and spectra. Data from a series of sporadic sarcomas of the same histological subtypes as found in our radiation-induced series (chondrosarcomas, hemangiosarcomas, leiomyosarcomas, liposarcomas, malignant fibrous histiocytomas, malignant peripheral nerve sheath tumours, osteosarcomas and sarcomas) were extracted from the IARC database to constitute the sporadic sarcoma set used for comparison.

DNA transient transfection
Saos-2 cell line (p53-null human osteosarcoma) was obtained from the American Type Culture Collection and maintained in DMEM medium supplemented with 10% fetal calf serum. The cDNAs of wild-type p53 and four of our mutants (C135F, V216E, M237I and E258K) were cloned into pcDNA3.1(–) expression plasmid (Invitrogen, Cergy-pontoise, France). All expression plasmids were checked by sequencing and by western blot after in vitro transcription–translation assay (TNT T7 Quick Coupled Transcription/Translation System, Promega). Expression in Saos-2 cells was studied by western blot analysis after transfection of 5 µg of each expression plasmid (30). Reporter plasmids pGL3-Mdm2-luc, pGL2-Bax-luc, WWP-WAF1-luc and PBR322pl-PIG3-luc were used. For the transactivation assay, Saos-2 cells were plated in 24-well plates (105 cells/well). After 24 h, cells were co-transfected using Lipofectamine 2000 (Invitrogen, Cergy-Pontoise, France) with 100 ng of reporter plasmid, 5 ng of expression plasmid and 395 ng of empty vector. Twenty-four hours later, cells were harvested using the Cell Culture Lysis Buffer (Promega, Charbonnieres-les-Bains, France). Cell extracts were normalized on the basis of total protein concentration. The luciferase activity was measured in duplicate using a luminometer (LUMAT LB9507, Berthold) in Luciferase assay System Buffer (Promega). Each experiment was repeated four times.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
The status of TP53 was characterized for 36 radiation-induced sarcomas, including 29 new cases in addition to 7 previously published cases (27) (Table I). Sequencing revealed somatic mutations in TP53 gene for 21 of the 36 sarcomas (58%) (Table II). No mutation was observed in DNA from peripheral lymphocytes. In patients with predisposition to radiation-induced tumours linked to a germline inactivation of one allele of RB1, 100% (12 out of 12) of the tumours had a somatic mutation in TP53. In sarcomas developing in patients without known predisposition, the rate of mutation was of 37.5% (9 out of 24). By comparison, the prevalence of TP53 mutations in the sporadic sarcomas set extracted from the IARC database (see Material and methods) was 16.8%. This value was significantly lower than that in our series of radiation-induced sarcomas for patients with or without known predisposition (Student's t-test, P < 0.001). When normal lymphocytes DNA was available (27 of the 36 cases, including 16 of the 21 mutated cases), allelic status analysis was performed using microsatellite sequences distributed along the whole chromosome 17. An LOH at the TP53 locus (17p13.1) was observed in 75% of the cases. The lost region covered at least a large part or the totality of the short arm chromosome, and in 30% of the cases the whole chromosome was lost [(27) and not shown]. An LOH for TP53 was found in all analysable cases with somatic mutation (Table II). In the five remaining mutated cases, not analysable for LOH because of the lack of normal lymphocyte DNA, sequencing showed homozygous mutations, suggesting the deletion of a part or of the whole second allele. Therefore, in each tumour harbouring an inactivating somatic mutation of an TP53 allele, the other allele was inactivated by loss.


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  		Table II. Mutations in the TP53 gene of the radiation-induced sarcomas analysed at DNA and mRNA levels

 
The 21 TP53 mutations consisted of 8 base substitutions (38%), 11 deletions (52%) and 2 insertions (9.5%), all being distributed between exons 4 and 9 (Table II and III).These percentages were similar in sarcomas from patients with predisposition and in sarcomas from our whole series (Table III). Mutations were compared with TP53 somatic mutations observed in the sporadic sarcoma set extracted from the IARC database. A significant excess of deletions was observed in radiation-induced tumours: the rate of deletions was about five times higher in radiation-induced than in sporadic sarcomas (Table III, {chi}2 = 32.84, P < 0.0001). In parallel, the percentage of base substitutions was halved in radiation-induced sarcomas as compared with sporadic sarcomas (Table III). These differences in mutation pattern were also observed when all tumours recorded in the database were compared with the radiation-induced sarcomas (Table III).


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  		Table III. TP53 mutation pattern in radiation-induced sarcomas

 
Ten of the 11 deletions ranged from 1 to 16 bp (1 bp, x3; 4bp, x2; 2, 3, 7, 12 and 16 bp, 1 case of each); the 11th deletion was of 134 bp (Table I). No complex mutation, associating deletion and insertion, was observed. Among the 11 deletions, 8 were frameshifts (cases 2, 3, 7, 11, 13, 18, 20 and 21), while 3 were inframe (cases 12, 10 and 17). Because of the limited number of deletions of each size in our series, no statistical comparison could be performed with the size of the sporadic deletions recorded in the IARC database. Two insertions of 2 bp, at codons 331 (case 9) and 126 (case 16), correspond to the duplication of the dinucleotide localized in 5'. These insertions induced a frameshift resulting in the formation of a stop codon at position 370 and 170, respectively.

Seven of the 8 base substitutions were missense mutations and resulted in a single amino acid change. The last case (case 8) was a nonsense mutation, leading to the formation of a stop codon downstream in the sequence (Table II). The rates of mutation at A : T and G : C base pairs, respectively 25 and 75%, were similar in radiation-induced and sporadic tumours. Two mutations were observed at codon 135, including one nonsense (TGC>TGA, case 8) and one missense mutation (TGC>TTC, case 4). Three missense mutations occurred at codon 237 [transition ATG>ATA (cases 15 and 19) and transversion ATG>ATC (case 1), all mutations leading to a Met to Ileu change] (Figure 1). In sporadic tumours, the G : C > A : T transitions account for 51.4% of base substitutions with 28.7% localized at CpG dinucleotides (Table IV). In radiation-induced sarcomas, no mutation was observed at CpG sites. Nevertheless, the rates of G : C > A : T transitions were similar in radiation-induced and in sporadic tumours, the absence of mutation at CpG in radiation-induced tumours being compensated by an increased rate of mutations at other G : C bases pairs (Table IV). No other specificity could be distinguished in the substitution pattern of radiation-induced sarcomas.


Figure 1
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  		Fig. 1. Adjacent sequences of the recurrent mutations in radiation-induced sarcomas in the viciny of codons 135 and 237. Star: base substitutions.

 

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  		Table IV. Comparaison between types of base substitution observed in radiation-induced sarcomas, and in the sporadic sarcomas and all tumours recorded in the IARC database

 
In this series of sarcomas, 11 mutations led to C-ter truncated p53 (10 deletions or insertions containing a non-p53 sequence due to a frameshift in cases 2, 3, 7, 9, 11, 13, 16, 18, 20 and 21, and a nonsense mutation in case 8). These proteins are likely to be functionally defective since the wild-type sequence is stopped before or in the core domain responsible for the sequence-specific DNA binding (31). For inframe deletions (cases 10, 12 and 17), it can be assumed that the loss of amino acids in the p53 core domain results in protein inactivation. The consequences of the missense mutations (7 cases, 5 different mutations) on protein functions are more questionable since it is currently established that all amino acid changes are not functionally equivalent (32,33). Functional properties have been previously investigated for some of the mutants found in this series. In a study using a yeast system, E258K (case 6) and F134I mutants were shown to be defective for promoter transactivation of three main p53 target genes: p21, Bax and PIG3 (33) and it can be assumed that the F134L mutant (case 14) is also inactive because of the structure similarities of Leu and Ileu. In order to better understand the p53 status in the analysed sarcomas, we studied the transactivation properties of three uncharacterized mutants: C135F and M237I, mutated two and three times respectively, and V216E (case 5). E258K was included as control. Transactivation properties were analysed in Saos-2 cells after co-transfection of expression plasmids containing either wild-type p53 or one of the mutated cDNA with reporter plasmids containing the luciferase gene under the control of p21waf1/Cip1, Mdm2, Bax or PIG3 promoters. All mutant proteins showed a similar strongly attenuated transcriptional activation of the various promoters compared with wild-type p53 (Figure 2). Thus, the 8 base substitutions observed in the radiation-induced sarcomas gave rise to proteins having lost major transactivation properties of the wild-type form.


Figure 2
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  		Fig. 2. Transactivation properties of p53 mutants. Luciferase activity of reporter plasmids for Mdm2, Waf1, Bax and PIG3 promotors in Saos-2 cells. Cells were transiently transfected with expression plasmids containing the cDNA of wild-type p53 or of mutants C135F, V216E, M237I or E258K. pcDNA3.1(–): empty expression vector.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
In our series of radiation-induced sarcomas, the prevalence of TP53 somatic mutations (58%) was among the highest values recorded in the IARC database. This prevalence was significantly higher than that in sporadic sarcomas (16.8%). Furthermore, the mutations that we observed were inactivating and systematically associated with the loss of the other allele. All LOH were due to the loss of a large fragment or of the whole chromosome, probably indicating a more general chromosome instability as previously described (27). All these data indicate that the biallelic inactivation of the TP53 pathway play a major role in the radiation tumorigenesis of sarcomas. However, other target genes are yet to be found since about 40% of these sarcomas expressed wild-type TP53.

The major characteristic of the TP53 mutations in radiation-induced sarcomas is the high rate of deletions (52% of the mutations) as compared with sporadic sarcomas (less than 10%) (P < 0.0001). The rate of deletion was not influenced by the presence of the RB1 predisposition, excluding a bias due to the genetic background of the individual (Table II). Only short deletions were observed in radiation-induced sarcomas [10 of 11 deletions were less than 17 bp (median 4 bp), while one was 134 bp]. Similar data were found in murine radiation-induced tumours where a high rate of short deletions was also observed: of a total of 22 Trp53 mutations described in the literature, at least 11 deletions were found and only one was longer than 100 bp (25,26). The formation of deletions is currently ascribed to the presence of DNA double-strand breaks. DNA breaks are a major consequence of ionizing radiation in cells (34). These breaks can be induced either directly by an energy deposit along the radiation track or indirectly during error-prone repair of damaged sites notably generated by radical oxygen species (35). The completion of break repair may give rise to the excision of a variable number of neighbouring bases depending on the damage and on the biological context (36,37). Among the various kinds of radiation-induced damage, the local multiply damaged sites, defined as multiple elemental radiation-induced lesions formed within 1–2 helical turns of DNA, are usually considered to be difficult to repair and then to possibly lead to the formation of double-strand breaks and deletions spreading over the cluster of damage (38,39). However, recent data show that repair processing of these lesions occurs sequentially, minimizing double-strand breaks and deletions formation (40,41). Thus, in radiation-induced tumours, the implication of these complex lesions in deletions formation could be low, in agreement with the finding that small deletions are mainly found. In conclusion, in human sarcomas and murine tumours, a high rate of short deletions in TP53 can be considered as specific of radiation induction.

The panel of base substitutions found in the TP53 gene differs between sporadic and radiation-induced sarcomas only by the absence, in the latter, of G : C > A : T transitions at CpG sites (Table IV). CpG are frequently involved in the formation of TP53 mutations in sporadic tumours since they represent 28.7% of base substitutions (42). The small number of analysed radiation-induced tumours prevents a rigorous statistical analysis. Nevertheless, experimental data are in favour of an under-representation of the CpG sites in the pattern of radiation-induced mutations. Cytosines in CpG dinucleotides are generally methylated (5-methyl-cytosine, meC) (43). The hypermutability of meCpG has been explained either by spontaneous deamination of the meC (44), a mechanism independent of the aetiology, or by the high reactivity of the guanine in 5' of a meC to bulky chemical carcinogens and the poor repair efficiency of the formed DNA adducts (45). One hypothesis to explain the low level of mutation in CpG nucleotides in our series of tumours is that, contrary to bulky chemical compounds, the numerous reactive oxygen species, which are randomly generated within the nucleus during radiation exposure, are too small to preferentially react with the particular structure of the meCpG dinucleotides. No other specificity was found regarding the base substitution pattern. However, it can be noticed that the G : C > T : A transversions, considered as the signature of 8-oxo-guanine formation after irradiation (46), were not over-represented in radiation-induced sarcomas, indicating their possible efficient repair in the mesenchymal tissues giving rise to sarcomas. Thus, the lack of mutation at CpG dinucleotides is the only characteristic found in the spectrum of base substitutions in radiation-induced sarcomas.

In sporadic tumours, five TP53 ‘hot spot’ codons (codons 175, 248, 273, 282 and 245) have been described, which account for about 30% of the TP53 missense mutations recorded in the IARC somatic mutation database and are detectable in almost all types of cancers (42,47). None of these hot spots was mutated in the radiation-induced sarcomas, a fact which could be explained by the presence of a CpG site in each of these codons. Six of the 8 observed base substitutions were clustered at codons 134–135 and 237 (Figure 1). Thus, in radiation-induced sarcomas, base substitutions seem to show specificities regarding the codon position even if the small number of analysed mutations prevents a robust conclusion. These base substitutions have been selected during tumour formation because they localized to major TP53 functional regions, that is, in the DNA binding region for Phe134-Cys135 or in the Zn-pocket for Met237 (31) and lead to non-functional proteins. The recurrence of these base substitutions could originate from a preferential reactivity of the DNA sequence toward the mutagen. However, with our current knowledge, the mutation sites do not display specific sequence features that could explain their preferential reactivity toward direct or indirect ionizing radiation effects. Presently, for ionizing radiation as well as for tobacco smoke compounds and aflatoxin B1 (16,17), the rationale linking the mutagen and the preferential reactivity of some TP53 sequences is not yet understood.

In conclusion, the high frequency of deletions observed in the radiation-induced sarcomas is in good agreement with some well-known effects of ionizing radiation such as DNA strand breaks. Other characteristics, such as the lack of hyper-reactivity of CpG and the presence of recurrent sites of mutation, seem to be specific for radiation tumorigenesis but need further investigations. The high frequency of deletions in the TP53 gene of sarcomas does not alone constitute a signature for radiation-induced mutagenesis in human tumours. Mutation studies including other tumour types and target genes will be necessary to get an overall picture of this signature. In addition, other marks of the ionizing radiation in tumours could be researched using whole genome approaches at DNA, RNA and protein levels.


   Acknowledgments
 
We thank Dr R.Dendale and A.Mazal for tumour samples and Dr T.Soussi for the gift of the expression plasmids. N.G.-L. was a fellow of the Ministère de l'Education Nationale et de la Recherche and of the Association pour la Recherche contre le Cancer (ARC). Grant support: Institut Curie-CEA ‘Programme Incitatif et Coopératif Instabilité génétique et radiorésistance des tumeurs’; Institut Curie "Programme Incitatif et Coopératif Rétinoblastome"; Electricité de France (RB2005-10).

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

  1. Wakeford,R. (2004) The cancer epidemiology of radiation. Oncogene, 23, 6404–6428.[CrossRef][Web of Science][Medline]
  2. Thompson,D.E., Mabuchi,K., Ron,E. et al. (1994) Cancer incidence in atomic bomb survivors. Part II: Solid tumors, 1958–1987. Radiat. Res., 137, S17–S67.[Web of Science][Medline]
  3. Preston,D.L., Kusumi,S., Tomonaga,M. et al. (1994) Cancer incidence in atomic bomb survivors. Part III. Leukemia, lymphoma and multiple myeloma, 1950–1987. Radiat. Res., 137, S68–S97.[Web of Science][Medline]
  4. Moysich,K.B., Menezes,R.J. and Michalek,A.M. (2002) Chernobyl-related ionising radiation exposure and cancer risk: an epidemiological review. Lancet Oncol., 3, 269–279.[CrossRef][Web of Science][Medline]
  5. Pizzarello,D.J., Roses,D.F., Newall,J. and Barish,R.J. (1984) The carcinogenicity of radiation therapy. Surg. Gynecol. Obstet., 159, 189–200.[Web of Science][Medline]
  6. Little,J.B. (2003) Genomic instability and bystander effects: a historical perspective. Oncogene, 22, 6978–6987.[CrossRef][Web of Science][Medline]
  7. Cahan,W.G., Woodard,H.Q., Higinbotham,N.L., Stewart,F.W. and Coley,B.L. (1998) Sarcoma arising in irradiated bone: report of eleven cases 1948. Cancer, 82, 8–34.[CrossRef][Web of Science][Medline]
  8. Mark,R.J., Poen,J., Tran,L.M., Fu,Y.S., Selch,M.T. and Parker,R.G. (1994) Postirradiation sarcomas. A single-institution study and review of the literature. Cancer, 73, 2653–2662.[CrossRef][Web of Science][Medline]
  9. Travis,L.B. (2002) Therapy-associated solid tumors. Acta Oncol., 41, 323–333.[CrossRef][Web of Science][Medline]
  10. Robinson,E., Neugut,A.I. and Wylie,P. (1988) Clinical aspects of postirradiation sarcomas. J. Natl Cancer Inst., 80, 233–240.[Abstract/Free Full Text]
  11. Menu-Branthomme,A., Rubino,C., Shamsaldin,A. et al. (2004) Radiation dose, chemotherapy and risk of soft tissue sarcoma after solid tumours during childhood. Int. J. Cancer, 110, 87–93.[CrossRef][Web of Science][Medline]
  12. Lohmann,D.R. and Gallie,B.L. (2004) Retinoblastoma: revisiting the model prototype of inherited cancer. Am. J. Med. Genet. C Semin. Med. Genet., 129, 23–28.[Medline]
  13. Kleinerman,R.A., Tucker,M.A., Tarone,R.E., Abramson,D.H., Seddon,J.M., Stovall,M., Li,F.P. and Fraumeni,J.F.,Jr (2005) Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J. Clin. Oncol., 23, 2272–2279.[Abstract/Free Full Text]
  14. Aerts,I., Pacquement,H., Doz,F. et al. (2004) Outcome of second malignancies after retinoblastoma: a retrospective analysis of 25 patients treated at the Institut Curie. Eur. J. Cancer, 40, 1522–1529.[CrossRef][Web of Science][Medline]
  15. Vogelstein,B., Lane,D. and Levine,A.J. (2000) Surfing the p53 network. Nature, 408, 307–310.[CrossRef][Medline]
  16. Toyooka,S., Tsuda,T. and Gazdar,A.F. (2003) The TP53 gene, tobacco exposure, and lung cancer. Hum. Mutat., 21, 229–239.[CrossRef][Web of Science][Medline]
  17. Staib,F., Hussain,S.P., Hofseth,L.J., Wang,X.W. and Harris,C.C. (2003) TP53 and liver carcinogenesis. Hum. Mutat., 21, 201–216.[CrossRef][Web of Science][Medline]
  18. Giglia-Mari,G. and Sarasin,A. (2003) TP53 mutations in human skin cancers. Hum. Mutat., 21, 217–228.[CrossRef][Web of Science][Medline]
  19. Brat,D.J., James,C.D., Jedlicka,A.E., Connolly,D.C., Chang,E., Castellani,R.J., Schmid,M., Schiller,M., Carson,D.A. and Burger,P.C. (1999) Molecular genetic alterations in radiation-induced astrocytomas. Am. J. Pathol., 154, 1431–1438.[Abstract/Free Full Text]
  20. Joachim,T., Ram,Z., Rappaport,Z.H., Simon,M., Schramm,J., Wiestler,O.D. and von Deimling,A. (2001) Comparative analysis of the NF2, TP53, PTEN, KRAS, NRAS and HRAS genes in sporadic and radiation-induced human meningiomas. Int. J. Cancer, 94, 218–221.[CrossRef][Web of Science][Medline]
  21. Nakanishi,H., Tomita,Y., Myoui,A., Yoshikawa,H., Sakai,K., Kato,Y., Ochi,T. and Aozasa,K. (1998) Mutation of the p53 gene in postradiation sarcoma. Lab Invest., 78, 727–733.[Web of Science][Medline]
  22. Gafanovich,A., Ramu,N., Krichevsky,S., Pe'er,J., Amir,G. and Ben-Yehuda,D. (1999) Microsatellite instability and p53 mutations in pediatric secondary malignant neoplasms. Cancer Epidemiol. Biomarkers Prev., 85, 504–510.
  23. Brachman,D.G., Hallahan,D.E., Beckett,M.A., Yandell,D.W. and Weichselbaum,R.R. (1991) p53 gene mutations and abnormal retinoblastoma protein in radiation-induced human sarcomas. Cancer Res., 51, 6393–6396.[Abstract/Free Full Text]
  24. Tada,M., Sawamura,Y., Abe,H. and Iggo,R. (1997) Homozygous p53 gene mutation in a radiation-induced glioblastoma 10 years after treatment for an intracranial germ cell tumor: case report. Neurosurgery, 40, 393–396.[CrossRef][Web of Science][Medline]
  25. Gupta,A., Andrews,K.L., McDaniel,K.M., Nagle,R.B. and Bowden,G.T. (1999) Experimental induction of rhabdomyosarcoma in mice with fractionated doses of beta-irradiation. J. Cancer Res. Clin. Oncol., 125, 257–267.[CrossRef][Web of Science][Medline]
  26. Ootsuyama,A., Makino,H., Nagao,M., Ochiai,A., Yamauchi,Y. and Tanooka,H. (1994) Frequent p53 mutation in mouse tumors induced by repeated beta-irradiation. Mol. Carcinog., 11, 236–242.[Web of Science][Medline]
  27. Lefevre,S.H., Vogt,N., Dutrillaux,A.M., Chauveinc,L., Stoppa-Lyonnet,D., Doz,F., Desjardins,L., Dutrillaux,B., Chevillard,S. and Malfoy,B. (2001) Genome instability in secondary solid tumors developing after radiotherapy of bilateral retinoblastoma. Oncogene, 20, 8092–8099.[CrossRef][Web of Science][Medline]
  28. Vogt,N., Lefevre,S.H., Apiou,F., Dutrillaux,A.M., Cor,A., Leuraud,P., Poupon,M.F., Dutrillaux,B., Debatisse,M. and Malfoy,B. (2004) Molecular structure of double-minute chromosomes bearing amplified copies of the epidermal growth factor receptor gene in gliomas. Proc. Natl Acad. Sci. USA, 101, 11368–11373.[Abstract/Free Full Text]
  29. Olivier,M., Eeles,R., Hollstein,M., Khan,M.A., Harris,C.C. and Hainaut,P. (2002) The IARC TP53 database: new online mutation analysis and recommendations to users. Hum. Mutat., 19, 607–614.[CrossRef][Web of Science][Medline]
  30. Ryan,K.M. and Vousden,K.H. (1998) Characterization of structural p53 mutants which show selective defects in apoptosis but not cell cycle arrest. Mol. Cell Biol., 18, 3692–3698.[Abstract/Free Full Text]
  31. Cho,Y., Gorina,S., Jeffrey,P.D. and Pavletich,N.P. (1994) Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science, 265, 346–355.[Abstract/Free Full Text]
  32. Kato,S., Han,S.Y., Liu,W., Otsuka,K., Shibata,H., Kanamaru,R. and Ishioka,C. (2003) Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc. Natl Acad. Sci. USA, 100, 8424–8429.[Abstract/Free Full Text]
  33. Campomenosi,P., Monti,P., Aprile,A. et al. (2001) p53 mutants can often transactivate promoters containing a p21 but not Bax or PIG3 responsive elements. Oncogene, 20, 3573–3579.[CrossRef][Web of Science][Medline]
  34. Little,J.B. (2000) Radiation carcinogenesis. Carcinogenesis, 21, 397–404.[Abstract/Free Full Text]
  35. Hoeijmakers,J.H. (2001) Genome maintenance mechanisms for preventing cancer. Nature, 411, 366–374.[CrossRef][Medline]
  36. Lomax,M.E., Cunniffe,S. and O'Neill,P. (2004) Efficiency of repair of an abasic site within DNA clustered damage sites by mammalian cell nuclear extracts. Biochemistry, 43, 11017–11026.[CrossRef][Medline]
  37. Pfeiffer,P., Goedecke,W., Kuhfittig-Kulle,S. and Obe,G. (2004) Pathways of DNA double-strand break repair and their impact on the prevention and formation of chromosomal aberrations. Cytogenet. Genome Res., 104, 7–13.[CrossRef][Web of Science][Medline]
  38. Ward,J. and Skreta,M. (1988) Multi-centre general practitioner comparative study of controlled-release (‘Valrelease’) and conventional (‘Valium’) forms of diazepam in patients suffering from anxiety. Curr. Med. Res. Opin., 11, 87–92.[Web of Science][Medline]
  39. Gulston,M., Fulford,J., Jenner,T., de Lara,C. and O'Neill,P. (2002) Clustered DNA damage induced by gamma radiation in human fibroblasts (HF19), hamster (V79-4) cells and plasmid DNA is revealed as Fpg and Nth sensitive sites. Nucleic Acids Res., 30, 3464–3472.[Abstract/Free Full Text]
  40. Murray,D., Allalunis-Turner,M. and Weinfeld,M. (2005) VIIIth International Workshop on Radiation Damage to DNA. Int. J. Radiat. Biol., 81, 327–337.[CrossRef][Medline]
  41. Eot-Houllier,G., Eon-Marchais,S., Gasparutto,D. and Sage,E. (2005) Processing of a complex multiply damaged DNA site by human cell extracts and purified repair proteins. Nucleic Acids Res., 33, 260–271.[Abstract/Free Full Text]
  42. Guimaraes,D.P. and Hainaut,P. (2002) TP53: a key gene in human cancer. Biochimie, 84, 83–93.[Medline]
  43. Bird,A. (2002) DNA methylation patterns and epigenetic memory. Genes Dev., 16, 6–21.[Free Full Text]
  44. Shen,J.C., Rideout,W.M.III and Jones,P.A. (1994) The rate of hydrolytic deamination of 5-methylcytosine in double-stranded DNA. Nucleic Acids Res., 22, 972–976.[Abstract/Free Full Text]
  45. Pfeifer,G.P. (2000) p53 mutational spectra and the role of methylated CpG sequences. Mutat Res., 450, 155–166.[Web of Science][Medline]
  46. Kasai,H., Chung,M.H., Yamamoto,F., Ohtsuka,E., Laval,J., Grollman,A.P. and Nishimura,S. (1993) Formation, inhibition of formation, and repair of oxidative 8-hydroxyguanine DNA damage. Basic Life Sci., 61, 257–262.[Medline]
  47. Olivier,M., Hussain,S.P., Caron de Fromentel,C., Hainaut,P. and Harris,C.C. (2004) TP53 mutation spectra and load: a tool for generating hypotheses on the etiology of cancer. IARC Sci. Publ., 247–270.
Received December 12, 2005; revised January 20, 2006; accepted January 23, 2006.


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