Specific TP53 mutation pattern in radiation-induced sarcomas

Abstract

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.

RB1 and TP53 pathways in radiation-induced sarcomas

“…We recently analysed the presence of TP53 mutations in a series of sarcomas developing in the irradiation field in patients treated by radiotherapy. One-third of these patients have been treated for a bilateral retinoblastoma (Gonin-Laurent et al, 2006). In this series of sarcomas, the rate of TP53 mutations was high (58%), and the mutation spectrum was characteristic of radiation exposure.…”

“…Thirty-six sarcomas developing in the field of irradiation of a primary cancer were collected at the Institut Curie (Table 1 and (Gonin-Laurent et al, 2006). Twelve of these sarcomas developed in patients treated for bilateral retinoblastoma.…”

“…Such biallelic inactivation was observed in all sarcomas developing in predisposed patients, and only in nine of 24 (37%) of the tumours from patients without predisposition (Table 1; Gonin-Laurent et al, 2006). The status of RB1 was also known for tumours one to seven: in all cases, only the germline-inactivated allele was present in the tumour cells, the other allele being lost (Lefe`vre et al, 2001).…”

Radiation‐induced osteosarcomas of the calvarium and skull base

“…[13][14][15][16] It has also been shown that both the RB1 and p52 genes are commonly mutated in radiation-induced sarcomas, suggesting that loss of these tumor-suppressor genes plays a role in the development of these lesions. 17,18 Friend et al proposed a link between retinoblastomas and osteosarcomas. 19 Two patients in our series had retinoblastoma as the original lesion, for which they received radiation (Fig.…”

Viewpoint: using gene–environment interactions to dissect the effects of complex mixtures

“…While some exposures are thought to leave very specific somatic mutations in such genes as p53 (Jones et al, 1991;Gonin-Laurent et al, 2006), most cancers and other chronic diseases do not reveal their causes through any such specific ''fingerprints. '' Although Hunter (2005) suggested that ''the finding of an interaction between exposure to a complex mixture and a specific variant of a metabolic gene ''points the finger'' at the substrates of the gene as the causal components of the complex mixture'' and the germ of this idea can also be found elsewhere (Ames, 1999;Potter, 2001;Rothman et al, 2001;Brennan, 2002), these ideas appear not to have been developed in any formal statistical framework.…”