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Livrables
The study of chromosome alterations in a set of human radiation-induced tumours has led to the working hypothesis of the role of chromosome instability, telomere maintenance versus telomerase activation in the occurrence chromosome imbalances in radiation-induced tumours. In both cell models and human tumours SUSGENINRADCAR provide data on the importance of telomerase activation in cancer progression and individual survival (Soria et al, 2001; 2002; Smith et al submitted; Lantuejoul et al submitted, Ady et al, submitted; Fizazi et al, in prep).
The telomere shortening/telomerase activation plays a key role in the occurrence of chromosomal instability leading to the chromosome imbalances detected in epithelial tumours and in radiation-induced tumours (except thyroid) (Morat et al in prep). In mammalian cells, the consequence of telomere loss could be dramatically mutagenic for the cell 1) chromosome instability 2) gene amplification via breakage/fusion/bridge (B/F/B) cycle (demonstrated to be a mechanism for gene amplification in hamster cells) has been demonstrated to be directly linked to gene amplification in human cells 3) chromosome imbalances (gain and loss of chromosome arms). Chromosomes lacking one telomere remain unstable until they are capped. (Lo et al, 2002 a,b).
The generated aneuploidy will lead to unmasking, amplification� of radiation induced or pre-existing mutations, key events in the initiation and progression of multistage carcinogenesis. In SUSGENINRADCAR we contribute to identify the role of known cancer-related genes, telomeres and telomerase in tumour progression.
The identification of tumour suppressor genes central to the development of human breast cancer, an important tumour type in the context of ionizing radiation, produced two sets of major findings.
First, the gene responsible for the tumour suppressive activity of human chromosome-1 in breast cancer cells (located in the frequently lost 1p35 region) was identified unequivocally as that encoding the epithelial-specific marker and growth suppressor 14-3-3 sigma; this gene was subsequently shown to be involved in our in vitro breast cell transformation system, suggesting a role in radiation-induced transformation. Second, major advances were made in understanding the genetics and molecular biology of telomerase repression in normal human cells (which must be overcome for human cancers to develop). We showed that the all-important repressor gene acts via transcriptional repression of the gene encoding a component of telomerase (known as hTERT) by a mechanism that involves repackaging of the gene.
These results, recently published in high-impact journals, will be extremely valuable in facilitating the identification and isolation of the repressor gene itself, which we have recently been successful in locating to an extremely small region of normal human chromosome 3 (within band p21).
Genome alterations of seven secondary tumours (5 osteosarcomas, 1 malignant peripheral sheath nerve tumor, 1 leiomyosarcoma) occurring in the field of irradiation of patients treated for bilateral retinoblastoma have been studied. These patients were predisposed to develop radiation-induced tumours because of the presence of a germ line mutation in the retinoblastoma gene (RB1).
Tumour cells were characterized by high chromosome instability whereas micro-satellites and mini-satellites were found to be stable. In all tumours, 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-radiation-induced tumours, 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 effect of ionizing radiation. If confirmed, the "specific" mutagenesis observed in this series of radiation induced tumours could become the "sign" which discriminate between spontaneous and radiation induced tumours.
This possibility of discrimination should be very useful in the contexts of the social anxiety linked to the nuclear industry.
Publications
Identification and isolation of susceptibility genes involved in radiation-induced cancer in humans (SUS GENES IN RAD CAR)
Auteurs:
NEWBOLD R (Brunel University, Department of Biological Sciences, Uxbridge (GB))
Publié dans:
A project summary published in a DG Research brochure: "Understanding the effects of radiation on health". EUR 19959. Luxembourg, EUR-OP, 2002. pp.46-47, 2002, Page(s) 46-47, ISBN 92-894-3840-1
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