Human Radiosensitivity and Radiosusceptibility: What Are the Differences?
Abstract
:1. Introduction
1.1. Historical Features
1.2. A Current Confusion
1.3. The Evidence of a Molecular Difference
1.4. Univocal Definitions
- the “genomic approach” which consists of inventorying all the genes involved by their expression or polymorphisms in the high throughput studies of radiosensitivity, in order to establish causal links with clinical features [21]. The major advantage of this approach is to get a large number of candidate genes. The major inconvenience is to consider gene expression as a major feature of the response to radiation, while some cases of radiosensitivity are not necessarily linked to a higher or lower gene expression but to protein dysfunction [8];
- the “clinical approach” which consists of defining the major clinical features of the response to radiation, and thereafter to identify genes in each category. The major advantage of this approach is to gather all the different types of radiation-induced events observed by clinicians. The major inconvenience is to omit some genes that may be involved in the response to radiation while their mutations lead to non-viability and therefore are not associated with any described syndrome [8].
- The radiosensitivity is the proneness to the adverse tissue events that are considered as non-cancer radiation-induced effects and attributable to cell death. Radiosensitivity is generally correlated with unrepaired DNA damage [12];
- The radiosusceptibility is the proneness to the radiation-induced cancers that are non-toxic radiation-induced effects attributable to cell transformation and genomic instability. Radiosusceptibility is generally correlated with misrepaired DNA damage [22]. As IR is considered as a carcinogenic agent, radiosusceptibility is strongly linked to susceptibility to spontaneous cancers. The term “radiosusceptibility” was proposed through its similarities with “cancer susceptibility”, extensively used in the ICRP reports, and as it introduces the notions of stochastic events [8];
- The radiodegeneration responses are non-cancer effects attributable to mechanisms related to accelerated aging. Radiodegeneration should be correlated with unrepaired DNA damage that is tolerated by and can cumulate in cells [8]. Radiodegeneration responses cannot be considered similar to radiosensitivity responses as defined above, as their incidence rates, the types of cellular death, and the genes involved are different.
2. The Different Features of Human Radiosensitivity
2.1. What do We Learn from the Quantification of Human Radiosensitivity?
2.2. Genetic Syndromes Associated with Radiosensitivity from the Clinical, Cellular and Molecular Criteria
- AT patients show a very high risk of leukemia/lymphoma, and were treated by radiotherapy (total body irradiations) in the 1970s [16,34,35,36]. The severity of their post-radiotherapy reactions (nearly all fatal) and their extreme sensitivity to other DSB-inducing drugs have imposed a particular care for treating them with radiomimetic drugs [16,37,38,39]. AT is caused by homozygous or compound heterozygous mutations of the ATM gene [40,41];
- LIG4 syndrome was first described from an acute lymphoblastic leukemia patient who overresponded to radiation therapy and died following radiation morbidity, without showing any clinical features in common with AT. The radiobiological characterization of his cells revealed homozygous mutation of Ligase IV [42,43,44,45];
- a case of a Xeroderma Pigmentosum C patient who suffered from an angiosarcoma and showed a fatal reaction to radiotherapy was reported [50]. However, the radiosensitivity of this case has been shown to be complemented by the transfer of a wild-type chromosome 8, suggesting that this XPC variant patient may hold other gene mutation responsible of his abnormal response to radiation [51,52].
- as SF2 increases, the syndromes caused by homozygous mutations (leading to loss of functions) are progressively replaced by syndromes caused by heterozygous mutations (leading to “leaky” functions) (Table 1). Syndromes caused by heterozygous mutations being more frequent than those caused by homozygous mutations, SF2 increases with prevalence (Figure 2).
- homozygous mutations of ATM, LIG4, and NBS1, involved in the DSB repair and signalling pathways, cause the most hyper-radiosensitive syndromes; this hyper-radiosensitivity has been observed both clinically and in vitro;
- there is a continuum of SF2 values form 1% (ataxia telangiectasia) to about 60% (average radioresistance). Surprisingly, to the notable exceptions of the three precited syndromes, there are few syndromes caused by mutations of DSB repair proteins, probably as DSB is a key-DNA damage that impacts on each step of embryogenesis. About 50% of radiosensitive syndromes are caused by genes involved in the repair of radiation-induced DNA damage (other than DSB) that may affect cell survival after irradiation. The remaining 50% are caused by genes involved in the cell scaffold and the nuclear membrane, and whose encoded proteins are cytoplasmic (Figure 1).
3. The Different Features of Human Radiosusceptibility
3.1. What do We Learn from the Quantification of Human Radiosusceptibility?
- these cohorts/databases, derived from epidemiological data, do not highlight any individual predispositions to specific malignancies, but concern a whole population of individuals considered as equally radioresistant. The dose-effect curve shape may vary according to the type of radiation-induced cancer;
- there is no clinical equivalent of CTCAE/RTOG scales grading the different steps of carcinogenesis. Consequently, the relative risk (RR) or the excess of relative risk (ERR) are the only parameters to express cancer incidence as a function of dose. It is noteworthy that these parameters are calculated from epidemiological data [8];
- there is no consensual mathematical model that describes (similar to the LQ model for cell survival) the cancer incidence, or its risk as a function dose. Indeed, the radiation-induced cancer incidence curves are generally described as either linear with no threshold (LNT) or non-linear with a threshold (NLT). The LNT/NLT controversies have long reflected a societal issue, raising the question of the existence of a dose-threshold below which there are no significant association between malignancies and exposures to ionizing radiation [77,78]. From Hiroshima survivors data, the threshold doses have been found to be 100 mGy for radiation-induced leukemia and 200 mGy for radiation-induced solid cancers [75]. However, these dose thresholds are relevant only for high dose-rate (flash) exposures to radiation. The corresponding dose thresholds for low dose-rate exposures are still unknown [79].
3.2. Genetic Syndromes Associated with Radiosusceptibility from the Clinical, Cellular, and Molecular Criteria
- homozygous mutations of ATM, LIG4, and NBS1 genes are associated with high risks of leukaemia/lymphoma;
- there is no consensual parameter to quantify radiosusceptibility, notably as the intrinsic mechanisms of carcinogenesis are still unknown;
- the radiosensitive syndromes that are associated with radiosusceptibility may be associated with a large spectrum of malignancies for a single gene mutation;
- the radiosusceptible syndromes are caused by mutations of genes related to proto-oncogenes, to radiation-induced misrepaired DNA damage, or else to cell cycle checkpoints (Figure 1). Again, among these syndromes, some are caused by mutated cytoplasmic proteins.
4. Toward a Unified Model for Radiosensitivity and Radiosusceptibility
4.1. Biological Function of Proteins as Proteins or as Substrates?
4.2. The Nucleo-Shuttling of ATM as a Primum Movens of the Molecular Response to Radiation
- the “dosimetry step”: after irradiation, the production of reactive oxygen species (ROS) is dose-dependent. Under the effect of the radiation-induced oxidative stress, some cytoplasmic dimeric forms of ATM become monomeric in a dose-dependent manner;
- the “diffusion step”: the ATM monomers diffuse to the nucleus; however, during their course from the cytoplasm to the nucleus, they can meet some cytoplasmic ATM substrates with which they can form multiprotein complexes that prevents the nucleo-shutting;
- the “recognition step”: the remaining free ATM monomers diffuse to the nucleus and phosphorylate H2AX molecules at DSB sites, which activates NHEJ. The ATM monomers will re-dimerize during the DSB repair process and can be easily quantifiable as nuclear foci by immunofluorescence [61].
- DSB are not repaired, whatever the repair pathway: these DSB become lethal and lead to radiosensitivity. Less than two unrepaired DSB are sufficient to cause cell death in humans;
- DSB are not recognized by NHEJ, but they are managed by a rapid but illegitimate hyper-recombination process: these DSB become misrepaired and lead to radiosusceptibility; they can be accompanied by additional DNA strand breaks due to hyper-recombination early after irradiation;
- DSB are tolerated (i.e., non-lethal immediately, likely as a longer cellular death process such as senescence rather than mitotic death or apoptosis). Progressively with time, the number of these DSB and SSB cumulate in cells to give a late subset of additional DNA damage.
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Syndromes | Mutated Genes | Major Defective Mechanism | Prevalence per 100,000 | SF2 (%) | Cancer Predisposition | Aging Neurodegeneration | Immuno- Deficiency | Subcellular Localization of the Protein |
---|---|---|---|---|---|---|---|---|
Ataxia telangiectasia | Homoz ATM mutations | DSB signaling and repair | ~1 | 1–5 | Leukemia, Lymphoma | No | Yes | Nucleus Cytoplasm |
Ligase IV syndrome | Homoz LIG4 mutations | NHEJ | Few cases | 2–6 | Leukemia, Lymphoma | No | Yes | Nucleus |
Nijmegen’s syndrome | Homoz NBS1 mutations | DSB signaling and repair | ~1 | 5–9 | Leukemia, Lymphoma | No | Yes | Nucleus |
Hutchinson-Gilford Progeria syndrome | Heteroz* LMNA mutations | Nuclear membrane | 0.12–0.25 | 8–19 | No | Yes | No? | Inner nuclear membrane |
Agamma-globulinemia Bruton’s disease | X-linked homoz BTK mutations | V(D)J recombination | 1.4–2.8 | 10 | No Some cases of colorectal cancer due to infections | No | Yes | Nucleus Cytoplasm |
Hypogamma-globulinemia Lig I deficiency | compound heteroz LIGI mutations | NER | one case | 11 | No | No | Yes | Nucleus Golgi apparatus Vesicles |
ICF syndrome | Homoz, compound heteroz, DNMT3B mutations | DNA methylation | ~50 cases | 14 | No? | Yes? | Yes | Nucleus but also cytoplasm in mutated cells |
Glutathione synthetase deficiency | most compound heteroz GSS mutations | Glutathione cycle | ~70 cases ~0.1 | 14 | No | Cerebellar degeneration in some severe cases | No? | Nucleus |
NBSLD Syndrome | Homoz, compound heteroz RAD50 mutations | Few cases | 15 | No? | Yes? | No | Nucleus | |
ATLD Syndrome | Homoz or compound heteroz MRE11 mutations | Few cases | 15–30 | No | Yes? | No | Nucleus Cytoplasm | |
Cockayne’s syndrome | Homoz or compound heteroz CS mutations | NER/TCR | 0.4 | 15–30 | No | Yes | No | Nucleus |
Xeroderma pigmentosum | Homoz or compound heteroz XP mutations | NER/TCR | 0.4 to 1 | 15–30 | Skin cancer | Yes | No | Nucleus only, except for XPD (both nucleus and cytoplasm) |
Usher’s syndrome | Homoz USH mutations | 3–5 | 16 | No | Yes? | No | Cytoplasm | |
Huntington’s disease | Heteroz (gain-of-function) HTT mutations | DNA methylation | 4–7 | 19 | No | Yes | No | Nucleus Cytoplasm |
Duchesne’s dystrophy | X-linked DMD mutations | 1–9 | 16–28 | No | Yes | No | Cytoplasm | |
Fanconi Anemia | Homoz or heteroz X-linked FANC (A to D) mutations | 1 | 15–40 | Leukemia, squamous cell carcinoma Breast cancer | No | Yes | Nucleus only, except for FANCD both nucleus and cytoplasm | |
Bloom’s Syndrome | Homoz or compound heteroz BLM mutations | HR/TLS | 0.5–2 | 15–40 | leukemia, lymphoma | No | Yes | Nucleus Cytoplasm |
Gorlin’s (NF2) syndrome | Heteroz or de novo PTCH1 mutations | 1–9 | 12–30 | Non-melanoma skin cancer | No | No | Golgi apparatus Cytoplasm domains | |
Tuberous sclerosis Complex syndrome | Heteroz TSC mutations | DSB signaling and repair | 4–10 | 24 | CMS and PMS tumors | No | No | Cytoplasm |
Von Recklinghausen (NF1) syndrome | Heteroz or de novo NF1 mutations | DSB signaling and repair | 200–300 | 15–35 | CMS and PMS tumors | No | No | Nucleus Cytoplasm |
Li-Fraumeni syndrome | Heteroz p53 mutations | Cell cycle regulation | 4–10 | 20-50 | breast, brain, leukemia, sarcoma | No | No | Nucleus Cytoplasm |
Gardner’s syndrome | Heteroz APC mutations | Cell adhesion | 2.2–3.2 | 18–30 | Mainly colorectal cancer | No | No | Nucleus Golgi apparatus |
Turcot’s syndrome | Homoz, compound heteroz, heteroz MLH mutations | MMR | ~150 cases | 21–30 | Mainly colorectal cancer | No | No | Nucleus |
Hereditary retinoblastoma | Heteroz RB1 mutations | Cell cycle regulation | 5–7 | 25–35 | Retinoblastoma, sarcoma, melanoma, lung and breast cancer | No | No | Nucleus but also cytoplasm in mutated cells |
Hereditary breast/ovary cancer | Heteroz BRCA2 mutations | HR | ~125 | 20–40 | Breast/ovary cancer | No | No | Nucleus Cytoplasm |
Hereditary breast/ovary cancer | Heteroz BRCA1 mutations | HR | ~333 | 30–50 | Breast/ovary cancer | No | No | Nucleus Cytoplasm |
AT heterozygotes | Heteroz ATM mutations | DSB signaling and repair | 1000 | 20–55 | High risk of breast cancer | No | No | Nucleus Cytoplasm |
Werner syndrome | Homoz or compound heteroz WRN mutations | HR/TLS | 2.5–5 | 20–55 | some rare cancers | Yes | No | Nuclear Cytoplasm for some mutations |
Rothmund-Thomson syndrome | Homoz or compound heteroz RecQL4mutations | HR/TLS | ~300 cases | 30–50 | osteosarcoma | Yes | No | Nucleus Cytoplasm |
Severe combined immunodeficiency | Homoz or compound heteroz Cernnunos or Artemis mutations | V(D)J recombination NHEJ | ~33 | 30–50 | Some rare lymphoma | No | Yes | Nucleus |
Down’s syndrome | Chromosome 21 trisomy | 100–150 | 25 | High risk of ALL and AML | Yes | Yes | - | |
Lynch’s syndrome | Heteroz MLH1, MSH2/6, hPMS2 mutations | MMR | 100–125 | 30–50 | Mainly Colorectal cancer | No | No | Nucleus |
Alzheimer’s disease | 2000–4000 | No? | Yes | No | - |
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El-Nachef, L.; Al-Choboq, J.; Restier-Verlet, J.; Granzotto, A.; Berthel, E.; Sonzogni, L.; Ferlazzo, M.L.; Bouchet, A.; Leblond, P.; Combemale, P.; et al. Human Radiosensitivity and Radiosusceptibility: What Are the Differences? Int. J. Mol. Sci. 2021, 22, 7158. https://doi.org/10.3390/ijms22137158
El-Nachef L, Al-Choboq J, Restier-Verlet J, Granzotto A, Berthel E, Sonzogni L, Ferlazzo ML, Bouchet A, Leblond P, Combemale P, et al. Human Radiosensitivity and Radiosusceptibility: What Are the Differences? International Journal of Molecular Sciences. 2021; 22(13):7158. https://doi.org/10.3390/ijms22137158
Chicago/Turabian StyleEl-Nachef, Laura, Joelle Al-Choboq, Juliette Restier-Verlet, Adeline Granzotto, Elise Berthel, Laurène Sonzogni, Mélanie L. Ferlazzo, Audrey Bouchet, Pierre Leblond, Patrick Combemale, and et al. 2021. "Human Radiosensitivity and Radiosusceptibility: What Are the Differences?" International Journal of Molecular Sciences 22, no. 13: 7158. https://doi.org/10.3390/ijms22137158