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Clinical data in outcome models
Published in Issam El Naqa, A Guide to Outcome Modeling in Radiotherapy and Oncology, 2018
Nicholas J. DeNunzio, Sarah L. Kerns, Michael T. Milano
In recent years, there has been a burgeoning effort to study and understand how genetic predispositions might predict radiation toxicity. As evidenced by one early study examining skin telangiectasia after radiotherapy, 81–90% of the patient-to-patient variation in severity of post-radiotherapy telangiectasias could be explained by patient-related factors [43]. Though genetic syndromes exist that are known to predispose patients to increased radiosensitivity (e.g., ataxia telangiectasia, Nijmegen breakage syndrome, LIG4 syndrome [44], these are rare.
Nijmegen Breakage Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Differential diagnoses for NBD include several inherited disorders that also display microcephaly, growth delay, immunodeficiency, and bone marrow failure due to defective sensing, processing, and repair of DNA DSB (LIG4 syndrome [microcephaly, dysmorphic face, growth retardation, combined cellular and humoral immunodeficiency], NHEJ1 syndrome [microcephaly, dysmorphic facies, severe growth retardation, severe combined cellular and humoral immunodeficiency], Nijmegen breakage syndrome-like disorder [NBSLD or RAD50 deficiency; microcephaly, dysmorphic face, growth retardation, mild spasticity, non-progressive ataxia, normal puberty, chromosome instability at bands 7p13, 7q34, 14q11, and 14q32, absence of immunodeficiency and malignancy; due to mutation in RAD50 on chromosome 5q31.1], A-T [ovarian failure, neurodegeneration, telangiectasia, increased alpha fetal protein, immunodeficiency, cancer predisposition; due to biallelic mutations in the A-T mutated or ATM gene], A-T like disorder [ATLD; neurodegeneration, increased alpha fetal protein; due to MRE11 mutation], Fanconi anemia [occasional microcephaly, growth retardation, skeletal abnormalities—radial defect, reduced fertility—hypergonadotropic hypogonadism in males, pancytopenia, no immunodeficiency], Seckel syndrome [severe microcephaly, severe prenatal and postnatal growth retardation, developmental delay, mental retardation, pancytopenia, no immunodeficiency], Rubinstein−Taybi syndrome [microcephaly, distinctive facial features, mild growth restriction, short stature, intellectual disability, recurrent infections, defect in polysaccharide antibody response, leukemia, brain tumor], and Bloom syndrome [microcephaly, growth failure, increased cancer incidence; due to BLM mutation]) [1].
Some mutations in the xeroderma pigmentosum D gene may lead to moderate but significant radiosensitivity associated with a delayed radiation-induced ATM nuclear localization
Published in International Journal of Radiation Biology, 2020
Mélanie Ferlazzo, Elise Berthel, Adeline Granzotto, Clément Devic, Laurène Sonzogni, Jean-Thomas Bachelet, Sandrine Pereira, Michel Bourguignon, Alain Sarasin, Mauro Mezzina, Nicolas Foray
The radiosensitivity phenotype observed in the XP16BR, XP17PV and XP26VI fibroblasts is clearly different from the hyper-radiosensitivity observed in fibroblasts of patients suffering from ataxia telangiectasia and LIG4 syndrome (Badie et al. 1995b; Foray et al. 1997; Joubert et al. 2008). By contrast, similar radiobiological features were also found in cells from CS, Bloom’s syndrome, Fanconi anemia (Joubert et al. 2008), Huntington’s disease (Ferlazzo et al. 2014), tuberous sclerosis (Ferlazzo et al. 2017) and neurofibromatosis type 1 (Bencokova et al. 2018). From our previous data, the level of such radiosensitivity suggests a significant risk of post-radiotherapy grade 2–3 tissue reactions, which corresponds to dermatitis, erythema, fibrosis and ulceration in the irradiated cutaneous areas (Granzotto et al. 2016). Hence, the cellular radiosensitivity observed in the XP16BR, XP17PV and XP26VI fibroblasts pointed out a significant risk of adverse tissue post-radiotherapy reactions.
Fibroblasts from Retinoblastoma Patients Show Radiosensitivity Linked to Abnormal Localization of the ATM Protein
Published in Current Eye Research, 2021
Ismahane Moulay Lakhdar, Mélanie L. Ferlazzo, Joelle Al Choboq, Elise Berthel, Laurène Sonzogni, Clément Devic, Adeline Granzotto, Juliette Thariat, Nicolas Foray
It is noteworthy that the cellular radiosensitivity observed in the RB1-mutated fibroblasts is not comparable to the hyper-radiosensitivity characterizing ataxia telangiectasia (ATM mutations), the LIG4 syndrome (LIG4 mutations), the progeria (LMNA mutations) or the Nijmegen’s syndrome (NBS1 mutations) that elicit a SF2 lower than 10%.16 Conversely, the radiosensitivity observed in the RB1-mutated fibroblasts together with the γH2AX, pATM and MRE11 data are rather similar to cells from patients suffering from neurofibromatosis, Huntington’s disease and tuberous sclerosis syndromes30,39,53,54 with SF2 ranging from 20 to 30%. In the case of the radiosensitivity observed in the RB1-mutated fibroblasts tested, severe tissue reactions (whose severity grade is generally lower than 4 when consensual toxicity grade scale is considered), like bone malformations may have been observed in irradiated young Rb patients.30 Hence, Rb patients may not be considered as at high risk for fatal consequences like for ataxia telangiectasia but the risk is sufficient to justify recommendations about radiotherapy, especially for younger cases. In parallel to radiosensitivity, the risk of radiation-induced cancer is very high in the Rb patients.12–16 Often confounded with cellular radiosensitivity, the risk of radiation-induced cancer is not systematically linked to a risk of post-radiotherapy tissue reactions.16 For example, while fibroblasts from patients suffering from neurofibromatosis and Huntington’s disease show similar delay in the ATM nucleo-shuttling and SF2, neurofibromatosis is associated to high risk of spontaneous and radiation-induced cancers while Huntington’s disease is not.53,56 In order to better discriminate radiosensitivity and risk of radiation-induced cancer, we proposed the term of “radiosusceptibility” to describe the last notion.16,57 Further studies are however required to better quantify and predict the radiosusceptibility of the Rb patients, notably by quantifying misrepaired DNA damage in surviving cells. Such radiosusceptibility in the irradiated areas appears therefore to be one of the major limits for the application of radiotherapy to young Rb patients, whether against primary in ocular system or secondary malignancies in non-ocular tissues.