Clinical Radiation Sensitivity With DNA Repair Disorders: An Overview

Abstract

Adverse reactions to radiation therapy represent a confounding phenomenon in Radiation Oncology. These reactions are rare, and many have been associated with individuals with DNA repair disorders such as Ataxia-telangiectasia (A-T) and Nijmegen Breakage Syndrome (NBS). There is a paucity of literature detailing such circumstances. This overview describes four exemplary situations, a comprehensive list of 32 additional cases, and some insights gleaned from this overall experience. Fanconi Anemia was associated with over half of the reports. The lowest dose given to a patient that resulted in a reaction was 3 Gy, given to an A-T patient. Most patients died within months of exposure. It is clear that the patients discussed in this paper had complicated illnesses in addition to cancer, and the radiation therapy that administered was most likely their best option. However, the underlying DNA repair defects make conventional radiation therapy doses dangerous. Our review supports prior wisdom that radiation therapy should either be avoided, or doses should be selected with great care in the case of these radiosensitive genotypes which must be recognized with their characteristic phenotypes, until more rapid, reliable and functional assays of DNA repair become available.

Low-dose irradiation prior to bone marrow transplantation results in ATM activation and increased lethality in Atm-deficient mice

“…18 On the other hand, radiation therapy for patients with genomic instability syndromes is akin to replacing one evil with another. In this regard, Pollard and Gatti 30 summarized 32 cases of radiotherapy-induced mortality in DNA-repair disorders, such as A-T, NBS, FA and DNA Ligase IV deficiency, of which 13 were diagnosed with A-T. 30 Our present data underline the skepticism towards IR in A-T. Although radiation improved donor cell migration into bone marrow, blood, spleen and lung tissue in a dose-dependent manner, it increased lethality of Atm-deficient mice, even at low doses of 0.5 Gy.…”

Radiobiologische aspecten van tandheelkundige röntgendiagnostiek

“…Voorbeelden hiervan zijn mensen met het syndroom van Ataxia Telangiectasia of het Nijmegen-breuksyndroom. Zij zijn uitermate gevoelig voor deterministische effecten, maar hebben bovendien een verhoogde kans op het ontwikkelen van tumoren, de zogenoemde stochastische effecten (Pollard et al, 2009;Chaudhary et al, 2014). Ook voor de gezonde bevolking is aangetoond dat er verschillen in gevoeligheid voor stochastische effecten bestaan (Kato et al, 2009;Sodickson et al, 2009;Il'yasova et al, 2014).…”

Ovarian cancer and DNA repair: DNA ligase IV as a potential key

“…In NHEJ pathway, the broken strands are crudely joined together at a site of micro-homology, frequently resulting in small alterations at the site of fusion, being often described as error-prone. Although been able to operate throughout cell cycle, NHEJ is the predominant pathway during G0, G1 and early S phases of the cell cycle [27,34,[55][56][57][58][59][60] . NHEJ and HR proteins are highly conserved across all eukaryotes and ubiquitously expressed in multi-cellular organisms.…”

“…The increased incidence of certain pathologies, like cancer, associated with DNA repair-deficient human syndromes, illustrates the crucial role of these pathways in protection against genomic instability [73] . The LIG4 importance in the maintenance of genomic stability appears to be associated with the fact that mutations in this gene are associated with a rare autosomal syndrome (OMIM 606593) characterized by microcephaly, several immunodeficiency, spontaneous genomic instability and a higher susceptibility to complex diseases such as cancer [50,60,74,75] . Cells from LIG4 patients display increased radiosensitivity and are defective in NHEJ DSB repair [60,75,76] .…”