Clinical radiation sensitivity with DNA repair disorders: an overview

Abstract

Adverse reactions to radiotherapy 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 and Nijmegen Breakage syndrome. A paucity of published data is available 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 more than one-half of the reports. The lowest dose given to a patient that resulted in a reaction was 3 Gy, given to an ataxia-telangiectasia patient. Most patients died within months of exposure. It is clear that the patients discussed in this report had complicated illnesses, in addition to cancer, and the radiotherapy administered was most likely their best option. However, the underlying DNA repair defects make conventional radiation doses dangerous. Our findings support previous wisdom that radiotherapy should either be avoided or the doses should be selected with great care in the case of these radiosensitive genotypes, which must be recognized by their characteristic phenotypes, until more rapid, reliable, and functional assays of DNA repair become available.

Figure 1

Telangiectasia pattern in a patient with A-T.

Figure 2

The two major DNA repair pathways are non-homologous end-joining (NHEJ) and homologous recombination (HR). NHEJ occurs throughout the cell cycle and is initiated by Ku70 and Ku80 binding to DNA double-stranded ends. The MRE11/RAD50/NBS (MRN) complex, DNA PK and XRCC4/DNA Ligase IV is then recruited to the site of the break. DNA PK helps to process the ends, while, DNA Ligase IV causes the ligation. In HR, ATM is recruited to the site of the double-stranded break by the MRN complex and thereafter, ATM phosphorylates other downstream targets involved in cell cycle checkpoints, DNA repair or apoptosis.

Figure 3

ATM-S1981 immunofluorescent foci in human lymphoblastoid cells, 15 minutes after 2 Gy irradiation. Phosphorylated ATM on serine 1981 forms distinct nuclear foci at sites of DNA damage. These foci are depicted as the discrete green fluorescein isothiocyanate (FITC) stains on the blue nuclear 4, 6-diamidino-2-phenylindole (DAPI) counterstain.

Figure 4

Colony Survival Assay, following 1 Gy to human lymphoblastoid cell lines: 29 normals, 19 obligate heterozygotes, 104 A-T patients with varying ATM mutations, 5 NBS patients with varying mutations, 5 FA patients with varying complementation groups, and 2 LIG 4 patients (siblings). The A-T cells were more radiosensitive than the normals (P<.01).

Figure 5

Microcephaly and micrognathia of a patient with NBS.

Figure 6

Microcephaly and micrognathia, with low-set ears, in a patient with DNA Ligase IV deficiency.