Heritability of Radiation Response in Lung Cancer Families

Abstract

Radiation sensitivity is assumed to be a cancer susceptibility factor due to impaired DNA damage signalling and repair. Relevant genetic factors may also determine the observed familial aggregation of early onset lung cancer. We investigated the heritability of radiation sensitivity in families of 177 Caucasian cases of early onset lung cancer. In total 798 individuals were characterized for their radiation-induced DNA damage response. DNA damage analysis was performed by alkaline comet assay before and after in vitro irradiation of isolated lymphocytes. The cells were exposed to a dose of 4 Gy and allowed to repair induced DNA-damage up to 60 minutes. The primary outcome parameter Olive Tail Moment was the basis for heritability estimates. Heritability was highest for basal damage (without irradiation) 70% (95%-CI: 51%–88%) and initial damage (directly after irradiation) 65% (95%-CI: 47%–83%) and decreased to 20%–48% for the residual damage after different repair times. Hence our study supports the hypothesis that genomic instability represented by the basal DNA damage as well as radiation induced and repaired damage is highly heritable. Genes influencing genome instability and DNA repair are therefore of major interest for the etiology of lung cancer in the young. The comet assay represents a proper tool to investigate heritability of the radiation sensitive phenotype. Our results are in good agreement with other mutagen sensitivity assays.

On the non-linearity of radon-induced lung cancer

“…LNT is still used to estimate health risks caused by radiation exposure to radon and its short-lived progenies, even at very low doses. It is well accepted, that ionizing radiation induces oxidation of DNA bases and generates single-strand breaks (SSBs) and double-strand breaks (DSBs) (Rosenberger et al 2012). LNT theoretically corresponds to a stochastic process that associates a higher amount of SSBs/DSBs with an increased risk of cancer.…”

The German Uranium Miners’ Biobank—A Biobank for OMICs Radiation Research

“…For smokers a submultiplicative radon risk is the proposed model in Wismut uranium miners [35]. However, genetic factors affecting the DNA repair machinery also modify the radon-or radon and smoking-induced lung cancer risk [13,36]. The exact mode of action of each single factor and the combination of genetic and lifestyle factors, in combination with other noxae such as dust, are open questions in radon risk assessments and will also have an impact on proposed mitigation strategies in homes [37].…”

Clinical and Functional Assays of Radiosensitivity and Radiation-Induced Second Cancer

“…The data available to characterize the link between genotypes and cancer susceptibility largely follow the same approaches as for the radiotoxicity studies discussed above [ 79 ], with both epidemiology studies and the use of functional assays used as surrogate markers of cancer sensitivity (reviewed in [ 80 ]). These studies can involve the molecular characterization of cancers arising in radiation-exposed populations to investigate inter-individual variations in sensitivity ([ 81 ]; reviewed in [ 82 ]), radiosensitivity testing using functional assays in families suspected of heightened cancer predisposition [ 83 ], the identification of sub-populations at increased risk of second cancer after radiation exposure [ 84 , 85 ], or the specific investigation of radiation-induced cancer in individuals with known genetic predispositions [ 86 , 87 ].…”