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.
Highlights
Lung cancer (LC) is the most common cause of cancer death worldwide with a 5-year survival probability of only 10% [1]
The fact that a 3-fold risk for LC was found for first degree relatives in LC patients younger than 46 years of age supports the hypothesis of a genetic component in the etiology of early onset lung cancer [8]
The family component of the study comprised 177 index-persons with a mean age of 44.2 years, whereof 99 (57%) were males
Summary
Lung cancer (LC) is the most common cause of cancer death worldwide with a 5-year survival probability of only 10% [1]. A segregation analysis within 337 families showed that 70% of the early onset LC risk (patients younger than 50 years) can be attributed to rare autosomal genes [10,11] Another indication for a genetic contribution to lung cancer in the young is given by a larger increase of risk in monozygotic twins compared to dizygotic twins. The estimated heritability of several cellular effects based on DNA damage, like chromosomal or chromatid damage [20,21,22], micronucleus induction [23], apoptosis induction [24] and repair of DNA breaks [25], range from 60% to 80% This indicates that genetic factors contribute substantially to the observed phenotypic variation. The COMET assay detects gamma-radiation induced single- (SSB) and double strand breaks (DSB) induced by ionizing radiation on a single cell basis [27,28]
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