Genetic variation in radiation-induced cell death

Abstract

Radiation exposure through environmental, medical, and occupational settings is increasingly common. While radiation has harmful effects, it has utility in many applications such as radiotherapy for cancer. To increase the efficacy of radiation treatment and minimize its risks, a better understanding of the individual differences in radiosensitivity and the molecular basis of radiation response is needed. Here, we integrated human genetic and functional genomic approaches to study the response of human cells to radiation. We measured radiation-induced changes in gene expression and cell death in B cells from normal individuals. We found extensive individual variation in gene expression and cellular responses. To understand the genetic basis of this variation, we mapped the DNA sequence variants that influence expression response to radiation. We also identified radiation-responsive genes that regulate cell death; silencing of these genes by small interfering RNA led to an increase in radiation-induced cell death in human B cells, colorectal and prostate cancer cells. Together these results uncovered DNA variants that contribute to radiosensitivity and identified genes that can be targeted to increase the sensitivity of tumors to radiation. [Supplemental material is available for this article.]Radiation exposure is increasingly common. Medical diagnostic tools such as the X-ray and computed tomography imaging expose patients to ionizing radiation (IR), which can cause DNA damage and increase one's risk of malignancies. However, these radiation-based devices have greatly improved the diagnosis and treatment of many diseases. Thus, the solution is not to eliminate radiation exposure but to protect individuals who are the most sensitive to radiation and to minimize dose and exposure to all individuals (Barnett et al. 2009).Pharmacogenetics has made significant contributions in maximizing therapeutic gains while minimizing side effects; however, those studies have focused mainly on chemicals as therapeutics and have not included radiation. The exclusion of radiation in pharmacogenetics is not surprising since radiation presents a unique set of challenges. Most people are exposed to radiation in nonmedical settings in addition to medical exposures, thus complicating the monitoring of exposure. Safety trials of radiation are impossible given its known toxic effects. Third, most drugs are developed for one or a few diseases. In contrast, radiation is used in a wide range of treatment; over 50% of all cancer treatment protocols include the use of radiation. Target tissues range from skin to skeletal muscles and bone marrow; each tissue type has special cellular components that influence the absorbed radiation dose, and manifests side effects differently.In recent years, cell-based and genetic studies have improved our understanding of the molecular and genetic basis of radiosensitivity by identifying the genes and pathways that are involved in radiation response (Amundson et al. 2001(Amundson et al. , 2008Smirnov et al. ...

Assessment of the Radiation Effects of Cardiac CT Angiography Using Protein and Genetic Biomarkers

“…Our study found that exposure to radiation from CTA, like exposure to therapeutic doses of radiation (17, 18, 35, 36), activates biological pathways and genes and increases the activity of transcription factors involved in the regulation of cell repair, cell cycle progression, and apoptosis, which are critical in preventing the development of mutations, a finding that has not yet been previously reported. Although cells with DNA damage are mostly repaired, a small number of cells die after radiation exposure from CTA.…”

Comprehensive microRNA profiling in B-cells of human centenarians by massively parallel sequencing

“…B cells can act as surrogate tissues whenever there is correlation between the expression levels of B cells and phenotypes of interest [20,21] and a large number of eQTLs originally identified in B cells can also be detected in multiple primary tissues [22,23]. Thus B-cells have been increasingly utilized for expression quantitative trait loci (eQTLs) studies [19,24] and as a cell model to assess gene expression responses [25]. While comprehensive mRNA expression data for human B-cells, obtained by RNA-seq, are available for this purpose [26], to date no such analysis was performed to identify miRNAs expressed in B-cells.…”

Variable Activation of the DNA Damage Response Pathways in Patients Undergoing Single-Photon Emission Computed Tomography Myocardial Perfusion Imaging

“…Previous studies have demonstrated individual variability in radiation sensitivity at the level of gene expression. 33, 34 Using genetic mapping, Smirnov et al identified individual polymorphisms in regulators of gene expression that contributed to individual differences in radiation sensitivity. 33 However, questions as to whether there is any genetic predisposition among certain patients affecting the cellular response to SPECT MPI, or whether these changes at both gene and protein levels reflect persistent DNA damage, are beyond the scope of the present study.…”