Radiogenomics: A systems biology approach to understanding genetic risk factors for radiotherapy toxicity?

Abstract

Adverse reactions in normal tissue after radiotherapy (RT) limit the dose that can be given to tumour cells. Since 80% of individual variation in clinical response is estimated to be caused by patient-related factors, identifying these factors might allow prediction of patients with increased risk of developing severe reactions. While inactivation of cell renewal is considered a major cause of toxicity in early-reacting normal tissues, complex interactions involving multiple cell types, cytokines, and hypoxia seem important for late reactions. Here, we review ‘omics’ approaches such as screening of genetic polymorphisms or gene expression analysis, and assess the potential of epigenetic factors, posttranslational modification, signal transduction, and metabolism. Furthermore, functional assays have suggested possible associations with clinical risk of adverse reaction. Pathway analysis incorporating different ‘omics’ approaches may be more efficient in identifying critical pathways than pathway analysis based on single ‘omics’ data sets. Integrating these pathways with functional assays may be powerful in identifying multiple subgroups of RT patients characterized by different mechanisms. Thus ‘omics’ and functional approaches may synergize if they are integrated into radiogenomics ‘systems biology’ to facilitate the goal of individualised radiotherapy.

Individual patient data meta-analysis shows a significant association between the ATM rs1801516 SNP and toxicity after radiotherapy in 5456 breast and prostate cancer patients

“…Thus, ATM plays a crucial role in the biological response to ionizing radiation and influences the fate of the cell following irradiation [16]. Acute radiation toxicity typically takes place in skin or mucosal membranes and its pathogenesis is assumed to involve depletion of rapidly dividing cells in the basal layer [12]. In our meta-analysis, the rs1801516 SNP had a stronger impact on acute than late toxicity.…”

“…The vast majority of these studies has been underpowered to detect the small effect sizes usually found for SNPs [10]. Even though numerous significant associations were reported [10–12], only very few of these have been independently confirmed [13,14]. The gene product of ATM plays a crucial role in biological response to ionizing radiation.…”

Musashiexpression in intestinal stem cells attenuates radiation-induced decline in intestinal homeostasis and survival inDrosophila

“…Genetic variations influence sensitivity to genotoxic stress, the detrimental effects of radiation treatment, and the prognosis of radiation therapy [83][84][85][86][87][88][89][90][91][92]. We hypothesized that Drosophila with naturally occurring genetic variations might reveal novel pathways that enhance stem cell proliferative repair and reduce radiation-induced intestinal permeability.…”

The Role of Lymphocytes in Radiotherapy-Induced Adverse Late Effects in the Lung

“…Furthermore, several potential biomarkers such as pulmonary function, dose–volume histogram, end/pre-RT plasma levels of TGF-β1, IL1α, and IL6 have been described that may be suited to predict a higher risk for radiation-induced lung toxicity (226, 227). A promising novel approach to predict and understand genetic risk factors for radiation-induced toxicity may be the use of radiogenomics (228). …”