Involvement of Mitochondrial DNA Sequence Variations and Respiratory Activity in Late Complications following Radiotherapy

Abstract

Purpose: Mitochondria and ionizing radiation overlap in a number of features; for instance, both generate harmful reactive oxygen species, and that radiation can induce cell death through the intermediary of mitochondria. Because a number of genetic variations in nuclear genes are frequently associated with response to cancer treatment, the aim of this case-control study was to test the hypothesis that mitochondrial DNA (mtDNA) genetic variations can contribute to patient-to-patient variability in normal tissue response to radiotherapy. Experimental Design: Thirty-two nasopharyngeal carcinomas patients treated with definitive radiotherapy were included. The grade (G) of s.c. and deep tissue fibrosis was scored according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer grading system. Coding and RNA mtDNA (between 611 and 15,978 bp) were sequenced, and genetic variations were scored. Mitochondrial respiratory activity was measured by resazurin reduction assay. Results: Data showed a significantly (P = 0.003) higher number of nonsynonymous genetic variations in the radiosensitive (G 2 -G 3 ; 16 patients) as compared with the control (G 0 -G 1 ; 16 patients) groups. The nonsynonymous A10398G variation in the ND3 gene was significantly associated with fibrotic reaction (P = 0.01). The radiosensitive patients had a 7-fold (95% confidence interval, 1.16-51.65) higher risk of developing moderate to severe fibrosis (G 2 -G 3 ) following radiotherapy. This was significantly correlated with lower mitochondrial respiratory activity (P = 0.001). Conclusion: Mitochondria contribute to radiation sensitivity, and genetic variations can be associated with late reactions to radiotherapy. Predictive markers of radiosensitivity should take into account mtDNA genetic variations in addition to variations in nuclear genes. (Clin Cancer Res 2009;15(23):7352-60)

RETRACTED ARTICLE: SNPs in genes implicated in radiation response are associated with radiotoxicity and evoke roles as predictive and prognostic biomarkers

“…The patients were treated by standardized 3D conformal RT, before the implementation of IMRT, for nasopharyngeal carcinoma as described elsewhere [10,11]. Total radiation dose to the upper neck was 66 Gy.…”

Among 45 variants in 11 genes, HDM2 promoter polymorphisms emerge as new candidate biomarker associated with radiation toxicity

“…This illustrates that radiation response requires the concerted action of multiple genes and, therefore, it is a complex genetically controlled trait with the outcome being determined by multitude of additive effects. This conclusion is further substantiated by the assumption that the combined risk alleles effect on radiosensitivity may also incorporate variations in mitochondrial DNA, the energy producing cytoplasmic organelles, as a subset of patients of this study have also showed association with genetic variations in mtDNA (Alsbeih et al 2009b). The genomic revolution with the advent of high-throughput techniques can help uncovering the panoply of these interacting factors at the DNA (genome), RNA (transcriptome) or protein (proteome) level.…”

The REQUITE Project: Validating Predictive Models and Biomarkers of Radiotherapy Toxicity to Reduce Side-effects and Improve Quality of Life in Cancer Survivors

“…Three REQUITE centres will carry out the assay with early work focusing on crosscentre standardisation and establishing standardised operating procedures, which will be made available on the REQUITE website. The biorepository will allow for assessment of other promising biomarkers, such as RNA profiles (PAXgene tube collected sample) and mitochondrial DNA [26].…”