Mumbrekar Kamalesh Dattaram, Goutham Hassan Venkatesh, Vadhiraja Bejadi Manjunath, Bola Sadashiva Satish Rao
Department of Radiation Biology & Toxicology, School of Life Sciences, Manipal University, Manipal, Karnataka, India.
Department of Radiation Oncology, Manipal Hospital, Bangalore, Karnataka, India.
DNA Repair (Amst). 2016 Apr;40:27-34. doi: 10.1016/j.dnarep.2016.02.006. Epub 2016 Mar 4.
A range of individual radiosensitivity observed in humans can influence individual's susceptibility toward cancer risk and radiotherapy outcome. Therefore, it is important to measure the variation in radiosensitivity and to identify the genetic factors influencing it.
By adopting a pathway specific genotype-phenotype design, we established the variability in cellular radiosensitivity by performing γ-H2AX foci assay in healthy individuals. Further, we genotyped ten selected SNPs in candidate genes XRCC3 (rs861539), XRCC4 (rs1805377), XRCC5 (rs3835), XRCC6 (rs2267437), ATM (rs3218698, rs1800057), LIG4 (rs1805388), NBN (rs1805794), RAD51 (rs1801320) and PRKDC (rs7003908), and analysed their influence on observed variation in radiosensitivity.
The rs2267437 polymorphisms in XRCC6 was associated (P=0.0326) with increased DSB induction while rs1805388 in LIG4 (P=0.0240) was associated with increased radioresistance. Further, multiple risk alleles decreased the DSB repair capacity in an additive manner. Polymorphisms in candidate DSB repair genes can act individually or in combination to the efficacy of DSB repair process, resulting in variation of cellular radiosensitivity.
Current study suggests that γ-H2AX assay may fulfil the role of a rapid and sensitive biomarker that can be used for epidemiological studies to measure variations in radiosensitivity. DSB repair gene polymorphisms can impact the formation and repair of DSBs.
γ-H2AX foci analysis as well as DSBs repair gene polymorphisms can be used to assess cellular radiosensitivity, which will be useful in population risk assessment, disease prediction, individualization of radiotherapy and also in setting the radiation protection standards.
人类中观察到的一系列个体放射敏感性会影响个体对癌症风险和放疗结果的易感性。因此，测量放射敏感性的变化并识别影响它的遗传因素很重要。
通过采用特定途径的基因型-表型设计，我们在健康个体中进行γ-H2AX焦点分析，确定了细胞放射敏感性的变异性。此外，我们对候选基因XRCC3（rs861539）、XRCC4（rs1805377）、XRCC5（rs3835）、XRCC6（rs2267437）、ATM（rs3218698、rs1800057）、LIG4（rs1805388）、NBN（rs1805794）、RAD51（rs1801320）和PRKDC（rs7003908）中的十个选定单核苷酸多态性进行基因分型，并分析它们对观察到的放射敏感性变化的影响。
XRCC6中的rs2267437多态性与双链断裂（DSB）诱导增加相关（P = 0.0326），而LIG4中的rs1805388（P = 0.0240）与放射抗性增加相关。此外，多个风险等位基因以累加方式降低了DSB修复能力。候选DSB修复基因中的多态性可单独或联合作用于DSB修复过程的功效，导致细胞放射敏感性的变化。
当前研究表明，γ-H2AX分析可能发挥快速灵敏生物标志物的作用，可用于流行病学研究以测量放射敏感性的变化。DSB修复基因多态性可影响DSB的形成和修复。
γ-H2AX焦点分析以及DSB修复基因多态性可用于评估细胞放射敏感性，这将有助于人群风险评估、疾病预测、放疗个体化以及制定辐射防护标准。
