Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Section of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Sci Rep. 2022 Apr 29;12(1):7000. doi: 10.1038/s41598-022-10271-3.
Molecular biomarkers of ionizing radiation (IR) exposure are a promising new tool in various disciplines: they can give necessary information for adaptive treatment planning in cancer radiotherapy, enable risk projection for radiation-induced survivorship diseases, or facilitate triage and intervention in radiation hazard events. However, radiation biomarker discovery has not yet resolved the most basic features of personalized medicine: age and sex. To overcome this critical bias in biomarker identification, we quantitated age and sex effects and assessed their relevance in the radiation response across the blood proteome. We used high-throughput mass spectrometry on blood plasma collected 24 h after 0.5 Gy total body irradiation (15 MV nominal photon energy) from male and female C57BL/6 N mice at juvenile (7-weeks-old) or adult (18-weeks-old) age. We also assessed sex and strain effects using juvenile male and female BALB/c nude mice. We showed that age and sex created significant effects in the proteomic response regarding both extent and functional quality of IR-induced responses. Furthermore, we found that age and sex effects appeared non-linear and were often end-point specific. Overall, age contributed more to differences in the proteomic response than sex, most notably in immune responses, oxidative stress, and apoptotic cell death. Interestingly, sex effects were pronounced for DNA damage and repair pathways and associated cellular outcome (pro-survival vs. pro-apoptotic). Only one protein (AHSP) was identified as a potential general biomarker candidate across age and sex, while GMNN, REG3B, and SNCA indicated some response similarity across age. This low yield advocated that unisex or uniage biomarker screening approaches are not feasible. In conclusion, age- and sex-specific screening approaches should be implemented as standard protocol to ensure robustness and diagnostic power of biomarker candidates. Bias-free molecular biomarkers are a necessary progression towards personalized medicine and integral for advanced adaptive cancer radiotherapy and risk assessment.
电离辐射（IR）暴露的分子生物标志物是各学科中一种很有前途的新工具：它们可为癌症放射治疗中的适应性治疗计划提供必要的信息，使辐射诱导的生存疾病的风险预测成为可能，或有助于辐射危害事件的分诊和干预。然而，辐射生物标志物的发现尚未解决个性化医学最基本的特征：年龄和性别。为了克服生物标志物识别中的这一关键偏差，我们量化了年龄和性别的影响，并评估了它们在整个血液蛋白质组中的辐射反应中的相关性。我们使用高通量质谱法对雄性和雌性 C57BL/6N 小鼠在幼年（7 周龄）或成年（18 周龄）时接受 0.5Gy 全身照射（15MV 标称光子能量）后 24 小时采集的血浆进行检测。我们还使用幼年雄性和雌性 BALB/c 裸鼠评估了性别和品系的影响。我们表明，年龄和性别在与 IR 诱导反应的程度和功能质量有关的蛋白质组反应中产生了显著的影响。此外，我们发现年龄和性别效应呈非线性，并且通常是终点特异性的。总体而言，年龄对蛋白质组反应的差异影响大于性别，尤其是在免疫反应、氧化应激和凋亡细胞死亡方面。有趣的是，性别效应在 DNA 损伤和修复途径及其相关的细胞结局（促生存与促凋亡）方面非常明显。只有一种蛋白质（AHSP）被确定为跨年龄和性别的潜在通用生物标志物候选物，而 GMNN、REG3B 和 SNCA 则表明跨年龄存在一些反应相似性。这种低产量表明，unisex 或 uniage 生物标志物筛选方法不可行。总之，应实施年龄和性别特异性筛选方法作为标准方案，以确保生物标志物候选物的稳健性和诊断能力。无偏倚的分子生物标志物是迈向个性化医学的必要进展，也是先进的适应性癌症放疗和风险评估的必要组成部分。
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