Aguado-Flor Ester, Fuentes-Raspall María J, Gonzalo Ricardo, Alonso Carmen, Ramón Y Cajal Teresa, Fisas David, Seoane Alejandro, Sánchez-Pla Álex, Giralt Jordi, Díez Orland, Gutiérrez-Enríquez Sara
Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
Radiation Oncology Department, Santa Creu i Sant Pau Hospital, Barcelona, Spain.
Front Oncol. 2022 May 24;12:825703. doi: 10.3389/fonc.2022.825703. eCollection 2022.
Radiation-induced late effects are a common cause of morbidity among cancer survivors. The biomarker with the best evidence as a predictive test of late reactions is the radiation-induced lymphocyte apoptosis (RILA) assay. We aimed to investigate the molecular basis underlying the distinctive RILA levels by using gene expression analysis in patients with and without late effects and in whom we had also first identified differences in RILA levels.
Peripheral blood mononuclear cells of 10 patients with late severe skin complications and 10 patients without symptoms, selected from those receiving radiotherapy from 1993 to 2007, were mock-irradiated or irradiated with 8 Gy. The 48-h response was analyzed in parallel by RILA assay and gene expression profiling with Affymetrix microarrays. Irradiated and non-irradiated gene expression profiles were compared between both groups. Gene set enrichment analysis was performed to identify differentially expressed biological processes.
Although differentially expressed mRNAs did not reach a significant adjusted -value between patients suffering and not suffering clinical toxicity, the enriched pathways indicated significant differences between the two groups, either in irradiated or non-irradiated cells. In basal conditions, the main differentially expressed pathways between the toxicity and non-toxicity groups were the transport of small molecules, interferon signaling, and transcription. After 8 Gy, the differences lay in pathways highly related to cell senescence like cell cycle/NF-κB, G-protein-coupled receptors, and interferon signaling.
Patients at risk of developing late toxicity have a distinctive pathway signature driven by deregulation of immune and cell cycle pathways related to senescence, which in turn may underlie their low RILA phenotype.
辐射诱发的晚期效应是癌症幸存者发病的常见原因。作为晚期反应预测性检测的最有力证据的生物标志物是辐射诱导淋巴细胞凋亡（RILA）检测。我们旨在通过对有和没有晚期效应且我们首先发现RILA水平存在差异的患者进行基因表达分析，来研究RILA水平差异的分子基础。
从1993年至2007年接受放疗的患者中选出10例有严重晚期皮肤并发症的患者和10例无症状患者，其外周血单个核细胞进行假照射或8 Gy照射。通过RILA检测和使用Affymetrix微阵列进行基因表达谱分析，并行分析48小时的反应。比较两组之间照射和未照射的基因表达谱。进行基因集富集分析以识别差异表达的生物学过程。
虽然在有临床毒性和无临床毒性的患者之间，差异表达的mRNA未达到显著的校正P值，但富集的通路表明两组在照射或未照射细胞中均存在显著差异。在基础条件下，毒性组和无毒组之间主要的差异表达通路是小分子转运、干扰素信号传导和转录。8 Gy照射后，差异在于与细胞衰老高度相关的通路，如细胞周期/NF-κB、G蛋白偶联受体和干扰素信号传导。
有发生晚期毒性风险的患者具有由与衰老相关的免疫和细胞周期通路失调驱动的独特通路特征，这反过来可能是其低RILA表型的基础。
