Svensson J Peter, Stalpers Lukas J A, Esveldt-van Lange Rebecca E E, Franken Nicolaas A P, Haveman Jaap, Klein Binie, Turesson Ingela, Vrieling Harry, Giphart-Gassler Micheline
Department of Toxicogenetics, Leiden University Medical Center, Leiden, Netherlands.
PLoS Med. 2006 Oct;3(10):e422. doi: 10.1371/journal.pmed.0030422.
BACKGROUND: Radiation is an effective anti-cancer therapy but leads to severe late radiation toxicity in 5%-10% of patients. Assuming that genetic susceptibility impacts this risk, we hypothesized that the cellular response of normal tissue to X-rays could discriminate patients with and without late radiation toxicity. METHODS AND FINDINGS: Prostate carcinoma patients without evidence of cancer 2 y after curative radiotherapy were recruited in the study. Blood samples of 21 patients with severe late complications from radiation and 17 patients without symptoms were collected. Stimulated peripheral lymphocytes were mock-irradiated or irradiated with 2-Gy X-rays. The 24-h radiation response was analyzed by gene expression profiling and used for classification. Classification was performed either on the expression of separate genes or, to augment the classification power, on gene sets consisting of genes grouped together based on function or cellular colocalization.X-ray irradiation altered the expression of radio-responsive genes in both groups. This response was variable across individuals, and the expression of the most significant radio-responsive genes was unlinked to radiation toxicity. The classifier based on the radiation response of separate genes correctly classified 63% of the patients. The classifier based on affected gene sets improved correct classification to 86%, although on the individual level only 21/38 (55%) patients were classified with high certainty. The majority of the discriminative genes and gene sets belonged to the ubiquitin, apoptosis, and stress signaling networks. The apoptotic response appeared more pronounced in patients that did not develop toxicity. In an independent set of 12 patients, the toxicity status of eight was predicted correctly by the gene set classifier. CONCLUSIONS: Gene expression profiling succeeded to some extent in discriminating groups of patients with and without severe late radiotherapy toxicity. Moreover, the discriminative power was enhanced by assessment of functionally or structurally related gene sets. While prediction of individual response requires improvement, this study is a step forward in predicting susceptibility to late radiation toxicity.
背景：放射治疗是一种有效的抗癌疗法，但会导致5%-10%的患者出现严重的晚期放射毒性。假设遗传易感性会影响这种风险，我们推测正常组织对X射线的细胞反应可以区分有和没有晚期放射毒性的患者。 方法与结果：本研究招募了根治性放疗后2年无癌症证据的前列腺癌患者。收集了21例有严重晚期放射并发症的患者和17例无症状患者的血样。对刺激后的外周淋巴细胞进行假照射或2 Gy X射线照射。通过基因表达谱分析24小时的辐射反应并用于分类。分类基于单个基因的表达进行，或者为了增强分类能力，基于根据功能或细胞共定位分组的基因集进行。X射线照射改变了两组中辐射反应性基因的表达。这种反应在个体间存在差异，最显著的辐射反应性基因的表达与放射毒性无关。基于单个基因辐射反应的分类器正确分类了63%的患者。基于受影响基因集的分类器将正确分类率提高到了86%，尽管在个体水平上只有21/38（55%）的患者被高度准确地分类。大多数具有鉴别性的基因和基因集属于泛素、凋亡和应激信号网络。在未出现毒性的患者中，凋亡反应似乎更为明显。在一组独立的12例患者中，基因集分类器正确预测了8例患者的毒性状态。 结论：基因表达谱分析在一定程度上成功区分了有和没有严重晚期放疗毒性的患者群体。此外，通过评估功能或结构相关的基因集增强了鉴别能力。虽然个体反应的预测仍需改进，但本研究在预测晚期放射毒性易感性方面向前迈进了一步。
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