Abstract
BackgroundRadiation 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 FindingsProstate 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.ConclusionsGene 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.
Highlights
Radiotherapy is one of the most effective treatments for cancer
Gene expression profiling succeeded to some extent in discriminating groups of patients with and without severe late radiotherapy toxicity
The success of radiotherapy depends on its ability to kill cancer cells while sparing normal tissue [1]
Summary
The incidence of prostate cancer is high, but most patients will be cured or free from tumor symptoms within several years after radiotherapy. The success of radiotherapy depends on its ability to kill cancer cells while sparing normal tissue [1]. Late toxicity after radiotherapy for prostate cancer includes disturbed rectal, bladder, and sexual functions. The percentage of patients developing severe late toxicity determines the maximum acceptable radiation dose. 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. A few patients develop severe late radiation toxicity, months or years after their treatment. In prostate cancer—a tumor that forms in a gland in the male reproductive system that lies between the bladder and the end of the gut (the rectum)—late radiation toxicity affects rectal, bladder, and sexual function in 5%–10% of patients
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