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A radiation-induced gene expression signature as a tool to predict acute radiotherapy-induced adverse side effects

ABSTRACT: The majority of patients tolerate radiotherapy well, but some of them suffer from severe side effects. To find genes possibly predictive for radiosensitivity, mRNA profiles were generated before and 6 h after in vitro irradiation with 5 Gy. We analyzed lymphocytes from four head and neck and eight breast cancer patients with strong acute radiation toxicity and from 12 matching normal reacting patients in a blind study. In peripheral blood lymphocytes of all patients, 153 genes were identified which were statistically significantly altered by a fold change of more than 50% by irradiation. Pathway analysis revealed genes involved in p53 signalling, cell cycle control and apoptosis in response to radiation in primary lymphocytes. In these cells, a set of 67 radiation-induced genes was identified capable of differentiating between severe radiosensitive and normal reacting patients. More than one third of such classifying genes belong to the group of apoptosis or cell cycle regulating genes. Total RNA obtained from lymphocytes of cancer patients with strong acute radiation toxicity and from matching normal reacting patients were compared 6 hours after in vitro irradiation with 5 Gy.

ORGANISM(S): Homo sapiens

SUBMITTER: Schmezer Peter

PROVIDER: S-ECPF-GEOD-40640 | biostudies-other |

REPOSITORIES: biostudies-other

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A radiation-induced gene expression signature as a tool to predict acute radiotherapy-induced adverse side effects

Project description:The majority of patients tolerate radiotherapy well, but some of them suffer from severe side effects. To find genes possibly predictive for radiosensitivity, mRNA profiles were generated before and 6 h after in vitro irradiation with 5 Gy. We analyzed lymphocytes from four head and neck and eight breast cancer patients with strong acute radiation toxicity and from 12 matching normal reacting patients in a blind study. In peripheral blood lymphocytes of all patients, 153 genes were identified which were statistically significantly altered by a fold change of more than 50% by irradiation. Pathway analysis revealed genes involved in p53 signalling, cell cycle control and apoptosis in response to radiation in primary lymphocytes. In these cells, a set of 67 radiation-induced genes was identified capable of differentiating between severe radiosensitive and normal reacting patients. More than one third of such classifying genes belong to the group of apoptosis or cell cycle regulating genes. Total RNA obtained from lymphocytes of cancer patients with strong acute radiation toxicity and from matching normal reacting patients were compared 6 hours after in vitro irradiation with 5 Gy.

2012-09-06 | E-GEOD-40640 | biostudies-arrayexpress

A radiation-induced gene expression signature as a tool to predict acute radiotherapy-induced adverse side effects

2012-09-06 | GSE40640 | GEO

Harnessing genome-wide association studies to minimize adverse radiation-induced side effects.

Project description:Radiotherapy is used as definitive treatment in approximately two-thirds of all cancers. However, like any treatment, radiation has significant acute and long-term side effects including secondary malignancies. Even when similar radiation parameters are used, 5%-10% of patients will experience adverse radiation side effects. Genomic susceptibility is thought to be responsible for approximately 40% of the clinical variability observed. In the era of precision medicine, the link between genetic susceptibility and radiation-induced side effects is further strengthening. Genome-wide association studies (GWAS) have begun to identify single-nucleotide polymorphisms (SNPs) attributed to overall and tissue-specific toxicity following radiation for treatment of breast cancer, prostate cancer, and other cancers. Here, we review the use of GWAS in identifying polymorphisms that are predictive of acute and long-term radiation-induced side effects with a focus on chest, pelvic, and head-and-neck irradiation. Integration of GWAS studies with "omic" data, patient characteristics, and clinical correlates into predictive models could decrease radiation-induced side effects while increasing therapeutic efficacy.

| S-EPMC7785837 | biostudies-literature

Radiation-induced Circulating microRNAs predict cardiac dysfunction after radiotherapy

Project description:Patients treated with radiotherapy to the chest region are at risk of cardiac sequelae, however, identification of those with greatest risk of complications remains difficult. Here, we sought to determine whether short-term changes in circulating miRNA expression are related to measures of cardiac dysfunction in follow-up. miRNA expression analysis in the primary group showed marked changes in serum miRNAs immediately after RT compared to baseline. miRNAs with increased expression correlated positively with cardiopulmonary dose-volume histogram metrics, while those with decreased expression exhibited negative correlations.

2023-05-07 | GSE225243 | GEO

Chromosomal radiosensitivity and acute radiation side effects after radiotherapy in tumour patients--a follow-up study.

Project description:BACKGROUND: Radiotherapists are highly interested in optimizing doses especially for patients who tend to suffer from side effects of radiotherapy (RT). It seems to be helpful to identify radiosensitive individuals before RT. Thus we examined aberrations in FISH painted chromosomes in in vitro irradiated blood samples of a group of patients suffering from breast cancer. In parallel, a follow-up of side effects in these patients was registered and compared to detected chromosome aberrations. METHODS: Blood samples (taken before radiotherapy) were irradiated in vitro with 3 Gy X-rays and analysed by FISH-painting to obtain aberration frequencies of first cycle metaphases for each patient. Aberration frequencies were analysed statistically to identify individuals with an elevated or reduced radiation response. Clinical data of patients have been recorded in parallel to gain knowledge on acute side effects of radiotherapy. RESULTS: Eight patients with a significantly elevated or reduced aberration yield were identified by use of a t-test criterion. A comparison with clinical side effects revealed that among patients with elevated aberration yields one exhibited a higher degree of acute toxicity and two patients a premature onset of skin reaction already after a cumulative dose of only 10 Gy. A significant relationship existed between translocations in vitro and the time dependent occurrence of side effects of the skin during the therapy period. CONCLUSIONS: The results suggest that translocations can be used as a test to identify individuals with a potentially elevated radiosensitivity.

| S-EPMC3080817 | biostudies-other

Prevention and treatment of radiotherapy-induced side effects.

Project description:Radiotherapy remains a mainstay of cancer treatment, being used in roughly 50% of patients. The precision with which the radiation dose can be delivered is rapidly improving. This precision allows the more accurate targeting of radiation dose to the tumor and reduces the amount of surrounding normal tissue exposed. Although this often reduces the unwanted side effects of radiotherapy, we still need to further improve patients' quality of life and to escalate radiation doses to tumors when necessary. High-precision radiotherapy forces one to choose which organ or functional organ substructures should be spared. To be able to make such choices, we urgently need to better understand the molecular and physiological mechanisms of normal tissue responses to radiotherapy. Currently, oversimplified approaches using constraints on mean doses, and irradiated volumes of normal tissues are used to plan treatments with minimized risk of radiation side effects. In this review, we discuss the responses of three different normal tissues to radiotherapy: the salivary glands, cardiopulmonary system, and brain. We show that although they may share very similar local cellular processes, they respond very differently through organ-specific, nonlocal mechanisms. We also discuss how a better knowledge of these mechanisms can be used to treat or to prevent the effects of radiotherapy on normal tissue and to optimize radiotherapy delivery.

| S-EPMC7332214 | biostudies-literature

NFATC2 modulates radiation toxicity in dermal fibroblasts from patients with severe side-effects of radiotherapy

Project description:Although it is well established that 5 to 15% of radiotherapy patients exhibit severe side-effects in healthy tissue, the cellular and molecular mechanisms involved are still poorly known, and the link between cellular and tissue radiosensitivity is still debated. We here studied fibroblasts from normal skin of patients with severe sequels of radiotherapy in order to examine if specific basal cell activities might be involved in susceptibility to side-effects. When compared to control cells, patient fibroblasts exhibited higher radiosensitivity and defects in DNA double strand breaks (DSB) repair and 8-oxoGuanines, abasic sites and glycol damaged base repair. Transcriptome profiling of dermal fibroblast cell strains from 16 radiotherapy patients with severe side-effects and 8 healthy individuals identified 540 genes specifically deregulated in the patients. Nuclear factor of activated T cells 2 (NFATC2) was one of the most differentially expressed genes. This transcription factor involved in immune responses was found poorly expressed at transcript and protein level in patient cells, whereas the NFATC2 gene region was hypermethylated. Furthermore, NFATC2 expression correlated to the cell survival after irradiation. Finally, we observed that the silencing of NFATC2 in normal cells by RNA interference leads to increased cellular radiosensivity and defects in DNA DSB repair. This study demonstrates that patients with clinical hypersensitivity also exhibit intrinsic cellular radiosensitivity in normal skin cells. It further reveals a new role for NFATC2 as a potential regulator of the cellular sensitivity to ionizing radiations.

2020-12-10 | GSE154559 | GEO

Radiation-induced Circulating microRNAs predict cardiac dysfunction after radiotherapy

Project description:Radiation-induced Circulating microRNAs predict cardiac dysfunction after radiotherapy

| PRJNA934403 | ENA

NFATC2 Modulates Radiation Sensitivity in Dermal Fibroblasts From Patients With Severe Side Effects of Radiotherapy.

Project description:Although it is well established that 5 to 15% of radiotherapy patients exhibit severe side-effects in non-cancerous tissues, the molecular mechanisms involved are still poorly known, and the links between cellular and tissue radiosensitivity are still debated. We here studied fibroblasts from non-irradiated skin of patients with severe sequelae of radiotherapy, to determine whether specific basal cell activities might be involved in susceptibility to side-effects in normal tissues. Compared to control cells, patient fibroblasts exhibited higher radiosensitivity together with defects in DNA repair. Transcriptome profiling of dermal fibroblasts from 16 radiotherapy patients with severe side-effects and 8 healthy individuals identified 540 genes specifically deregulated in the patients. Nuclear factor of activated T cells 2 (NFATC2) was the most differentially expressed gene, poorly expressed at both transcript and protein level, whereas the NFATC2 gene region was hypermethylated. Furthermore, NFATC2 expression correlated with cell survival after irradiation. Finally, silencing NFATC2 in normal cells by RNA interference led to increased cellular radiosensitivity and defects in DNA repair. This study demonstrates that patients with clinical hypersensitivity also exhibit intrinsic cellular radiosensitivity in their normal skin cells. It further reveals a new role for NFATC2 as a potential regulator of cellular sensitivity to ionizing radiation.

| S-EPMC7772431 | biostudies-literature

Predicting adverse side effects of drugs.

Project description:BACKGROUND: Studies of toxicity and unintended side effects can lead to improved drug safety and efficacy. One promising form of study comes from molecular systems biology in the form of "systems pharmacology". Systems pharmacology combines data from clinical observation and molecular biology. This approach is new, however, and there are few examples of how it can practically predict adverse reactions (ADRs) from an experimental drug with acceptable accuracy. RESULTS: We have developed a new and practical computational framework to accurately predict ADRs of trial drugs. We combine clinical observation data with drug target data, protein-protein interaction (PPI) networks, and gene ontology (GO) annotations. We use cardiotoxicity, one of the major causes for drug withdrawals, as a case study to demonstrate the power of the framework. Our results show that an in silico model built on this framework can achieve a satisfactory cardiotoxicity ADR prediction performance (median AUC = 0.771, Accuracy = 0.675, Sensitivity = 0.632, and Specificity = 0.789). Our results also demonstrate the significance of incorporating prior knowledge, including gene networks and gene annotations, to improve future ADR assessments. CONCLUSIONS: Biomolecular network and gene annotation information can significantly improve the predictive accuracy of ADR of drugs under development. The use of PPI networks can increase prediction specificity and the use of GO annotations can increase prediction sensitivity. Using cardiotoxicity as an example, we are able to further identify cardiotoxicity-related proteins among drug target expanding PPI networks. The systems pharmacology approach that we developed in this study can be generally applicable to all future developmental drug ADR assessments and predictions.

| S-EPMC3287493 | biostudies-literature

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