Aberrant CDKN1A transcriptional response associates with abnormal sensitivity to radiation treatment

Abstract

Normal tissue reactions to radiation therapy vary in severity among patients and cannot be accurately predicted, limiting treatment doses. The existence of heritable radiosensitivity syndromes suggests that normal tissue reaction severity is determined, at least in part, by genetic factors and these may be revealed by differences in gene expression. To test this hypothesis, peripheral blood lymphocyte cultures from 22 breast cancer patients with either minimal (11) or very severe acute skin reactions (11) have been used to analyse gene expression. Basal and post-irradiation expression of four radiation-responsive genes (CDKN1A, GADD45A, CCNB1, and BBC3) was determined by quantitative real-time PCR in T-cell cultures established from the two patient groups before radiotherapy. Relative expression levels of BBC3, CCNB1, and GADD45A 2 h following 2 Gy X-rays did not discriminate between groups. However, post-irradiation expression response was significantly reduced for CDKN1A (Po0.002) in severe reactors compared to normal. Prediction of reaction severity of B91% of individuals sampled was achieved using this end point. Analysis of TP53 Arg72Pro and CDKN1A Ser31Arg single nucleotide polymorphisms did not show any significant association with reaction sensitivity. Although these results require confirmation and extension, this study demonstrates the possibility of predicting the severity of acute skin radiation toxicity in simple tests.

Ionizing radiation biomarkers for potential use in epidemiological studies

“…Several studies have been published that indicate that microarray based analysis of early transcriptional responses may predict early or late developing adverse normal tissue reactions to radiotherapy [156,157]. Furthermore, simple quantitative real-time PCR assays hold some promise as being predictive for normal tissue reactions [158].…”

Time, Dose and Ataxia Telangiectasia Mutated (ATM) Status Dependency of Coding and Noncoding RNA Expression after Ionizing Radiation Exposure

“…Studying gene transcription in human cells after radiation exposure provides a molecular approach for assessing radiation doses (55), detecting inter-individual differences in response (56) and aiding assessment of long-term risks (57). Indeed, transcription is much more complex than simply the production of transcripts of protein-coding genes and a number of miRNAs have been identified which target DDR components, e.g., miR-100, miR-101 and miR-421 down-regulate ATM expression (58-60), miR-125b and miR-504 directly regulate TP53 expression (61, 62) and miR-605 and miR-661 target the MDM2 gene (63,64).…”

Deoxyribonucleic acid damage-associated biomarkers of ionising radiation: current status and future relevance for radiology and radiotherapy

“…This dramatically dropped to 61% in patients who previously received chemotherapy, a problematic factor with this approach. There are a few consistently up-regulated genes, FDXR, CDKN1A, PUMA, PHPT1, SESN1 and GADD45, identified in microarray studies that have been followed up extensively by the more sensitive and reproducible quantitative polymerase chain reaction (QPCR) technique, which can produce data within hours [38,[44][45][46][47]. A linear dose-reponse has been observed by reverse transcriptase-QPCR from doses 1-3 Gy [47] and 0.5-4 Gy [48].…”

“…Gene sets have been developed to identify late radiation toxicity in patients from a population of ex vivo irradiated lymphocytes, with a 64% [104] and 55% [73] success rate of predicting severe acute and late toxicity in individual patients. Expression of the gene P21 by QPCR has been shown to predict adverse sensitivity 2 h after irradiation [45]. The gene BCL-X has been shown to exhibit protective properties in cells exposed to IR and chemotherapy and to be a determinant of the rate of apoptosis and therefore clinical outcome [105].…”