Prediction of In Vivo Radiation Dose Status in Radiotherapy Patients using Ex Vivo and In Vivo Gene Expression Signatures

Abstract

After a large-scale nuclear accident or an attack with an improvised nuclear device, rapid biodosimetry would be needed for triage. As a possible means to address this need, we previously defined a gene expression signature in human peripheral white blood cells irradiated ex vivo that predicts the level of radiation exposure with high accuracy. We now demonstrate this principle in vivo using blood from patients receiving total-body irradiation (TBI). Whole genome microarray analysis has identified genes responding significantly to in vivo radiation exposure in peripheral blood. A 3-nearest neighbor classifier built from the TBI patient data correctly predicted samples as exposed to 0, 1.25 or 3.75 Gy with 94% accuracy (P < 0.001) even when samples from healthy donor controls were included. The same samples were classified with 98% accuracy using a signature previously defined from ex vivo irradiation data. The samples could also be classified as exposed or not exposed with 100% accuracy. The demonstration that ex vivo irradiation is an appropriate model that can provide meaningful prediction of in vivo exposure levels, and that the signatures are robust across diverse disease states and independent sample sets, is an important advance in the application of gene expression for biodosimetry.

Comparable dose estimates of blinded whole blood samples are obtained independently of culture conditions and analytical approaches. Second RENEB gene expression study

“…It has been reported many times that the quantification of gene expression in response to radiation exposure by microarray technology is robust and reliable (Paul & Amundson 2008;Boldt et al 2012;Knops et al 2012), and the obtained gene signatures derived in ex situ irradiated blood are shown to be predictive for the radiation dose in vitro as well as in vivo (Paul et al 2011). The gene signature developed by Boldt et al (2012) was reported to be robust in terms of dose prediction.…”

Intestinal Microbiota as Novel Biomarkers of Prior Radiation Exposure

“…Microarray analysis of peripheral blood has been used to predict radiation doses received in vivo in a heterogeneous population of total-body irradiation patients, and to compare the predictive ability of signatures derived from in vivo versus ex vivo exposures (23). A total of 413 genes were significantly expressed following irradiation.…”

Biological Dosimetry of Ionizing Radiation

“…Cellular damages usually induce cellular stress which leads to a response through activation of several cellular pathways that result in modulations of gene expression. Microarray technology is used to study these modulations with the aim of identifying the corresponding gene or group of genes whose profile shows a dose-effect relationship (Paul, 2011). Amundson et al in 2000 were among the first to use gene expression as biological dosimetry in peripheral blood lymphocytes.…”