Gene Expression Analysis in Radiotherapy Patients and C57BL/6 Mice as a Measure of Exposure to Ionizing Radiation

Abstract

Dose assessment after radiological disasters is imperative to decrease mortality through rationally directed medical intervention. Our goal was to identify biomarkers capable of qualitative (nonirradiated/irradiated) and/or quantitative (dose) assessment of radiation exposure. Using real-time quantitative PCR, biodosimetry genes were identified in blood samples from cancer patients undergoing total-body irradiation. Time- (5, 12, 23, 48 h) and dose- (0-8 Gy) dependent changes in gene expression were examined in C57BL/6 mice. A training set was used to derive weighted voting classification algorithms (nonirradiated/irradiated) and continuous regression (dose assessment) models that were tested in a separate validation set of mice. Of eight biodosimetry genes identified in cancer patients ( ACTA2 , BBC3 , CCNG1 , CDKN1A , GADD45A , MDK , SERPINE1 , Tnfrsf10b ), expression of BBC3 , CCNG1 , CDKN1A , SERPINE1 and Tnfrsf10b was significantly (P < 0.05) increased in irradiated mice. CCNG1 and CDKN1A expression segregated irradiated mice from controls with an accuracy, specificity and sensitivity of 96.3, 100.0 and 94.4%, respectively, at 48 h. Multiple linear regression analysis predicted doses for the 0-, 1-, 2-, 4-, 6- and 8-Gy treatment groups as 0.0 ± 0.2, 1.6 ± 1.0, 2.9 ± 1.4, 5.1 ± 2.0, 5.3 ± 0.7 and 10.5 ± 5.6 Gy, respectively. These results suggest that gene expression analysis could be incorporated into biodosimetry protocols for qualitative and quantitative assessment of radiation exposure.

Dose-specific transcriptional responses in thyroid tissue in mice after 131I administration

“…None of the 102 genes was regulated at all absorbed doses, and 88 genes were not regulated at any absorbed dose level. Among the previously proposed biomarkers, the Acta2, Bbc3, Cdkn1a, and Gadd45a genes were also regulated in the present study, however not at all absorbed doses levels [21]. The 102 genes were derived primarily from in vitro and/or ex vivo studies, which may explain the discordance between the previous studies and the present study in addition to the differences in radiation quality.…”

“…Few of the 102 genes previously proposed as radiation exposure biomarkers found in the literature were detected in the present investigation [7,8,21,22]. None of the 102 genes was regulated at all absorbed doses, and 88 genes were not regulated at any absorbed dose level.…”

“…3). Previously suggested 102 biomarkers for radiation were evaluated in the present dataset (Table 3) [7,8,21,22]. The majority of these genes (88/102) were not detected at any absorbed dose level in our data, and none of the gene was detected at all absorbed dose levels.…”

Intragenic Controls Utilizing Radiation-Induced Alternative Transcript Regions Improves Gene Expression Biodosimetry

“…Similarly, the assessment of micronuclei have provided another measurable biodosimetry end point (17). Other end points include phosphorylation of histone, H2AX (18,19), electron paramagnetic resonance (20,21), protein expression (22)(23)(24)(25), metabolites (26)(27)(28) and gene expression levels (29)(30)(31)(32)(33)(34)(35). These methods have all shown promise to predict exposure dose, but also have limitations.…”

Gene Expression Biodosimetry: Quantitative Assessment of Radiation Dose with Total Body Exposure of Rats

“…The changes in the GE and quantity of RNA transcripts in 3 cells that have been exposed to ionizing radiation suggest the possibility of that the GE analysis providing not only qualitative assessments of dose but also quantitative dose determination. It may provide high-throughput assessments of radiation exposure in a large number of exposed individuals (Filiano et al 2011). …”