The first in vivo multiparametric comparison of different radiation exposure biomarkers in human blood

Abstract

The increasing risk of acute large-scale radiological/nuclear exposures of population underlines the necessity of developing new, rapid and high throughput biodosimetric tools for estimation of received dose and initial triage. We aimed to compare the induction and persistence of different radiation exposure biomarkers in human peripheral blood in vivo. Blood samples of patients with indicated radiotherapy (RT) undergoing partial body irradiation (PBI) were obtained soon before the first treatment and then after 24 h, 48 h, and 5 weeks; i.e. after 1, 2, and 25 fractionated RT procedures. We collected circulating peripheral blood from ten patients with tumor of endometrium (1.8 Gy per fraction) and eight patients with tumor of head and neck (2.0–2.121 Gy per fraction). Incidence of dicentrics and micronuclei was monitored as well as determination of apoptosis and the transcription level of selected radiation-responsive genes. Since mitochondrial DNA (mtDNA) has been reported to be a potential indicator of radiation damage in vitro, we also assessed mtDNA content and deletions by novel multiplex quantitative PCR. Cytogenetic data confirmed linear dose-dependent increase in dicentrics (p < 0.01) and micronuclei (p < 0.001) in peripheral blood mononuclear cells after PBI. Significant up-regulations of five previously identified transcriptional biomarkers of radiation exposure (PHPT1, CCNG1, CDKN1A, GADD45, and SESN1) were also found (p < 0.01). No statistical change in mtDNA deletion levels was detected; however, our data indicate that the total mtDNA content decreased with increasing number of RT fractions. Interestingly, the number of micronuclei appears to correlate with late radiation toxicity (r2 = 0.9025) in endometrial patients suggesting the possibility of predicting the severity of RT-related toxicity by monitoring this parameter. Overall, these data represent, to our best knowledge, the first study providing a multiparametric comparison of radiation biomarkers in human blood in vivo, which have potential for improving biological dosimetry.

Induction of Micronuclei in Cervical Cancer Treated with Radiotherapy

“…Intratumoral MN showed a 5.4-fold increase after RT for 10 Gy in 5 fractions compared with pre-treatment setting. The increase in MN after irradiation was comparable with that reported previously in peripheral blood lymphocytes [ 12 , 13 , 14 , 15 ]. The novelty of this study is that, for the first time, we demonstrated the induction of MN in primary tumors treated with clinical radiation beams.…”

“…Taken together, RT-induced intratumoral MN may be used as a biomarker of the response to cancer immunotherapy combined with radiotherapy. Induction of MN by RT has been demonstrated in peripheral blood lymphocytes obtained from individuals treated with RT [ 12 , 13 , 14 , 15 ]. However, the induction of MN by RT in solid tumors has not been reported.…”

Generation of a Transcriptional Radiation Exposure Signature in Human Blood Using Long-Read Nanopore Sequencing

“…Blood samples from a previous study (13,36) were analyzed to monitor the radiation response in vivo of apolipoprotein B mRNA editing enzyme catalytic subunit 3H (APOBEC3H) and FDXR. This cohort was comprised of patients with the following cancer diagnoses (n): endometrial (4), breast (5), lung (4), prostate (3), esophageal (2) and colon (1). Patients received intensity modulated radiotherapy using a linear accelerator.…”

“…Over the last decade, gene expression analysis has emerged as a realistic approach for assessing radiation exposure in human blood samples after medical exposure or during emergency situations, due to its high throughput and time efficiency (1)(2)(3)(4). Although many studies have used microarrays (5,6), qPCR analyses have proven to provide accurate dose estimates by focusing on specific radiationresponsive genes (7)(8)(9)(10)(11)(12)(13)(14)(15) in only 7 h (16) and now in only 4 h (17).…”

In Vivo Validation of Alternative FDXR Transcripts in Human Blood in Response to Ionizing Radiation

“…Gene expression analyses of white blood cells have proven to be an accurate and fast method to assess IR exposure in blood samples for biodosimetry purposes [8][9][10][11][12][13][14]. From arrays and sequencing efforts [14][15][16], a broad number of genes have been identified whose response to IR can qualify as reliable biomarkers of exposure.…”