A frequency-based gene selection method to identify robust biomarkers for radiation dose prediction

Abstract

Purpose: A fast, radiation-specific and highly accurate prediction of the radiation dose of accidentally exposed individuals is essential for medical decision-making. The aim of the present study is to identify small gene signatures allowing the discrimination between low and medium dose exposure of low linear energy transfer (LET)-radiation.

Material and methods: We developed a framework for dose prediction using a frequency-based gene selection approach, based on a p-value and fold-change criterion applied to microarray expression data. A repeated cross-validated classification guarantees unbiased performance results. Human blood from six healthy donors was irradiated ex vivo with 0.5, 1, 2 and 4 Gy (Cs-137 γ-rays). Expression levels of isolated blood lymphocytes were measured at 6, 24 and 48 h after irradiation.

Results: We identified radiation-responsive genes, most of them functionally linked to apoptosis, DNA-damage or cell-cycle regulation. We extracted small subsets of genes, with which 95.7% of all samples can be correctly predicted, regardless of the time post irradiation. Seven of these genes were used for validation by Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR).

Conclusion: The genes identified are potential robust biomarkers, which are particularly suitable for dose level discrimination at a window of time that would be appropriate for life-saving medical triage.

Keywords::

• Biodosimetry
• ionizing radiation
• lymphocytes
• gene expression

Acknowledgements

S.B., K.K., R.K. and O.W. are funded by the German Federal Ministry of Education and Research (BMBF) as part of the Biodosimetry project (FKZ 02NUK005). QRT-PCR prediction analyses were performed using BRB-ArrayTools developed by Dr Richard Simon and BRB-ArrayTools Development Team. The authors wish to thank Sabine Kall and her colleagues for taking the blood samples and Dominik Oskamp and Marcel von Ameln for technical support.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.