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Biodosimetric transcriptional and proteomic changes are conserved in irradiated human tissue

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Abstract

Transcriptional dosimetry is an emergent field of radiobiology aimed at developing robust methods for detecting and quantifying absorbed doses using radiation-induced fluctuations in gene expression. A combination of RNA sequencing, array-based and quantitative PCR transcriptomics in cellular, murine and various ex vivo human models has led to a comprehensive description of a fundamental set of genes with demonstrable dosimetric qualities. However, these are yet to be validated in human tissue due to the scarcity of in situ-irradiated source material. This represents a major hurdle to the continued development of transcriptional dosimetry. In this study, we present a novel evaluation of a previously reported set of dosimetric genes in human tissue exposed to a large therapeutic dose of radiation. To do this, we evaluated the quantitative changes of a set of dosimetric transcripts consisting of FDXR, BAX, BCL2, CDKN1A, DDB2, BBC3, GADD45A, GDF15, MDM2, SERPINE1, TNFRSF10B, PLK3, SESN2 and VWCE in guided pre- and post-radiation (2 weeks) prostate cancer biopsies from seven patients. We confirmed the prolonged dose-responsivity of most of these transcripts in in situ-irradiated tissue. BCL2, GDF15, and to some extent TNFRSF10B, were markedly unreliable single markers of radiation exposure. Nevertheless, as a full set, these genes reliably segregated non-irradiated and irradiated tissues and predicted radiation absorption on a patient-specific basis. We also confirmed changes in the translated protein product for a small subset of these dosimeters. This study provides the first confirmatory evidence of an existing dosimetric gene set in less-accessible tissues—ensuring peripheral responses reflect tissue-specific effects. Further work will be required to determine if these changes are conserved in different tissue types, post-radiation times and doses.

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Author information

Author notes

  1. Scott G. Williams and Ygal Haupt contributed equally to this study.

Authors and Affiliations

  1. Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Simon P. Keam, Twishi Gulati, Cristina Gamell, Franco Caramia & Ygal Haupt

  2. The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia

    Cristina Gamell, Paul J. Neeson & Ygal Haupt

  3. Molecular Genomics Facility, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Gisela Mir Arnau

  4. Monash Biomedical Proteomics Facility, Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia

    Cheng Huang, Ralf B. Schittenhelm & Ygal Haupt

  5. The Smoler Proteomics Center Technion, Israel Institute of Technology, Haifa, Israel

    Oded Kleifeld

  6. Cancer Immunology Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Paul J. Neeson

  7. Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Scott G. Williams

  8. Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia

    Paul J. Neeson & Ygal Haupt

Authors
  1. Simon P. Keam
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  2. Twishi Gulati
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  3. Cristina Gamell
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  4. Franco Caramia
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  5. Gisela Mir Arnau
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  6. Cheng Huang
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  7. Ralf B. Schittenhelm
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  8. Oded Kleifeld
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  9. Paul J. Neeson
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  10. Scott G. Williams
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  11. Ygal Haupt
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Contributions

SK, SW, PN and YH conceived and designed the study. SK designed and performed the experiments and analysed and the data. TG, CG, GMA and CH assisted with experimental design. SK and FC designed and performed the bioinformatics analyses. RS and OK designed and performed mass spectrometry and analysed the data. SK drafted the manuscript. SK, SW and YH critically revised the manuscript.

Corresponding author

Correspondence to Simon P. Keam.

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Conflict of interest

We have no conflicts of interest to disclose.

Ethics approval and consent to participate

All participants provided consent covering tissue research as part of a prospective tissue collection study for prostate radiobiology research approved by the Human Research Ethics Committee at the Peter MacCallum Cancer Centre (PMCC; HREC approvals 10/68 and 13/167).

Availability of data and material

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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Keam, S.P., Gulati, T., Gamell, C. et al. Biodosimetric transcriptional and proteomic changes are conserved in irradiated human tissue. Radiat Environ Biophys 57, 241–249 (2018). https://doi.org/10.1007/s00411-018-0746-5

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  • DOI: https://doi.org/10.1007/s00411-018-0746-5

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