PMID- 35681629
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220716
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 14
IP  - 11
DP  - 2022 May 26
TI  - Transcriptional Dynamics of DNA Damage Responsive Genes in Circulating Leukocytes 
      during Radiotherapy.
LID - 10.3390/cancers14112649 [doi]
LID - 2649
AB  - External beam radiation therapy leads to cellular activation of the DNA damage 
      response (DDR). DNA double-strand breaks (DSBs) activate the ATM/CHEK2/p53 
      pathway, inducing the transcription of stress genes. The dynamic nature of this 
      transcriptional response has not been directly observed in vivo in humans. In 
      this study we monitored the messenger RNA transcript abundances of nine DNA 
      damage-responsive genes (CDKN1A, GADD45, CCNG1, FDXR, DDB2, MDM2, PHPT1, SESN1, 
      and PUMA), eight of them regulated by p53 in circulating blood leukocytes at 
      different time points (2, 6-8, 16-18, and 24 h) in cancer patients (lung, neck, 
      brain, and pelvis) undergoing radiotherapy. We discovered that, although the 
      calculated mean physical dose to the blood was very low (0.038-0.169 Gy), an 
      upregulation of Ferredoxin reductase (FDXR) gene transcription was detectable 2 h 
      after exposure and was dose dependent from the lowest irradiated percentage of 
      the body (3.5% whole brain) to the highest, (up to 19.4%, pelvic zone) reaching a 
      peak at 6-8 h. The radiation response of the other genes was not strong enough 
      after such low doses to provide meaningful information. Following multiple 
      fractions, the expression level increased further and was still significantly 
      up-regulated by the end of the treatment. Moreover, we compared FDXR 
      transcriptional responses to ionizing radiation (IR) in vivo with healthy donors' 
      blood cells exposed ex vivo and found a good correlation in the kinetics of 
      expression from the 8-hours time-point onward, suggesting that a molecular 
      transcriptional regulation mechanism yet to be identified is involved. To 
      conclude, we provided the first in vivo human report of IR-induced gene 
      transcription temporal response of a panel of p53-dependant genes. FDXR was 
      demonstrated to be the most responsive gene, able to reliably inform on the low 
      doses following partial body irradiation of the patients, and providing an 
      expression pattern corresponding to the % of body exposed. An extended study 
      would provide individual biological dosimetry information and may reveal 
      inter-individual variability to predict radiotherapy-associated adverse health 
      outcomes.
FAU - Cruz-Garcia, Lourdes
AU  - Cruz-Garcia L
AUID- ORCID: 0000-0002-7804-974X
AD  - Centre for Radiation, Chemical and Environmental Hazards, UK Health Security 
      Agency, Chilton, Didcot OX11 0RQ, UK.
FAU - Nasser, Farah
AU  - Nasser F
AD  - Centre for Radiation, Chemical and Environmental Hazards, UK Health Security 
      Agency, Chilton, Didcot OX11 0RQ, UK.
FAU - O'Brien, Grainne
AU  - O'Brien G
AD  - Centre for Radiation, Chemical and Environmental Hazards, UK Health Security 
      Agency, Chilton, Didcot OX11 0RQ, UK.
FAU - Grepl, Jakub
AU  - Grepl J
AUID- ORCID: 0000-0003-0732-1344
AD  - Department of Oncology and Radiotherapy, University Hospital, 500 05 Hradec 
      Kralove, Czech Republic.
AD  - Department of Radiobiology, Faculty of Military Health Sciences, Hradec Kralove, 
      University of Defence, 662 10 Brno, Czech Republic.
FAU - Vinnikov, Volodymyr
AU  - Vinnikov V
AD  - Grigoriev Institute for Medical Radiology and Oncology of the National Academy of 
      Medical Science of Ukraine, 61024 Kharkiv, Ukraine.
FAU - Starenkiy, Viktor
AU  - Starenkiy V
AD  - Grigoriev Institute for Medical Radiology and Oncology of the National Academy of 
      Medical Science of Ukraine, 61024 Kharkiv, Ukraine.
FAU - Artiukh, Sergiy
AU  - Artiukh S
AD  - Grigoriev Institute for Medical Radiology and Oncology of the National Academy of 
      Medical Science of Ukraine, 61024 Kharkiv, Ukraine.
FAU - Gramatiuk, Svetlana
AU  - Gramatiuk S
AUID- ORCID: 0000-0003-4238-7031
AD  - Ukraine Association of Biobank, 61000 Kharkiv, Ukraine.
FAU - Badie, Christophe
AU  - Badie C
AUID- ORCID: 0000-0003-4572-5008
AD  - Centre for Radiation, Chemical and Environmental Hazards, UK Health Security 
      Agency, Chilton, Didcot OX11 0RQ, UK.
AD  - Environmental Research Group within the School of Public Health, Faculty of 
      Medicine at Imperial College of Science, Technology and Medicine, London SW7 2BX, 
      UK.
LA  - eng
GR  - RC21066/International Atomic Energy Agency/
PT  - Journal Article
DEP - 20220526
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC9179543
OTO - NOTNLM
OT  - FDXR
OT  - PBMCs
OT  - biomarkers
OT  - ionizing radiation
OT  - radiation exposure
OT  - radiotherapy
COIS- The authors declare no conflict of interest.
EDAT- 2022/06/11 06:00
MHDA- 2022/06/11 06:01
PMCR- 2022/05/26
CRDT- 2022/06/10 01:08
PHST- 2022/03/29 00:00 [received]
PHST- 2022/05/19 00:00 [revised]
PHST- 2022/05/24 00:00 [accepted]
PHST- 2022/06/10 01:08 [entrez]
PHST- 2022/06/11 06:00 [pubmed]
PHST- 2022/06/11 06:01 [medline]
PHST- 2022/05/26 00:00 [pmc-release]
AID - cancers14112649 [pii]
AID - cancers-14-02649 [pii]
AID - 10.3390/cancers14112649 [doi]
PST - epublish
SO  - Cancers (Basel). 2022 May 26;14(11):2649. doi: 10.3390/cancers14112649.