In vivo formation of gamma-H2AX and 53BP1 DNA repair foci in blood cells after radioiodine therapy of differentiated thyroid cancer.
DNA double-strand breaks (DSBs) are critical cellular lesions that can result from ionizing radiation exposure. A marker for DSB formation is the phosphorylated form of the histone H2 variant H2AX (gamma-H2AX). DSBs also attract the damage sensor p53-binding protein 1 (53BP1) to the DSB-containing chromatin, because 53BP1 associates with the DSB-surrounding chromatin. We studied the induction, persistence, and disappearance of radiation-induced gamma-H2AX and 53BP1 foci after the first (131)I therapy of patients with differentiated thyroid carcinoma, a model for protracted, continuous, internal whole-body irradiation.


METHODS
Twenty-six patients (7 men, 19 women; mean age +/- SD, 42 +/- 13 y) underwent posttherapeutic blood dosimetry according to the standard operating procedure of the European Association of Nuclear Medicine, including peripheral blood sampling and external dose rate measurements at 2-144 h after administration of (131)I for thyroid remnant ablation. The mean time curves of dose accumulation and dose rate to the blood were compared with the mean gamma-H2AX and 53BP1 foci counts over the same period in samples of mononuclear peripheral blood leukocytes.


RESULTS
The mean absorbed dose to the blood in 24 patients evaluable for physical dosimetry was 0.31 +/- 0.10 Gy (minimum, 0.17 Gy; maximum, 0.57 Gy). After 24 h, the mean daily dose increment was less than 0.05 Gy. The excess focus counts per nucleus--that is, nuclear foci in excess of the low background count--peaked at 2 h after radioiodine administration (median excess foci for gamma-H2AX [n = 21 patients], 0.227, and for 53BP1 [n = 19 patients], 0.235) and progressively declined thereafter. Significantly elevated numbers of excess focus counts per nucleus (median excess foci for gamma-H2AX [n = 8 patients], 0.054, and for 53BP1 [n = 6 patients], 0.046) still were present at 120-144 h after therapy. Because the rate of occurrence of radiation-induced focus counts per nucleus per absorbed dose varied considerably among patients, a dose-response relationship could not be established for this series as a whole. The number of excess radiation-induced focus counts per nucleus per absorbed dose rate increased with time, potentially indicating a slower rate of DNA repair or, alternatively, a higher de novo rate of focus formation. The values over time of both radiation-induced DSB markers correlated closely (r(2) = 0.973).


CONCLUSIONS
Radiation-induced gamma-H2AX and 53BP1 nuclear foci are useful markers for detecting radiation exposure after radionuclide incorporation, even for absorbed doses to the blood below 20 mGy.
Lassmann
Michael
M
Department of Nuclear Medicine, University of Würzburg, Würzburg, Germany. Lassmann_m@klinik.uni-wuerzburg.de
Hänscheid
Heribert
H
Gassen
Daniela
D
Biko
Johannes
J
Meineke
Viktor
V
Reiners
Christoph
C
Scherthan
Harry
H
D000328:Adult; D000368:Aged; D000465:Algorithms; D001773:Blood Cells / Q000378:metabolism* / Q000528:radiation effects*; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D004249:DNA Damage; D004260:DNA Repair; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005455:Fluorescent Antibody Technique; D006657:Histones / Q000097:blood* / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000097:blood* / Q000235:genetics*; D007457:Iodine Radioisotopes / Q000009:adverse effects* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D013965:Thyroidectomy; D000071857:Tumor Suppressor p53-Binding Protein 1; D014916:Whole-Body Irradiation
C468783:H2AX protein, human; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1