DNA repair alterations in children with pediatric malignancies: novel opportunities to identify patients at risk for high-grade toxicities.
OBJECTIVE
To evaluate, in a pilot study, the phosphorylated H2AX (γH2AX) foci approach for identifying patients with double-strand break (DSB) repair deficiencies, who may overreact to DNA-damaging cancer therapy.


METHODS
The DSB repair capacity of children with solid cancers was analyzed compared with that of age-matched control children and correlated with treatment-related normal-tissue responses (n = 47). Double-strand break repair was investigated by counting γH2AX foci in blood lymphocytes at defined time points after irradiation of blood samples.


RESULTS
Whereas all healthy control children exhibited proficient DSB repair, 3 children with tumors revealed clearly impaired DSB repair capacities, and 2 of these repair-deficient children developed life-threatening or even lethal normal-tissue toxicities. The underlying mutations affecting regulatory factors involved in DNA repair pathways were identified. Moreover, significant differences in mean DSB repair capacity were observed between children with tumors and control children, suggesting that childhood cancer is based on genetic alterations affecting DSB repair function.


CONCLUSIONS
Double-strand break repair alteration in children may predispose to cancer formation and may affect children's susceptibility to normal-tissue toxicities. Phosphorylated H2AX analysis of blood samples allows one to detect DSB repair deficiencies and thus enables identification of children at risk for high-grade toxicities.
Rübe
Claudia E
CE
Department of Radiation Oncology, Saarland University, Homburg/Saar, Germany. claudia.ruebe@uks.eu
Fricke
Andreas
A
Schneider
Ruth
R
Simon
Karin
K
Kühne
Martin
M
Fleckenstein
Jochen
J
Gräber
Stefan
S
Graf
Norbert
N
Rübe
Christian
C
D000293:Adolescent; D001260:Ataxia Telangiectasia / Q000097:blood / Q000235:genetics*; D015415:Biomarkers / Q000032:analysis; D001769:Blood / Q000528:radiation effects; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000502:physiology*; D005240:Feasibility Studies; D005260:Female; D005455:Fluorescent Antibody Technique / Q000379:methods; D006579:Heterozygote; D006657:Histones / Q000032:analysis* / Q000235:genetics; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D008214:Lymphocytes / Q000502:physiology / Q000528:radiation effects; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D010865:Pilot Projects; D011832:Radiation Injuries / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics*; D018709:Statistics, Nonparametric; D013997:Time Factors; D000071857:Tumor Suppressor p53-Binding Protein 1; D055815:Young Adult
D015415:Biomarkers; C468783:H2AX protein, human; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1