Abstract
BackgroundHigh expression of constitutive histone γ-H2AX, a sensitive marker of DNA damage, might be indicative of defective DNA repair pathway or genomic instability. 53BP1 (p53-binding protein 1) is a conserved checkpoint protein with properties of a DNA double-strand breaks sensor. This study explores the relationship between the clinical radiosensitivity of tumor patients and the expression/induction of γ-H2AX and 53BP1 in vitro.MethodsUsing immunostaining, we assessed spontaneous and radiation-induced foci of γ-H2AX and 53 BP1 in peripheral blood mononuclear cells derived from unselected breast cancer (BC) patients (n=57) undergoing radiotherapy (RT). Cells from apparently healthy donors (n=12) served as references.ResultsNon-irradiated cells from controls and unselected BC patients exhibited similar baseline levels of DNA damage assessed by γ-H2AX and 53BP1 foci. At the same time, the γ-H2AX assay of in vitro irradiated cells revealed significant differences between the control group and the group of unselected BC patients with respect to the initial (0.5 Gy, 30 min) and residual (2 Gy, 24 h post-radiation) DNA damage. The numbers of 53BP1 foci analyzed in 35 BC patients were significantly higher than in controls only in case of residual DNA damage. A weak correlation was found between residual foci of both proteins tested. In addition, cells from cancer patients with an adverse acute skin reaction (grade 3) to RT showed significantly increased radiation-induced γ-H2AX foci and their protracted disappearance compared to the group of BC patients with normal skin reaction (grade 0–1). The mean number of γ-H2AX foci after 5 clinical fractions was significantly higher than that before RT, especially in clinically radiosensitive patients.ConclusionsThe γ-H2AX assay may have potential for screening individual radiosensitivity of breast cancer patients.Trial registrationhttp://www.krebshilfe.de/wir-foerdern.html
Highlights
Breast cancer (BC) is the common type of tumor in females, accounting for approximately 21% of all cancer cases in women worldwide [1]
The discrepancies cited above prompted us to explore whether the histone γ-H2AX assay is able to predict the clinical radiation reaction of breast cancer (BC) patients and to discriminate them from healthy subjects. We examined both baseline and radiation-induced DNA damage in Peripheral blood mononuclear cells (PBMCs) from a group of 57 unselected BC patients compared with a group of healthy subjects (n=12)
Subjects The assay was performed on PBMCs isolated from two groups of individuals: (1) a group (n=57) of unselected BC patients who were prospectively involved in the study and their blood samples were collected before and during (72 h after 5 clinical fractions) clinical radiation; and (2) a group of apparently healthy donors (n=12), mainly hospital personal
Summary
Breast cancer (BC) is the common type of tumor in females, accounting for approximately 21% of all cancer cases in women worldwide [1]. Among BC patients 2% have a strong genetic predisposition, caused by the mutations in highly penetrant BRCA1 and BRCA2 genes [2] Because these genes cannot explain the overall increased risk in the relatives of BC cases [3], it was suggested that a substantial proportion of BC patients may be predisposed to cancer through mutations in low Several DNA damage repair pathways constitute a guard system that protects cells against genetic instability and tumorigenesis. The biological significance of genetic instability and DNA repair mechanisms in cancer development is well illustrated by the autosomal recessive disorders, such as Ataxia telangiectasia, Fanconi anemia and Nijmegen breakage syndrome These chromosome breakage syndromes are characterized by defects in DNA repair, predisposition to different forms of malignancy and increased radiosensitivity (for review, see [9]). This study explores the relationship between the clinical radiosensitivity of tumor patients and the expression/induction of γ-H2AX and 53BP1 in vitro
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