Relationship between in vitro chromosomal radiosensitivity of peripheral blood lymphocytes and the expression of normal tissue damage following radiotherapy for breast cancer

Barber, Jim; Burrill, W.; Spreadborough, Anne R; Levine, Edward; Warren, C; Kiltie, Anne E.; Roberts, Stephen A; Scott, David

doi:10.1016/s0167-8140(99)00158-9

Cited by 116 publications

(84 citation statements)

References 34 publications

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“…None of the patients had had a mastectomy or had received chemotherapy, but most of the patients involved in the study were taking tamoxifen. The previously published work demonstrated no significant relationship between chromosomal radiosensitivity, tamoxifen intake, menopausal status, age or smoking history (Barber et al, 2000). Consent was obtained from the patients and South Manchester Medical Research Ethics Committee approved the study.…”

Section: Samplesmentioning

confidence: 96%

“…Lymphocyte samples, separated on Histopaque-1077 (Sigma Aldrich, Poole, Dorset, UK) and frozen within 24 h of blood collection from 22 sporadic breast cancer patients 30 -72 years old treated at the Christie Hospital in Manchester, were obtained between 1993 and 1996 after local excision but before radiotherapy, in a prospective study of acute skin reactions (Barber et al, 2000). None of the patients had had a mastectomy or had received chemotherapy, but most of the patients involved in the study were taking tamoxifen.…”

Section: Samplesmentioning

confidence: 99%

“…However, normal cell radiosensitivity in some cases may be an important factor predictive of radiation therapy response as illustrated by West et al (2001) whose results showed that blood lymphocyte radiosensitivity (SF2) is a highly significant prognostic factor for the risk of developing late radiation morbidity. In terms of other end points, Barber et al (2000) evaluated the predictive value of lymphocyte chromosome radiosensitivity in patients receiving radiotherapy for breast cancer and concluded that these assays perform poorly in predicting normal tissue effects. Wang et al (2005) and Lopez et al (2005) both failed to find a correlation between DNA repair capacities in peripheral blood lymphocytes and acute skin reaction during radiotherapy.…”

mentioning

confidence: 99%

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Aberrant CDKN1A transcriptional response associates with abnormal sensitivity to radiation treatment

Badie¹,

Dziwura²,

Raffy³

et al. 2008

Br J Cancer

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Normal tissue reactions to radiation therapy vary in severity among patients and cannot be accurately predicted, limiting treatment doses. The existence of heritable radiosensitivity syndromes suggests that normal tissue reaction severity is determined, at least in part, by genetic factors and these may be revealed by differences in gene expression. To test this hypothesis, peripheral blood lymphocyte cultures from 22 breast cancer patients with either minimal (11) or very severe acute skin reactions (11) have been used to analyse gene expression. Basal and post-irradiation expression of four radiation-responsive genes (CDKN1A, GADD45A, CCNB1, and BBC3) was determined by quantitative real-time PCR in T-cell cultures established from the two patient groups before radiotherapy. Relative expression levels of BBC3, CCNB1, and GADD45A 2 h following 2 Gy X-rays did not discriminate between groups. However, post-irradiation expression response was significantly reduced for CDKN1A (Po0.002) in severe reactors compared to normal. Prediction of reaction severity of B91% of individuals sampled was achieved using this end point. Analysis of TP53 Arg72Pro and CDKN1A Ser31Arg single nucleotide polymorphisms did not show any significant association with reaction sensitivity. Although these results require confirmation and extension, this study demonstrates the possibility of predicting the severity of acute skin radiation toxicity in simple tests.

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Section: Samplesmentioning

confidence: 96%

Section: Samplesmentioning

confidence: 99%

mentioning

confidence: 99%

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Aberrant CDKN1A transcriptional response associates with abnormal sensitivity to radiation treatment

Badie¹,

Dziwura²,

Raffy³

et al. 2008

Br J Cancer

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“…[3][4][5][6] The discrepancy in patient radiosensitivity is attributed then to patient genetic backgrounds and/or predispositions to adverse reactions. Previously, others group have attempted to correlate radiosensitivity in patient populations with in vitro assessments of patient initial DNA damage and repair efficacies, single nucleotide polymorphism (SNPs) in DNA repair genes, lymphocyte apoptosis efficiencies, fibroblast clonogenic survival, and chromosomal aberrations in response to RT.…”

Section: Introductionmentioning

confidence: 99%

“…Previously, others group have attempted to correlate radiosensitivity in patient populations with in vitro assessments of patient initial DNA damage and repair efficacies, single nucleotide polymorphism (SNPs) in DNA repair genes, lymphocyte apoptosis efficiencies, fibroblast clonogenic survival, and chromosomal aberrations in response to RT. [3][4][5][6] Even with large patient cohorts and multiple studies, these reports have failed to validate any potential predictive biomarkers for RT-induced skin toxicities. RT inadvertently affects immune cells and triggers a pro-inflammatory response leading to various immune responses with a different extent for the wound healing response, which may account for the onset of acute skin toxicities following radiation tissue damage.…”

Section: Introductionmentioning

confidence: 99%

ElevatedARG1expression in primary monocytes-derived macrophages as a predictor of radiation-induced acute skin toxicities in early breast cancer patients

Jung

Sabri

Hanson

et al. 2015

Cancer Biology & Therapy

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Radiation therapy (RT) the front-line treatment after surgery for early breast cancer patients is associated with acute skin toxicities in at least 40% of treated patients. Monocyte-derived macrophages are polarized into functionally distinct (M1 or M2) activated phenotypes at injury sites by specific systemic cytokines known to play a key role in the transition between damage and repair in irradiated tissues. The role of M1 and M2 macrophages in RT-induced acute skin toxicities remains to be defined. We investigated the potential value of M1 and M2 macrophages as predictive factors of RT-induced skin toxicities in early breast cancer patients treated with adjuvant RT after lumpectomy. Blood samples collected from patients enrolled in a prospective clinical study (n D 49) were analyzed at baseline and after the first delivered 2Gy RT dose. We designed an ex vivo culture system to differentiate patient blood monocytes into macrophages and treated them with M1 or M2-inducing cytokines before quantitative analysis of their "M1/M2" activation markers, iNOS, Arg1, and TGFß1. Statistical analysis was performed to correlate experimental data to clinical assessment of acute skin toxicity using Common Toxicity Criteria (CTC) grade for objective evaluation of skin reactions. Increased ARG1 mRNA significantly correlated with higher grades of erythema, moist desquamation, and CTC grade. Multivariate analysis revealed that increased ARG1 expression in macrophages after a single RT dose was an independent prognostic factor of erythema (p D 0 .032), moist desquamation (p D 0 .027), and CTC grade (p D 0 .056). Interestingly, multivariate analysis of ARG1 mRNA expression in macrophages stimulated with IL-4 also revealed independent prognostic value for predicting acute RT-induced toxicity factors, erythema (p D 0 .069), moist desquamation (p D 0 .037), and CTC grade (p D 0 .046). To conclude, our findings underline for the first time the biological significance of increased ARG1 mRNA levels as an early independent predictive biomarker of RT-induced acute skin toxicities.

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Radiation‐induced chromosome aberrations: Insights gained from biophysical modeling

et al. 2002

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Enzymatic misrepair of ionizing-radiation-induced DNA damage can produce large-scale rearrangements of the genome, such as translocations and dicentrics. These and other chromosome exchange aberrations can cause major phenotypic alterations, including cell death, mutation and neoplasia. Exchange formation requires that two (or more) genomic loci come together spatially. Consequently, the surprisingly rich aberration spectra uncovered by recently developed techniques, when combined with biophysically based computer modeling, help characterize large-scale chromatin architecture in the interphase nucleus. Most results are consistent with a picture whereby chromosomes are mainly confined to territories, chromatin motion is limited, and interchromosomal interactions involve mainly territory surfaces. Aberration spectra and modeling also help characterize DNA repair/misrepair mechanisms. Quantitative results for mammalian cells are best described by a breakage-and-reunion model, suggesting that the dominant recombinational mechanism during the G(0)/G(1) phase of the cell cycle is non-homologous end-joining of radiogenic DNA double strand breaks. In turn, better mechanistic and quantitative understanding of aberration formation gives new insights into health-related applications.

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Relationship between in vitro chromosomal radiosensitivity of peripheral blood lymphocytes and the expression of normal tissue damage following radiotherapy for breast cancer

Cited by 116 publications

References 34 publications

Aberrant CDKN1A transcriptional response associates with abnormal sensitivity to radiation treatment

Aberrant CDKN1A transcriptional response associates with abnormal sensitivity to radiation treatment

ElevatedARG1expression in primary monocytes-derived macrophages as a predictor of radiation-induced acute skin toxicities in early breast cancer patients

Radiation‐induced chromosome aberrations: Insights gained from biophysical modeling

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