Individual differences in chromosomal aberrations after in vitro irradiation of cells from healthy individuals, cancer and cancer susceptibility syndrome patients

Distel, Luitpold; Neubauer, Susann; Keller, Ulrike; Sprung, Carl N.; Sauer, Rolf; Grabenbauer, Gerhard G.

doi:10.1016/j.radonc.2006.10.012

Cited by 50 publications

(42 citation statements)

References 29 publications

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“…22e26 Chromosomal aberrations (mainly translocations and dicentrics) and clonogenic survival are the classic and most reliable end points for predicting individual RS. 23,24,27,28 However, they are time-consuming, and the latter often requires cell transformation for conferring indefinite proliferation and facilitate propagation, which itself changes cell properties. 29e31 Although sequencing techniques, including exome sequencing, enhance the detection of mutations in candidate genes conferring RS-SCID and RS-CID, functional assays can provide an important additional tool for establishing, for example, whether missense mutations affect functioning.…”

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confidence: 99%

Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity

Lobachevsky

Woodbine

Hsiao

et al. 2015

The Journal of Molecular Diagnostics

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Pediatric patients with severe or nonsevere combined immunodeficiency have increased susceptibility to severe, life-threatening infections and, without hematopoietic stem cell transplantation, may fail to thrive. A subset of these patients have the radiosensitive (RS) phenotype, which may necessitate conditioning before hematopoietic stem cell transplantation, and this conditioning includes radiomimetic drugs, which may significantly affect treatment response. To provide statistical criteria for classifying cellular response to ionizing radiation as the measure of functional RS screening, we analyzed the repair capacity and survival of ex vivo irradiated primary skin fibroblasts from five dysmorphic and/or developmentally delayed pediatric patients with severe combined immunodeficiency and combined immunodeficiency. We developed a mathematical framework for the analysis of g histone 2A isoform X foci kinetics to quantitate DNA-repair capacity, thus establishing crucial criteria for identifying RS. The results, presented in a diagram showing each patient as a point in a 2D RS map, were in agreement with findings from the assessment of cellular RS by clonogenic survival and from the genetic analysis of factors involved in the nonhomologous end-joining repair pathway. We provide recommendations for incorporating into clinical practice the functional assays and genetic analysis used for establishing RS status before conditioning. This knowledge would enable the selection of the most appropriate treatment regimen, reducing the risk for severe therapy-related adverse effects. Severe combined immunodeficiency (SCID) and combined immunodeficiency (CID) are rare genetic disorders. The incidence of SCID in Australia is 1 in 69,000 live births, 1 comparable to the reported incidence of 1 in 100,000 births worldwide. CID patients have increased susceptibility to invasive and opportunistic bacterial, viral, and fungal infections due to poor T-lymphocyte production and/or function, in addition to failure of B lymphocytes to generate functional antibodies. SCID is the extreme form of CID. Patients with this condition often present in the first year of life, with severe life-threatening infections, and consequently failure to thrive, requiring prompt intervention. SCID without treatment is usually fatal within the first year of life. 2 Both SCID and CID are genetically diverse syndromes, and over 50 molecular defects resulting in these syndromes have been described. 3 Approximately 30% of SCID patients have defects in V(D)J recombination (antigen receptor

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confidence: 99%

Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity

Lobachevsky

Woodbine

Hsiao

et al. 2015

The Journal of Molecular Diagnostics

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“…Assays that have shown promise include colony survival assays (Brock et al, 1995;West et al, 1998), chromosomal aberration frequency (Neubauer et al, 1997(Neubauer et al, , 2002Distel et al, 2006), comet assay (Brammer et al, 2001), DNA damage and repair based on pulsedfield gel electrophoresis (PFGE) (Wurm et al, 1994;McKay and Kefford, 1995;Zhou et al, 1998), micronucleus assay (Nachtrab et al, 1998;Sprung et al, 2005), telomere length (McIlrath et al, 2001;Sprung et al, 2008), SNP analysis (Severin et al, 2001;Gurska et al, 2007;Wilding et al, 2007;Alsner et al, 2008), DNA end binding complexes (Ismail et al, 2004) and transcriptional profiling (Rieger et al, 2004;Svensson et al, 2006;Sprung et al, in preparation). Thus, many potential endpoints exist, most of which have been partially successful in identifying clinical RS.…”

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H2AX phosphorylation screen of cells from radiosensitive cancer patients reveals a novel DNA double-strand break repair cellular phenotype

et al. 2010

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BACKGROUND: About 1 -5% of cancer patients suffer from significant normal tissue reactions as a result of radiotherapy (RT). It is not possible at this time to predict how most patients' normal tissues will respond to RT. DNA repair dysfunction is implicated in sensitivity to RT particularly in genes that mediate the repair of DNA double-strand breaks (DSBs). Phosphorylation of histone H2AX (phosphorylated molecules are known as gH2AX) occurs rapidly in response to DNA DSBs, and, among its other roles, contributes to repair protein recruitment to these damaged sites. Mammalian cell lines have also been crucial in facilitating the successful cloning of many DNA DSB repair genes; yet, very few mutant cell lines exist for non-syndromic clinical radiosensitivity (RS). METHODS: Here, we survey DNA DSB induction and repair in whole cells from RS patients, as revealed by gH2AX foci assays, as potential predictive markers of clinical radiation response. RESULTS: With one exception, both DNA focus induction and repair in cell lines from RS patients were comparable with controls. Using gH2AX foci assays, we identified a RS cancer patient cell line with a novel ionising radiation-induced DNA DSB repair defect; these data were confirmed by an independent DNA DSB repair assay. CONCLUSION: gH2AX focus measurement has limited scope as a pre-RT predictive assay in lymphoblast cell lines from RT patients; however, the assay can successfully identify novel DNA DSB repair-defective patient cell lines, thus potentially facilitating the discovery of novel constitutional contributions to clinical RS.

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“…Several studies have shown that enhanced chromosomal radiosensitivity is also present in a significant proportion of cancer patients (Scott et al, 1994(Scott et al, , 1998Parshad et al, 1996;Patel et al, 1997;Terzoudi et al, 2000;Baria et al, 2001Baria et al, , 2002Buchholz and Wu, 2001;Papworth et al, 2001;Riches et al, 2001;Baeyens et al, 2002Baeyens et al, , 2005Ban et al, 2004;Howe et al, 2005;Kolusayin Ozar and Orta, 2005;Mozdarani et al, 2005;Distel et al, 2006;Lisowska et al, 2006;Varga et al, 2006). The majority of data have been collected in studies considering breast cancer patients whose lymphocytes were irradiated in the G 2 phase of the cell cycle (Scott et al, 1994Parshad et al, 1996;Patel et al, 1997;Terzoudi et al, 2000;Baria et al, 2001;Buchholz and Wu, 2001;Riches et al, 2001;Baeyens et al, 2002Baeyens et al, , 2005Howe et al, 2005;Djuzenova et al, 2006;Docherty et al, 2007).…”

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confidence: 99%

“…Until recently, most of the studies evaluating phenotypic assays as possible marker for head and neck cancer susceptibility focused on the analysis of chromosomal damage in lymphocytes after mutagen exposure Bondy et al, 1993;Spitz et al, 1993;Cloos et al, 1996;Wang et al, 1998;Wu et al, 1998;Zhu et al, 2002;Szekely et al, 2005;Xiong et al, 2007). Studies analysing chromosomal damage after in vitro irradiation are, however, limited and often comprise a low number of patients (Terzoudi et al, 2000;Papworth et al, 2001;Ban et al, 2004;Distel et al, 2006;Lisowska et al, 2006). Nevertheless, both Terzoudi et al (2000) and Lisowska et al (2006) reported enhanced chromosomal radiosensitivity in larynx cancer patients, and Papworth et al (2001) observed increased chromosomal radiosensitivity in young head and neck cancer patients.…”

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Chromosomal radiosensitivity in head and neck cancer patients: evidence for genetic predisposition?

et al. 2008

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The association between chromosomal radiosensitivity and genetic predisposition to head and neck cancer was investigated in this study. In all, 101 head and neck cancer patients and 75 healthy control individuals were included in the study. The G 2 assay was used to measure chromosomal radiosensitivity. The results demonstrated that head and neck cancer patients had a statistically higher number of radiation-induced chromatid breaks than controls, with mean values of 1.23 and 1.10 breaks per cell, respectively (Po0.001). Using the 90th percentile of the G 2 scores of the healthy individuals as a cutoff value for chromosomal radiosensitivity, 26% of the cancer patients were radiosensitive compared with 9% of the healthy controls (P ¼ 0.008). The mean number of radiation-induced chromatid breaks and the proportion of radiosensitive individuals were highest for oral cavity cancer patients (1.26 breaks per cell, 38%) and pharynx cancer patients (1.27 breaks per cell, 35%). The difference between patients and controls was most pronounced in the lower age group (p50 years, 1.32 breaks per cell, 38%) and in the non-and light smoking patient group (p10 pack-years, 1.28 breaks per cell, 46%). In conclusion, enhanced chromosomal radiosensitivity is a marker of genetic predisposition to head and neck cancer, and the genetic contribution is highest for oral cavity and pharynx cancer patients and for early onset and non-and light smoking patients.

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Individual differences in chromosomal aberrations after in vitro irradiation of cells from healthy individuals, cancer and cancer susceptibility syndrome patients

Cited by 50 publications

References 29 publications

Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity

Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity

H2AX phosphorylation screen of cells from radiosensitive cancer patients reveals a novel DNA double-strand break repair cellular phenotype

Chromosomal radiosensitivity in head and neck cancer patients: evidence for genetic predisposition?

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