Reduced Activity of Double-Strand Break Repair Genes in Prostate Cancer Patients With Late Normal Tissue Radiation Toxicity

Oorschot, Bregje van; Hovingh, Suzanne E.; Moerland, Perry D.; Medema, Jan Paul; Stalpers, Lukas J.A.; Vrieling, Harry; Franken, Nicolaas A.P.

doi:10.1016/j.ijrobp.2013.11.219

Cited by 41 publications

(31 citation statements)

References 34 publications

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“…Results from the comet assay (mainly DNA single strand breaks and base damage) suggested that low repair kinetics and higher amounts of residual damage after a dose of 2 Gy increased the risk of early reaction (188) and higher levels of damage were significantly related to severity of the reaction (179). Similar findings were obtained in several recent studies using the more sensitive method of DSB detection by γH2AX repair foci (152, 189-196) though some studies found no significant correlation (149, 151, 197-199). However, in all studies, a large overlap in γH2AX levels was observed between RT sensitive and resistant patients making predictions based on these assays difficult.…”

Section: Functional Assayssupporting

confidence: 90%

“…In this study, gene sets were involved in protein turnover, development, stress signalling and apoptosis, the latter being more pronounced in patients without late reaction. Further studies supported associations between lymphocyte gene expression profiles and the risk of early reaction in head-and-neck (n=30) (149) or mixed head-and-neck and breast patients (n=24) (150), and late toxicity in breast (n=59) (151) and prostate cancer RT patients (n=61) (152). …”

Section: ‘Omics’ Approachesmentioning

confidence: 75%

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Radiogenomics: A systems biology approach to understanding genetic risk factors for radiotherapy toxicity?

et al. 2016

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Adverse reactions in normal tissue after radiotherapy (RT) limit the dose that can be given to tumour cells. Since 80% of individual variation in clinical response is estimated to be caused by patient-related factors, identifying these factors might allow prediction of patients with increased risk of developing severe reactions. While inactivation of cell renewal is considered a major cause of toxicity in early-reacting normal tissues, complex interactions involving multiple cell types, cytokines, and hypoxia seem important for late reactions. Here, we review ‘omics’ approaches such as screening of genetic polymorphisms or gene expression analysis, and assess the potential of epigenetic factors, posttranslational modification, signal transduction, and metabolism. Furthermore, functional assays have suggested possible associations with clinical risk of adverse reaction. Pathway analysis incorporating different ‘omics’ approaches may be more efficient in identifying critical pathways than pathway analysis based on single ‘omics’ data sets. Integrating these pathways with functional assays may be powerful in identifying multiple subgroups of RT patients characterized by different mechanisms. Thus ‘omics’ and functional approaches may synergize if they are integrated into radiogenomics ‘systems biology’ to facilitate the goal of individualised radiotherapy.

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Section: Functional Assayssupporting

confidence: 90%

Section: ‘Omics’ Approachesmentioning

confidence: 75%

Radiogenomics: A systems biology approach to understanding genetic risk factors for radiotherapy toxicity?

et al. 2016

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“…In two studies with 41 and 47 pediatric solid tumors and leukemia patients receiving DNA-damaging therapy, γ-H2AX foci were evaluated in ex-vivo irradiated PBL which enabled the identification of patients at risk for high-grade acute and late toxicities and allowed for detection of DSB repair deficiencies, although not all treatment-associated normal-tissue toxicities could be explained by DSB repair insufficiencies 124 , 125 . Similar observations were made with regard to severe late effects in prostate cancer patients and acute (grade >2) dermatitis in breast cancer patients 106 , 126 . In contrast to these findings, a number of studies which also used blood lymphocytes for γ-H2AX evaluation could not find a correlation with acute side effects 109,127,128 However, caution must be taken with the interpretation of these results.…”

Section: γ-H2ax Assays For Biodosimetry and Prediction Of Normal Tisssupporting

confidence: 79%

DNA Damage Response Assessments in Human Tumor Samples Provide Functional Biomarkers of Radiosensitivity

Willers

Gheorghiu

Liu

et al. 2015

Seminars in Radiation Oncology

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Predictive biomarkers are urgently needed for individualization of radiation therapy and treatment with radiosensitizing anti-cancer agents. Genomic profiling of human cancers will provide us with unprecedented insight into the mutational landscape of genes directly or indirectly involved in the response to radiation-induced DNA damage. However, to what extent this wealth of structural information about the cancer genome will produce biomarkers of sensitivity to radiation remains to be seen. Investigators are increasingly studying the subnuclear accumulation (i.e., foci) of proteins in the DNA damage response (DDR), such as γ-H2AX, 53BP1, or RAD51, as a surrogate of treatment sensitivity. Recent findings from preclinical studies have demonstrated the predictive potential of DDR foci by correlating foci with clinically relevant endpoints such as tumor control probability. Therefore, pre-clinical investigations of DDR foci responses are increasingly moving into cells and tissues from patients, which is the major focus of this review. The advantage of using DDR foci as functional biomarkers is that they can detect alterations in DNA repair due to various mechanisms. Moreover, they provide a global measurement of DDR network function without needing to know the identities of all the components, many of which remain unknown. Foci assays are thus expected to yield functional insight that may complement or supersede genomic information, thereby giving radiation oncologists unique opportunities to individualize cancer treatments in the near future.

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“…Similarly, Goutham et al (15) showed that the amount of residual gH2AX foci correlated with increased early radiation toxicity in head and neck cancer patents. A study of a series of over-responding patients with prostate cancer treated with radiation therapy found that persistently high gH2AX levels 24 hours after ex vivo lymphocyte irradiation correlated with increased late tissue sequelae (16). It is stressed, however, that PBMCs is an early responding tissue and whether the sensitivity for late effects goes along with early sensitivity is an obscure issue, as yet.…”

Section: Discussionmentioning

confidence: 99%

Survival Fraction at 2 Gy and γH2AX Expression Kinetics in Peripheral Blood Lymphocytes From Cancer Patients: Relationship With Acute Radiation-Induced Toxicities

Pouliliou¹,

Lialiaris²,

Dimitriou³

et al. 2015

International Journal of Radiation Oncology*Biology*Physics

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Reduced Activity of Double-Strand Break Repair Genes in Prostate Cancer Patients With Late Normal Tissue Radiation Toxicity

Cited by 41 publications

References 34 publications

Radiogenomics: A systems biology approach to understanding genetic risk factors for radiotherapy toxicity?

Radiogenomics: A systems biology approach to understanding genetic risk factors for radiotherapy toxicity?

DNA Damage Response Assessments in Human Tumor Samples Provide Functional Biomarkers of Radiosensitivity

Survival Fraction at 2 Gy and γH2AX Expression Kinetics in Peripheral Blood Lymphocytes From Cancer Patients: Relationship With Acute Radiation-Induced Toxicities

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