γ-H2AX in Cancer Cells: A Potential Biomarker for Cancer Diagnostics, Prediction and Recurrence

Sedelnikova, Olga A.; Bonner, William M.

doi:10.4161/cc.5.24.3569

Cited by 171 publications

(78 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both molecular markers, γH2AX and 53BP1, and their co-localization have consistently shown statistically significantly increased constitutive level of DSBs in hematopoietic cells of pediatric ALL patients. This data are in line with results showing increased constitutive DNA damage in variety of cancer cell lines [19,32] and tumors [16,33] by analyzing constitutive γH2AX. Similarly, normal cells express less 53BP1 constitutive foci than variety of cancer cells [34,35].…”

Section: Discussionsupporting

confidence: 78%

See 1 more Smart Citation

Constitutive 53BP1/γH2AX foci are increased in cells of ALL patients dependent on BCR-ABL and TEL-AML1 preleukemic gene fusions

Somsedíková¹,

Markovà²,

Kolenová³

et al. 2014

neo

View full text Add to dashboard Cite

Childhood leukemia arises from hematopoietic stem cells by induction of mutations. Quite often chromosomal translocations arise prenatally as first key event in multistage process of leukemogenesis. These translocations result in so called preleukemic gene fusions (PGFs), such as BCR-ABL and TEL-AML1, which generate hybrid proteins with altered properties. Critical DNA damage resulting in translocations are DNA double-strand breaks (DSBs). BCR-ABL and TEL-AML1 were shown to be associated with increased constitutive DSBs in various model systems. We analyzed cells from peripheral blood and CD34-/CD34+ cells from bone marrow of pediatric acute lymphoblastic leukemia (ALL) patients harboring BCR-ABL or TEL-AML1. We used sensitive technique that is based on automated enumeration of DSB co-localizing proteins γH2AX and 53BP1, which form so called DNA repair foci. We found that level of constitutive γH2AX/53BP1 foci is significantly higher in cells of ALL pediatric patients than in healthy subjects. There was also significant increased level of constitutive γH2AX/53BP1 foci in cells from ALL patients harboring BCR-ABL or TEL-AML1 compared to patients without PGFs. The same increase was observed regardless cell type for both PGFs. Our data on increased DSB levels in the BCR-ABL/TEL-AML1 patient's cells support a model where BCR-ABL/TEL-AML1 induces DNA instability through facilitating mutagenesis and appearance of additional genetic alterations driving leukemogenesis.

show abstract

Section: Discussionsupporting

confidence: 78%

“…Elevated constitutive levels of DNA repair foci were found in various human cancer cell lines, premalignant lesions and solid tumors suggesting that increased DNA damage is a general characteristic of cancer development [16][17][18]. Seo et al found a >8-fold increase in H2AX expression in Jurkat cell line, a model for acute T-cell leukemia [18].…”

mentioning

confidence: 99%

Constitutive 53BP1/γH2AX foci are increased in cells of ALL patients dependent on BCR-ABL and TEL-AML1 preleukemic gene fusions

Somsedíková¹,

Markovà²,

Kolenová³

et al. 2014

neo

View full text Add to dashboard Cite

show abstract

“…Elevated endogenous γ-H2AX foci levels are suggested to be a characteristic of carcinogenesis and also are associated with tumors positive for the human papilloma virus (HPV) 2,115,116 . The latter is likely related to the observation that HPV-positive human HNSCC cell lines and tumors are more radiosensitive than HPV-negative cancers due to compromised DSB repair 117–119 …”

Section: Technical Challenges Of Foci Studies In Tumor Tissues In-vivmentioning

confidence: 99%

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

Willers

Gheorghiu

Liu

et al. 2015

Seminars in Radiation Oncology

View full text Add to dashboard Cite

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.

show abstract

“…Based on H2AX function in DNA repair and in maintaining DNA stability, the use of H2AX / γH2AX as marker for early cancer detection, prognosis and therapeutics has been proposed [70]. Elevated endogenous levels of γH2AX have been found in various human cancer cell lines such as cervical [71], ovarian [72], breast [73], leukaemia and melanoma, colon, renal, and prostate cancer cell lines [70].…”

Section: Introductionmentioning

confidence: 99%

“…Elevated endogenous levels of γH2AX have been found in various human cancer cell lines such as cervical [71], ovarian [72], breast [73], leukaemia and melanoma, colon, renal, and prostate cancer cell lines [70]. Many therapeutic agents act by introducing sufficient DSBs into cancer cells to activate the apoptotic pathway [74].…”

Section: Introductionmentioning

confidence: 99%

Expression and functionality of histone H2A variants in cancer

et al. 2014

View full text Add to dashboard Cite

Regulation of gene expression includes the replacement of canonical histones for non-allelic histone variants, as well as their multiple targeting by postranslational modifications. H2A variants are highly conserved between species suggesting they execute important functions that cannot be accomplished by canonical histones. Altered expression of many H2A variants is associated to cancer. MacroH2A variants are enriched in heterocromatic foci and are necessary for chromatin condensation. MacroH2A1.1 and macroH2A1.2 are two mutually exclusive isoforms. MacroH2A1.1 and macroH2A2 inhibit proliferation and are associated with better cancer prognosis; while macroH2A1.2 is associated to cancer progression. H2AX variant functions as a sensor of DNA damage and defines the cellular response towards DNA repair or apoptosis; therefore, screening approaches and therapeutic options targeting H2AX have been proposed. H2A.Z is enriched in euchromatin, acting as a proto-oncogene with established roles in hormone responsive cancers and overexpressed in endocrine-resistant disease. Other H2A family members have also been found altered in cancer, but their function remains unknown. Substantial progress has been made to understand histone H2A variants, their contribution to normal cellular function and to cancer development and progression. Yet, implementation of high resolution mass spectrometry is needed to further our knowledge on highly homologous H2A variants expression and function.

show abstract

γ-H2AX in Cancer Cells: A Potential Biomarker for Cancer Diagnostics, Prediction and Recurrence

Cited by 171 publications

References 34 publications

Constitutive 53BP1/γH2AX foci are increased in cells of ALL patients dependent on BCR-ABL and TEL-AML1 preleukemic gene fusions

Constitutive 53BP1/γH2AX foci are increased in cells of ALL patients dependent on BCR-ABL and TEL-AML1 preleukemic gene fusions

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

Expression and functionality of histone H2A variants in cancer

Contact Info

Product

Resources

About