Expression of γ-H2AX in endometrial carcinomas: An immunohistochemical study with p53

Brunner, Andreas; Hinterholzer, Susanne; Riss, P.; Heinze, Georg; Weiss, Katharina; Brustmann, Hermann

doi:10.1016/j.ygyno.2010.11.037

Cited by 33 publications

(33 citation statements)

References 28 publications

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“…This theory is in accordance with the model of Halazonetis et al, who propose a barrier to tumorigenesis predominated by the apoptotic index and characterized by low levels of activation of the DDR system at normal tissues, a peak at precancerous lesions and sustained high levels at tumors 26. The link between p53 and γ-H2AX has already been proposed by Brunner et al showing that increased expression levels of γ-H2AX are associated with bad prognostic features in endometrial carcinomas 27. Nagelkerke et al also found that in triple-negative breast carcinomas, a high number of γ-H2AX foci indicated a significantly worse prognosis 28.…”

Section: Discussionsupporting

confidence: 88%

γ-H2AX expression detected by immunohistochemistry correlates with prognosis in early operable non-small cell lung cancer

Matthaios¹,

Foukas²,

Kefala³

et al. 2012

OTT

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BackgroundPhosphorylation of the H2AX histone is an early indicator of DNA double-strand breaks and of the resulting DNA damage response. In the present study, we assessed the expression and prognostic significance of γ-H2AX in a cohort of 96 patients with operable non-small cell lung carcinoma.MethodsNinety-six paraffin-embedded specimens of non-small cell lung cancer patients were examined. All patients underwent radical thoracic surgery of primary tumor (lobectomy or pneumonectomy) and regional lymph node dissection. γ-H2AX expression was assessed by standard immunohistochemistry. Follow-up was available for all patients; mean duration of follow-up was 27.50 ± 14.07 months (range 0.2–57 months, median 24 months).ResultsSixty-three patients (65.2%) died during the follow-up period. The mean survival time was 32.2 ± 1.9 months (95% confidence interval [CI]: 28.5–35.8 months; median 30.0 months); 1-, 2- and 3-year survival rates were 86.5% ± 3.5%, 57.3% ± 5.1%, and 37.1% ± 5.4%, respectively. Low γ-H2AX expression was associated with a significantly better survival as compared with those having high γ-H2AX expression (35.3 months for low γ-H2AX expression versus 23.2 months for high γ-H2AX expression, P = 0.009; hazard ratio [HR] 1.95, 95% CI: 1.15–3.30). Further investigation with multivariate Cox proportional hazards regression analysis revealed that high expression of γ-H2AX remained an independent prognostic factor of shorter overall survival (HR 2.15, 95% CI: 1.22–3.79, P = 0.026). A combined p53/γ-H2AX analysis was performed, and we found that the p53 low/γ-H2AX low phenotype was associated with significantly better survival compared with all other phenotypes.ConclusionOur study is the first to demonstrate that expression of γ-H2AX detected by immunohistochemistry may represent an independent prognostic indicator of overall survival in patients with non-small cell lung cancer. Further studies are needed to confirm our results.

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Section: Discussionsupporting

confidence: 88%

γ-H2AX expression detected by immunohistochemistry correlates with prognosis in early operable non-small cell lung cancer

Matthaios¹,

Foukas²,

Kefala³

et al. 2012

OTT

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“…56 Carlson et al 57 indicate that gH2AX is overexpressed in lichen sclerosus of the vulva/ penis and squamous cell carcinoma. Brunner et al 58 investigated the role of gH2AX in endometrial tumorigenesis. Increased staining levels are positively related to classical prognostic factors, such as tumor stage, tumor grade, histological type, vascular space involvement, as well as shortened disease-free and overall survival.…”

Section: Gh2ax Studies: Biosamplingmentioning

confidence: 99%

“…The authors indicate that gH2AX could potentially be useful as an additional histopathological prognostic factor in patients with endometrial cancer. 58 Another study revealed that expression of gH2AX detected by immunohistochemistry may represent an independent prognostic indicator of overall survival in patients with non-small cell lung cancer, with a 2.15-fold increase in risk of death in individuals with high expression of gH2AX. 59 Ibuki et al 60 showed that gH2AX is a sensitive marker of DNA adducts and provides a possible system for genotoxicity screening of chemicals such as NNK (4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone), which need metabolic activation to induce DNA damage and which in this case is responsible for lung cancer.…”

Section: Gh2ax Studies: Biosamplingmentioning

confidence: 99%

gamma-H2AX: Can it be established as a classical cancer prognostic factor?

Palla¹,

Karaolanis

Katafigiotis

et al. 2017

Tumour Biol.

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Double-strand breaks are among the first procedures taking place in cancer formation and progression as a result of endogenic and exogenic factors. The histone variant H2AX undergoes phosphorylation at serine 139 due to doublestrand breaks, and the gamma-H2AX is formatted as a result of genomic instability. The detection of gamma-H2AX can potentially serve as a biomarker for transformation of normal tissue to premalignant and consequently to malignant tissues. gamma-H2AX has already been investigated in a variety of cancer types, including breast, lung, colon, cervix, and ovary cancers. The prognostic value of gamma-H2AX is indicated in certain cancer types, such as breast or endometrial cancer, but further investigation is needed to establish gamma-H2AX as a prognostic marker. This review outlines the role of gamma-H2AX in cell cycle, and its formation as a result of DNA damage. We investigate the role of gamma-H2AX formation in several cancer types and its correlation with other prognostic factors, and we try to find out whether it fulfills the requirements for its establishment as a classical cancer prognostic factor.

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“…Methylation of these genes could, therefore, play a role in the progression from noninvasive to invasive cancer. H2AFX, which was specific for FTC but not for ovarian cancer, is involved in DNA damage repair and has been implicated in several other cancer types (Warters et al 2005, Brunner et al 2011.…”

Section: Discussionmentioning

confidence: 99%

Promoter hypermethylation patterns in fallopian tube epithelium of BRCA1 and BRCA2 germ line mutation carriers

Bijron

Groep

Dorst

et al. 2011

Endocrine-Related Cancer

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BRCA1/2 germ line mutation carriers have a high risk of developing fallopian tube carcinoma (FTC), thought to occur through different early (p53 signatures) and later (dysplasia, intraepithelial carcinoma) premalignant stages. Promoter hypermethylation of tumour suppressor genes is known to play a key role in (early) carcinogenesis. However, little is known about methylation in normal and (pre)malignant fallopian tube tissue. We identified 14 areas of p53 accumulation in the fallopian tubes of BRCA mutation carriers. Cells from these areas were harvested together with cells from adjacent benign appearing areas. An age-matched non-BRCA sporadic control group (nZ13) and eight sporadic FTCs were included as negative and positive controls respectively. Methylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 70 tumour suppressor genes in all samples. We observed a gradual increase in methylation from sporadic control tissue (median cumulative methylation index (CMI) 568.19) through normal tissue and from areas of p53 accumulation in BRCA carriers (median CMI 687.54 and 676.72) to FTC (median CMI 780.97). Furthermore, the methylation percentage of many individual tumour suppressor genes differed significantly between these groups, gradually increasing as for CMI. Between areas with and without p53 accumulation in BRCA mutation carriers no significant differences were found. In this paper, we have shown that BRCA mutation carriers display increased methylation of tumour suppressor genes in their nonmalignant fallopian tube epithelium, closer to methylation levels in FTC than to normal sporadic tissue. Methylation could, therefore, play an important role in the increased risk of gynaecological malignancies in BRCA mutation carriers.

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Expression of γ-H2AX in endometrial carcinomas: An immunohistochemical study with p53

Cited by 33 publications

References 28 publications

γ-H2AX expression detected by immunohistochemistry correlates with prognosis in early operable non-small cell lung cancer

γ-H2AX expression detected by immunohistochemistry correlates with prognosis in early operable non-small cell lung cancer

gamma-H2AX: Can it be established as a classical cancer prognostic factor?

Promoter hypermethylation patterns in fallopian tube epithelium of BRCA1 and BRCA2 germ line mutation carriers

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Expression of γ-H2AX in endometrial carcinomas: An immunohistochemical study with p53

Cited by 33 publications

References 28 publications

&gamma;-H2AX expression detected by immunohistochemistry correlates with prognosis in early operable non-small cell lung cancer

&gamma;-H2AX expression detected by immunohistochemistry correlates with prognosis in early operable non-small cell lung cancer

gamma-H2AX: Can it be established as a classical cancer prognostic factor?

Promoter hypermethylation patterns in fallopian tube epithelium of BRCA1 and BRCA2 germ line mutation carriers

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γ-H2AX expression detected by immunohistochemistry correlates with prognosis in early operable non-small cell lung cancer

γ-H2AX expression detected by immunohistochemistry correlates with prognosis in early operable non-small cell lung cancer