Clinical Significance of Epigenetic Inactivation of hMLH1 and BRCA1 in Tunisian Patients with Invasive Breast Carcinoma

Karray-Chouayekh, Sondes; Trifa, Fatma; Khabir, Abdelmajid; Boujelbane, Nouredine; Sellami‐Boudawara, Tahya; Daoud, J.; Frikha, M.; Gargouri, Ali; Mokdad-Gargouri, Raja

doi:10.1155/2009/369129

Cited by 24 publications

(19 citation statements)

References 42 publications

(39 reference statements)

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“…However, Xu X et al (29) on the basis of a large population-based study demonstrated decreased survival associated with BRCA1 promoter methylation among women with BC. Similar were the findings of Karray-Chouayekh S et al (28) and Chen Y et al (23). The better survival rate found here by the Kaplan-Meier method was supported by a protective, though not statistically significant, effect of BRCA1 hypermethylation as revealed by the univariate Cox proportional hazards model.…”

Section: Discussionsupporting

confidence: 91%

“…Heterogeneity is observed both with respect to frequency and clinical correlations. The reported frequency of BRCA1 promoter hypermethylation in sporadic breast carcinomas is in the range of 9 to 59% (15,(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). The frequency found here is the first reported in Bulgarian patients with BC and is a little below the average BRCA1 hypermethylation frequency.…”

Section: Discussionmentioning

confidence: 43%

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Breast cancer patients with hypermethylation in the promoter of BRCA1 gene exhibit favorable clinical status

Krasteva¹,

Bozhanov²,

G³

et al. 2012

neo

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Promoter hypermethylation was shown to be involved in human cancerogenesis through silencing gene expression. Several studies were dedicated to explore the frequency and clinical significance of BRCA1 hypermethylation in sporadic breast cancer to identify a specific molecular and clinico-pathological phenotype. However the available data are limited and rather too heterogeneous. In this study we investigated the level of methylation in the promoter region of BRCA1 and its correlation with clinico-pathological and molecular characteristics in a group of 135 Bulgarian patients. Methylation specific PCR was applied to determine methylation status of tumor samples. Clinical impact of BRCA1 hypermethylation was estimated using standard statistical methods including Fisher's exact and the Chi-squared tests, the Kaplan-Meier method, the univariate and multivariate Cox proportional hazards regression model. We found that hypermethylation was present in 17.04% of the cases (23/135). Patients with hypermethylation in BRCA1 displayed favorable clinical status as their tumors were smaller in size (P = 0.066), lacked p53 gene mutations (P = 0.073) and were of lobular type (P = 0.046). The presence of hypermethylation was weakly associated with better overall survival (P = 0.2) with a hazard ratio of 0.47 (95% CI 0.14-1.54, P = 0.213). Our study provides the first data on the BRCA1 hypermethylation of Bulgarian patients and contributes to elucidation of its clinical significance in sporadic breast cancer. Key words: Breast cancer, BRCA1, Hypermethylation, Clinicopathological characteristics, Overall survivalBreast cancer (BC) represents a major challenge to modern human oncology because of its high and constantly increasing frequency, and growing mortality and morbidity rate in women below the age of 45. Every year in Bulgaria, approximately 3600 women are diagnosed and about 1300 die of BC (1). The major risk factors are sex, age, family predisposition, as well as some reproductive and hormonal factors like early menarche and late menopause, late first childbirth, shorter breastfeeding period, use of oral contraceptives and hormone replacement therapy. Clinically BC is very heterogeneous, which is due to heterogeneity in disease mechanisms.BC results from accumulation of genetic and epigenetic changes in tumor suppressor genes and proto-oncogenes. Some of these genes -р53, PIK3CA, CHEK2, АТМ, HER2, are involved in the pathogenesis of different type of tumors. Others are specific only to breast/ovarian cancer -BRCA1 and BRCA2. A large number of studies demonstrate a correlation between the genetic/epigenetic status of BC related genes and clinicopathological characteristics of the patients. Such investigations could contribute to a more effective BC prevention and therapy, which will increase the survival rate and will significantly improve the quality of life of the patients. However, the results so far are contradictory and need further elucidation.BRCA1 (BReast CAncer susceptibility gene 1) tumor suppressor gene maps to 17...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 43%

Breast cancer patients with hypermethylation in the promoter of BRCA1 gene exhibit favorable clinical status

Krasteva¹,

Bozhanov²,

G³

et al. 2012

neo

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“…Together, our results suggest that regulation of BRCA1 by hypoxia occurs through at least two mechanisms: activation of the E2F/p130 pathway to mediate acute downregulation (1) and induction of repressive histone modifications, especially H3K4 demethylation by LSD1, as a step toward epigenetic silencing (2). Silencing of BRCA1 has previously been associated with promoter DNA hypermethylation at CpG islands, based on observations in human tumor specimens (8,14,21,35,50). However, we could not detect any cytosine methylation either at the endogenous BRCA1 promoter in MCF-7 cells after hypoxia exposure or at hypoxia-induced, silenced BRCA1 promoters in BSH8-derived cells.…”

Section: Discussionmentioning

confidence: 60%

Hypoxia-Induced Epigenetic Regulation and Silencing of the BRCA1 Promoter

Lü

Chu

Turker

et al. 2011

Molecular and Cellular Biology

120

104

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Disruption of the BRCA1 tumor suppressor can be caused not only by inherited mutations in familial cancers but also by BRCA1 gene silencing in sporadic cancers. Hypoxia, a key feature of the tumor microenvironment, has been shown to downregulate BRCA1 at the transcriptional level via repressive E2F4/p130 complexes. Here we showed that hypoxia also drives epigenetic modification of the BRCA1 promoter, with decreased H3K4 methylation as a key repressive modification produced by the lysine-specific histone demethylase LSD1. We also observed increased H3K9 methylation coupled with decreased H3K9 acetylation. Similar modifications were seen in the RAD51 promoter, which is also downregulated by hypoxia, whereas exactly opposite changes were seen in the promoter of the hypoxia-inducible gene VEGF. In cells containing the BRCA1 promoter driving a selectable HPRT gene, long-term silencing of the promoter was observed following exposure to hypoxic stress. Clones with silenced BRCA1 promoters were detected at frequencies of 2% or more following hypoxia, but at less than 6 ؋ 10 ؊5 without hypoxia. The silenced clones showed decreased H3K4 methylation and decreased H3K9 acetylation in the BRCA1 promoters, consistent with the acute effects of hypoxic stress. Hypoxia-induced BRCA1 promoter silencing persisted in subsequent normoxic conditions but could be reversed by treatment with a histone deacetylase (HDAC) inhibitor but not with a DNA methylation inhibitor. Interestingly, treatment of cells with inhibitors of poly(ADP-ribose) polymerase (PARP) can cause short-term repression of BRCA1 expression, but such treatment does not produce H3K4 or H3K9 histone modification or BRCA1 promoter silencing. These results suggest that hypoxia is a driving force for long-term silencing of BRCA1, thereby promoting genome instability and tumor progression.Solid tumors constitute a unique tissue type, characterized by hypoxia, low pH, and nutrient deprivation. Previous work has shown that hypoxic stress is a source of genetic instability in tumors (3,5,7,40,58), causing increased point mutations (40), gene amplification (11, 58), and fragile-site induction (12). Our previous work revealed that BRCA1 and RAD51, key genes in the homology-dependent repair (HDR) pathway, and MLH1, a key DNA mismatch (MMR) repair gene, are downregulated at the mRNA and protein levels in response to hypoxia via specific pathways of transcriptional regulation (3-5, 7). Moreover, BRCA1 and MLH1 have been found to be silenced in many sporadic cancers of multiple sites (8,14,16). The silencing of BRCA1 and MLH1 has been attributed primarily to promoter DNA hypermethylation at CpG sites (14). However, recent studies suggest that silenced promoters in cancer cells are also marked by characteristic histone modifications (9, 33, 48), and evidence is emerging that histone methylation may be a mediator of silencing that is independent of DNA methylation (26,29,30).Posttranslational modification of histones is widely recognized as an important epigenetic mechanism in the orga...

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“…20 These primers amplify a 182-bp product. 20,21 The PCR was carried out in a 25 μL mixture containing 10 mM tris hydrochloride (pH, 8.3), 50 mM potassium chloride, 1.5 mM magnesium chloride, 5 units of recombinant Taq DNA polymerase, 200 µM of dNTP, 0.6 µM of each primer, and 2.5 µL of bisulfate-treated template DNA.…”

Section: Methylation-specific Pcrmentioning

confidence: 99%

BRCA1Promoter Methylation Status in Ovarian Cancer

Nikbakht¹,

Shabanizadeh²,

Salehi³

et al. 2012

Lab Med

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Objective: To evaluate the methylation status of the breast cancer 1, early onset (BRCA1) promoter in ovarian cancer in Iranian patients. Methods:The BRCA1 promoter methylation status of tissue from 60 patients with Müllerian-type ovarian cancer and matched benign ovarian tissue from the same patients was evaluated using bisulfate-modified DNA in methylation-specific polymerase chain reaction (MSP CR) assays.Results: Analysis of BRCA1 promoter methylation status showed that 8 of 60 cases (13%) were methylated and 11 of 60 cases (18%) were unmethylated.Conclusion: Methylation of the BRCA1 promoter may be a risk factor or cause of ovarian cancer.Abbreviations BRCA1, breast cancer 1, early onset; PCR, polymerase chain reaction; MSP, methylation-specific

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Clinical Significance of Epigenetic Inactivation of hMLH1 and BRCA1 in Tunisian Patients with Invasive Breast Carcinoma

Cited by 24 publications

References 42 publications

Breast cancer patients with hypermethylation in the promoter of BRCA1 gene exhibit favorable clinical status

Breast cancer patients with hypermethylation in the promoter of BRCA1 gene exhibit favorable clinical status

Hypoxia-Induced Epigenetic Regulation and Silencing of the BRCA1 Promoter

BRCA1Promoter Methylation Status in Ovarian Cancer

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