Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 9  |  Page : 354-361

Extent of breast cancer type 1 promoter methylation correlates with clinicopathological features in breast cancers


1 Department of the Second Section Office of Breast Tumor (Second Department of Breast Cancer), Jilin Cancer Hospital, Changchun 130000, P.R. China
2 Department of the Second Section Office of Breast Tumor (Second Department of Breast Cancer), Tianjin Cancer Hospital, Tianjin 300000, P.R. China

Date of Web Publication29-Jun-2018

Correspondence Address:
Chang-Qing Wang
Department of the Second Section Office of Breast Tumor (Second Department of Breast Cancer), Jilin Cancer Hospital, No. 1018 Huguang Road, Chaoyang District, Changchun 130000
P.R. China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.235354

Rights and Permissions
 > Abstract 

Aim of Study: The current meta-analysis investigated the correlation between breast cancer type 1 (BRCA1) promoter methylation and the clinicopathological features of breast cancer (BC).
Materials and Methods: An electronic literature search was performed to identify and select cohort studies, by employing stringent inclusion and exclusion criteria, for data relevant to promoter methylation of BRCA1 and BC. Statistical analysis of the extracted data was performed using comprehensive meta-analysis 2.0 software (CMA 2.0) (Biostat Inc., Englewood, New Jersey, USA).
Results: A total of 125 published studies were retrieved from the literature search, and finally, 18 cohort studies meeting our inclusion criteria were incorporated into our meta-analysis. The 18 studies contained a total of 3213 BC patients. Meta-analysis results revealed that BRCA1 promoter methylation in BC patients with high and moderately differentiated tumors (I-II) was significantly lower than patients with poorly-differentiation tumors (III) (odds ratio [OR] =0.450, 95% confidence interval [95% CI] =0.241–0.838, P = 0.012). BRCA1 promoter methylation in BC patients with lymph node (LN) metastasis was significantly higher than patients without LN metastasis (OR = 2.244, 95% CI = 1.278–3.940, P = 0.005). The results of ethnicity-based subgroup analysis showed a significant difference in histological grade of BC on Asians, LN metastasis of BC in Asians and Caucasians, subtypes of BC in Caucasians, and age at diagnosis of BC patients in Caucasians (all P < 0.05).
Conclusions: Our meta-analysis revealed that BRCA1 promoter methylation status is linked to tumor grade and LN metastasis of BC.

Keywords: Breast cancer type 1, breast cancers, clinicopathological features, lymph node metastasis, methylation, tumor grade


How to cite this article:
Sun MY, Chang XZ, Xu GY, Dong Y, Zhou ZJ, Liu T, Wang CQ, Li YS. Extent of breast cancer type 1 promoter methylation correlates with clinicopathological features in breast cancers. J Can Res Ther 2018;14, Suppl S2:354-61

How to cite this URL:
Sun MY, Chang XZ, Xu GY, Dong Y, Zhou ZJ, Liu T, Wang CQ, Li YS. Extent of breast cancer type 1 promoter methylation correlates with clinicopathological features in breast cancers. J Can Res Ther [serial online] 2018 [cited 2019 Sep 22];14:354-61. Available from: http://www.cancerjournal.net/text.asp?2018/14/9/354/235354


 > Introduction Top


Breast cancer (BC) results from malignant proliferation and transformation of epithelial cells lining the ducts or lobules of the breast, and is the second leading cause of cancer-related deaths in women globally.[1],[2] More than 1 million women are diagnosed with BC every year worldwide, and approximately 0.65% of these women are under 30 years of age, 2.4% are <35 years and 6.6% are <40 years.[3],[4] Surprisingly, the prevalence and mortality rates of BC continue to be higher in majority of the developed countries, compared to developing countries.[5] BC is very heterogeneous disease, and multiple risk factors, such as age at menarche, age at menopause, obesity, lack of physical activity, breastfeeding, tobacco smoking, heavy alcohol consumption, body mass index, and other unhealthy lifestyles, significantly contribute to individual variations in the underlying pathophysiology of BC among given population.[6],[7] Both invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) with the same causes of BC, are two pathological types of BC, and ILC is more often related with higher age at diagnosis, bilaterality, larger tumor size, multifocality, lower cell proliferation rate compared to IDC.[8] Cancer metastasis to axillary lymph nodes (LNs) and histological grade are the two main prognostic determinants in BC patients, and the overall 5 year survival for BC patients with LN metastasis is 40% lower than patients who do not have LNs metastasis.[9],[10] In light of the high incidence and poor prognosis of BC, we are broadly interested in BC tumor suppressor genes, and in this study, were specifically interested in the association between breast cancer type 1 (BRCA1) gene promoter methylation and the development and progression of BC.[11],[12]

BRCA1 gene is localized on chromosome 17 (locus 17q21) and consists of 24 exons, spanning 81 kb of DNA and encodes an 1863 amino acids long multi-functional protein.[13],[14]BRCA1 is a tumor suppressor gene participating in several important cellular functions, including regulation of transcription, DNA repair, and protein ubiquitination as well as cell cycle regulation.[15] BRCA1 protein is also highly expressed in proliferative cells and its loss of expression results in genetic instability and growth arrest.[16] The promoter methylation is a common mechanism for inactivation of BRCA1 gene expression, frequently observed in breast and ovarian cancers.[17] It is reported that methylation of BRCA1 promoter has previously been linked to reduced expression of mRNA in approximately 11–31% primary BC samples and the inactivation of BRCA1 by promoter methylation also has been proved be correlated with decreasing gene copy number, reduction of transcripts and chromosome 17 aneusomy in BRCA1 mutated tumors.[18] A growing body of evidence also suggests that BRCA1 promoter methylation is closely correlated with clinicopathological features in BC.[17],[19] However, the clinical significance of the degree of promoter methylation and the link between BRCA1 promoter methylation and clinicopathological features in BC remain weak and inconclusive.[20] In order to address this issue, we used a meta-analysis approach, pooling data from high quality published studies, for a comprehensive evaluation of the correlation between BRCA1 promoter methylation status and clinicopathological features in BC.


 > Materials and Methods Top


Literature search

An exhaustive literature search was performed using following electronic databases: PubMed, EBSCO, Ovid, SpringerLink, Wiley Online Library, Web of Science, China National Knowledge Infrastructure, the Wanfang, and the VIP (since inception to October 2014). We utilized the following combination of MeSH and Medline medical index terms, together with free words, to retrieve studies broadly relevant to the topic of interest: (“Genes, BRCA1” or “BRCA1 genes” or “gene, BRCA1” or “BRCA1 gene”), (“methylation” or “DNA methylation” or “DNA methylations” or “methylations, DNA” or “hypermethylation” or “demethylation” or “hypermethylation”), and (“breast neoplasms” or “BC” or “breast tumors” or “breast carcinoma” or “mammary cancer” or “mammary carcinoma” or “mammary neoplasms” or “mastocarcinoma” or “mastocarcinoma” or “malignant neoplasm of breast”). We also manually searched the reference lists of original and review articles for additional pertinent literature from cross-references.

Inclusion and exclusion criteria

The studies enrolled into our meta-analysis met the following inclusion criteria: (1) study design: cohort studies evaluating BRCA1 promoter methylation and the clinicopathological features of BC; (2) study subjects: BC patients with confirmed diagnosis by the pathology; (3) detection method: Methylation specific-polymerase chain reaction; (4) end outcomes: BRCA1 promoter methylation data from tumor grade, LN metastasis, menopausal state, tissue typing, and age at diagnosis, respectively. (5) English and Chinese studies. The exclusion criteria were: (1) studies with incomplete data; (2) duplicates; (3) study subjects with undefined diagnostic criteria.

Statistical analysis

Data were independently extracted via two investigators employing a standardized abstraction form, and consensus was sought on all extracted items, where consensus could not be reached, the disagreements in data extraction were resolved by a third investigator. The data extracted from each individual study included name of first author, publication year, country, ethnicity, language, disease, the total number of subjects, age, gender, and detection method. Comprehensive meta-analysis 2.0 (CMA 2.0) software (Biostat Inc., Englewood, New Jersey, USA) was employed for statistical analysis. We calculated the odds ratio (OR) with 95% confidence intervals (95% CIs) to evaluate the connection between BRCA1 promoter methylation and the clinicopathological features of BC, and utilized Z-test to examine the significance of the overall effect size.[21] Heterogeneity among enrolled studies was evaluated by the Cochran's Q-statistic and P < 0.05 indicated the existence of heterogeneity.[22] Subsequently, I2statistics was utilized to quantify inter-study variability.[23] It ranged from 0% to 100%, where I2 < 50% indicated no observed heterogeneity, and higher values of I2 suggested an increasing degree of heterogeneity. Random-effects model was applied for the evidence of significant heterogeneity (P < 0.05 or I2 test exhibited >50%), otherwise, fixed-effects model was utilized.[24] Risk of publication bias was evaluated by funnel plot graphics, analyzed by both classic fail-safe N and Egger's linear regression test to demonstrate the reliability of overall results.[25],[26] All tests were two-sided (P < 0.05 was considered significant).


 > Results Top


Baseline characteristics of included study

The electronic database search initially identified 125 citations. Subsequently, 107 were excluded for the following reasons: 3 for duplicates; 2 for non-English or non-Chinese; 1 for the nonhuman study; 22 for not relating to our research topic, leaving 97 for further evaluation. Full-text manuscript of each study was obtained and thoroughly reviewed. Next, 79 studies were further excluded for failing to meet the predetermined selection criteria (18 for noncohort studies; 14 for not relating to BRCA1 gene; 46 for the absence of data on clinical indexes, including tumor grade, LN metastasis or menopausal state), finally leaving 18 eligible studies, published between 2001 and 2014, for selection into our meta-analysis study.[17],[19],[20],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41] These 18 studies contained a total of 3213 BC patients. Of the 18 eligible studies, 11 studies were performed in Asian subjects, 6 in Caucasian subjects, and 1 in African subjects. The baseline characteristics selected studies was presented in [Table 1].
Table 1: Baseline characteristics of the enrolled studies in this meta-analysis

Click here to view


Results of the meta-analysis

There was significant heterogeneity among twelve studies reporting the relationship between BRCA1 promoter methylation and histological grade of BC, thus random-effects model was utilized (I2 = 73.262%, P < 0.001). The results of our meta-analysis showed that BRCA1 promoter methylation in high and moderately differentiated tumors (I-II) was lower than poorly-differentiated (III) tumors, and the difference was statistically significant (OR = 0.450, 95% CI = 0.241–0.838, P = 0.012) [Figure 1]a. A subgroup analysis on ethnicity showed that a significant difference in histological grade of BC was found in Asians (OR = 0.319, 95% CI = 0.143–0.711, P = 0.005), while no such significance was found on other ethnicities (P > 0.05) [Figure 2]a. Eleven studies reported BRCA1 promoter methylation in relation to LN metastasis of BC. Random-effects model was carried out due to heterogeneity among these 11 studies (I2 = 68.957%, P < 0.001). The results of our meta-analysis suggested that BRCA1 promoter methylation in BC patients with LN metastasis was also remarkably higher than in patients without LN metastasis, at statistically significant rate (OR = 2.244, 95% CI = 1.278–3.940, P = 0.005) [Figure 1]b. Ethnicity-based subgroup analysis revealed a significant difference in LN metastasis of BC in Asians and Caucasians (Asians: OR = 2.688, 95% CI = 1.186–6.091, P = 0.018; Caucasians: OR = 2.226, 95% CI = 1.306–3.796, P = 0.003), nevertheless, there was no statistical difference in Africans (P > 0.05) [Figure 2]b. Nine studies investigated BRCA1 promoter methylation in subtypes of BC. Fixed-effect model was used due to absence of heterogeneity among these nine studies (I2 = 25.417%, P = 0.218). The results from our meta-analysis revealed that the difference in BRCA1 promoter methylation between IDC and ILC showed no statistical significance (OR = 0.883, 95% CI = 0.527–1.479, P = 0.636) [Figure 1]c. Subgroup analysis based on ethnicity presented existence of statistically significant differences in subtypes of BC in Caucasians (OR = 0.437, 95% CI = 0.204–0.933, P = 0.032), while no such difference was found in other ethnicities (P > 0.05) [Figure 2]c. Six studies explored the connection between BRCA1 promoter methylation and menopausal status of BC patients. Fixed-effect model was used because heterogeneity test indicated no heterogeneity among these six studies (I2 = 42.411%, P = 0.122). The results of the current meta-analysis indicated that BRCA1 promoter methylation status was not significantly different between premenopausal and postmenopausal patients (OR = 1.152, 95% CI = 0.898–1.478, P = 0.266) [Figure 1]d. The result of ethnicity-based subgroup analysis showed no significant difference existed in menopausal status of BC among all ethnicities (all P > 0.05) [Figure 2]d. Finally, twelve studies provided data on BRCA1 promoter methylation and age at diagnosis of BC patients. Random-effects model was adopted owing to heterogeneity among twelve studies (I2 = 60.488%, P < 0.001). The results showed that the difference in BRCA1 promoter methylation status between younger BC patients and older BC patients was not statistically significant (OR = 1.520, 95% CI = 0.940–2.459, P = 0.088) [Figure 1]e. A subgroup analysis on ethnicity clarified existence of statistically significant differences in age at diagnosis of BC patients in caucasians (OR = 2.437, 95% CI = 1.262–4.704, P = 0.008), however, there was no statistical difference in other ethnicities (P > 0.05) [Figure 2]e.
Figure 1: Forest plots showing the connection between breast cancer type 1 promoter methylation status and the clinicopathological features of breast cancer (a) tumor grade, (b) lymph node metastasis, (c) historical type, (d) menopausal status, and (e) age at diagnosis

Click here to view
Figure 2: Ethnicity-based subgroup analyses about the connection between breast cancer type 1 promoter methylation status and the clinicopathological features of breast cancer (a) tumor grade, (b) lymph node metastasis, (c) historical type, (d) menopausal status, and (e) age at diagnosis

Click here to view


Sensitivity analysis and publication bias

The results after sensitivity analyses suggested that each individual study exerted no remarkable influence on the OR values of the connections between BRCA1 promoter methylation and tumor grade, LN metastasis, histological type, menopausal status, and age at diagnosis of BC patients, respectively [Figure 3]a, [Figure 3]b, [Figure 3]c, [Figure 3]d, [Figure 3]e. Symmetric funnel plots indicated the absence of publication bias, which was further confirmed by classic fail-safe N and Egger's linear regression test (all P > 0.05) [Figure 4]a, [Figure 4]b, [Figure 4]c, [Figure 4]d, [Figure 4]e.
Figure 3: Sensitivity analyses about the connection between breast cancer type 1 promoter methylation status and the clinicopathological features of breast cancer (a) tumor grade, (b) lymph node metastasis, (c) historical type, (d) menopausal status, and (e) age at diagnosis

Click here to view
Figure 4: Funnel plot demonstrating publication biases about connection between breast cancer type 1 promoter methylation status and the clinicopathological features of breast cancer (a) tumor grade, (b) lymph node metastasis, (c) historical type, (d) menopausal status, and (e) age at diagnosis

Click here to view



 > Discussion Top


In this current meta-analysis, we investigated whether data from previously published studies contained definitive information to obtain a correlation between BRCA1 promoter methylation and the clinicopathological features of BC. The main results obtained from our meta-analysis suggest that BRCA1 promoter methylation status correlated with histological grade and LN metastasis in BC. Approximately, 1.7 million individuals were diagnosed with BC and 522,000 deaths were linked to BC in 2012 alone, based on worldwide numbers, indicating the urgency to fill the current void in diagnosis and treatment through discovering additional genetic and epigenetic factors contributing to the development and progression of BC.[42] Gene methylation studies of tumor suppressors, such as BRCA1, are important to understand the underlying subtle differences in epigenetic events influencing the disease phenotype, given the diversity of molecular defects influencing the disease progression in BCs. DNA methylation occurs when methyl groups are added to cytosine in CpG dinucleotides, resulting in closed chromatin conformation and inactivation of gene transcription, thus resulting in gene silencing.[43],[44] Cells with inactivated tumor suppressor genes have lost the ability to negatively regulate critical pathways controlled by the tumor suppressor gene, leading to malignant changes, uncontrolled cell proliferation, and tumor initiation and progression.[45],[46] Besides, most of the present literatures underscored the clinical relevance of the methylation of BRCA1 promoter in patients with BC, which showed poor survival of BC.[34],[38]BRCA1 is a tumor suppressor gene and plays an essential role in DNA repair and maintenance of genome integrity, and BC is strongly associated with inactivation of BRCA1.[47]BRCA1 methylation results in decreased expression of BRCA1 at mRNA and protein level, and therefore the damaged DNA in the breast epithelial cell are not repaired efficiently, enhancing the risk for BC.[48],[49] Reduction or loss of BRCA1 expression is also common in sporadic BC, owing to epigenetic or posttranslational modifications, and is most frequently observed in BC patients with a basal-like phenotype.[15] It is also reported that the expression of BRCA1 mRNA level was correlated with BC, and the expression of mRNA level was regulated by methylation.[50] The decreased activity of BRCA1 promoter may result in the decreasing of anti-carcinoma function which may further lead to the occurrence of cancers.[51] Furthermore, the aberrant methylation in promoter region of BRCA1 may also cause the decreasing or inactivation of BRCA1 expression level to result in the occurrence of BC, and the inactivating anti-carcinoma genes cannot negative regulate the cycle proliferation of cell, thereby lead to the malignant change of cells.[52],[53] Birgisdottir et al. showed that 9–26% of sporadic BC is caused by BRCA1 promoter methylation, and also is negative for estrogen receptor, and is associated with highly malignant and invasive histology, with a poor 5-year survival rate.[36] In addition, Hsu et al. employed multivariate analysis and found that high BRCA1 promoter methylation status was an unfavorable prognostic factor in the overall survival rate of 139 patients with early indications of BC, in a Taiwanese population.[38] In order to assess other influencing factors affecting the validity of our overall results, we explored if histologic type, menopausal status, or age at diagnosis exhibited any significant links with BRCA1 promoter methylation status. In our meta-analysis, the results showed that there was no significant correlation between BRCA1 promoter methylation status and different histological types, menopausal status, and age at diagnosis of BC patients.

Besides, we also conducted subgroup analysis on the basis of ethnicity. In histological grade of BC, a significant difference was found in Asians, not in other ethnicities. While, in LN metastasis of BC, both Asians and Caucasians were found significant differences and no statistical difference in Africans. A significant difference was observed in subtypes of BC in Caucasians, not in other ethnicities. A subgroup analysis on ethnicity clarified the existence of statistically significant differences in age at diagnosis of BC patients in Caucasians not in in other ethnicities. Interestingly, no significant difference existed in the menopausal status of BC among all ethnicities.

Limitations in our meta-analysis are worth the mention. First, data extracted in our meta-analysis may not be as comprehensive, and might have reduced the reliability of this study. Second, significant differences in sample sizes are seen across the selected studies, for example, study by Xu et al. included 1508 BC patients, while Wu et al. and Ma et al. involved only 30 BC patients each, and thus the absence of subgroup analysis based on sample size in our meta-analysis may also have a negative influence on the strength of our meta-analysis.


 > Conclusions Top


Our meta-analysis showed that BRCA1 promoter methylation status is correlated with tumor grade and LN metastasis in BC. The relationship between histological type, menopausal status and age at diagnosis of BC, and BRCA1 promoter methylation status was not evident in our study, but such links still need to be further investigation with better study design and larger sample sizes.

Acknowledgments

We would like to appreciate the reviewers for their helpful comments on this paper.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

1.
Cancer statistics. JAMA 2013;310:982.  Back to cited text no. 1
    
2.
DeSantis C, Siegel R, Bandi P, Jemal A. Breast cancer statistics, 2011. CA Cancer J Clin 2011;61:409-18.  Back to cited text no. 2
[PUBMED]    
3.
Youlden DR, Cramb SM, Dunn NA, Muller JM, Pyke CM, Baade PD. The descriptive epidemiology of female breast cancer: An international comparison of screening, incidence, survival and mortality. Cancer Epidemiol 2012;36:237-48.  Back to cited text no. 3
[PUBMED]    
4.
Assi HA, Khoury KE, Dbouk H, Khalil LE, Mouhieddine TH, El Saghir NS. Epidemiology and prognosis of breast cancer in young women. J Thorac Dis 2013;5 Suppl 1:S2-8.  Back to cited text no. 4
[PUBMED]    
5.
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11-30.  Back to cited text no. 5
[PUBMED]    
6.
Yang XR, Chang-Claude J, Goode EL, Couch FJ, Nevanlinna H, Milne RL, et al. Associations of breast cancer risk factors with tumor subtypes: A pooled analysis from the Breast Cancer Association Consortium studies. J Natl Cancer Inst 2011;103:250-63.  Back to cited text no. 6
[PUBMED]    
7.
Nelson HD, Zakher B, Cantor A, Fu R, Griffin J, O'Meara ES, et al. Risk factors for breast cancer for women aged 40 to 49 years: A systematic review and meta-analysis. Ann Intern Med 2012;156:635-48.  Back to cited text no. 7
    
8.
Narbe U, Bendahl PO, Grabau D, Rydén L, Ingvar C, Fernö M. Invasive lobular carcinoma of the breast: Long-term prognostic value of Ki67 and histological grade, alone and in combination with estrogen receptor. Springerplus 2014;3:70.  Back to cited text no. 8
    
9.
Wu SG, He ZY, Li Q, Sun JY, Li FY, Lin Q, et al. Prognostic value of metastatic axillary lymph node ratio for Chinese breast cancer patients. PLoS One 2013;8:e61410.  Back to cited text no. 9
[PUBMED]    
10.
Rakha EA, Reis-Filho JS, Baehner F, Dabbs DJ, Decker T, Eusebi V, et al. Breast cancer prognostic classification in the molecular era: The role of histological grade. Breast Cancer Res 2010;12:207.  Back to cited text no. 10
[PUBMED]    
11.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90.  Back to cited text no. 11
[PUBMED]    
12.
Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, et al. Oral poly (ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010;376:235-44.  Back to cited text no. 12
[PUBMED]    
13.
Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 1990;250:1684-9.  Back to cited text no. 13
[PUBMED]    
14.
Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994;266:66-71.  Back to cited text no. 14
[PUBMED]    
15.
Martinez-Outschoorn UE, Balliet R, Lin Z, Whitaker-Menezes D, Birbe RC, Bombonati A, et al. BRCA1 mutations drive oxidative stress and glycolysis in the tumor microenvironment: Implications for breast cancer prevention with antioxidant therapies. Cell Cycle 2012;11:4402-13.  Back to cited text no. 15
[PUBMED]    
16.
Zhu Q, Pao GM, Huynh AM, Suh H, Tonnu N, Nederlof PM, et al. BRCA1 tumour suppression occurs via heterochromatin-mediated silencing. Nature 2011;477:179-84.  Back to cited text no. 16
[PUBMED]    
17.
Ignatov T, Poehlmann A, Ignatov A, Schinlauer A, Costa SD, Roessner A, et al. BRCA1 promoter methylation is a marker of better response to anthracycline-based therapy in sporadic TNBC. Breast Cancer Res Treat 2013;141:205-12.  Back to cited text no. 17
[PUBMED]    
18.
Wei M, Xu J, Dignam J, Nanda R, Sveen L, Fackenthal J, et al. Estrogen receptor alpha, BRCA1, and FANCF promoter methylation occur in distinct subsets of sporadic breast cancers. Breast Cancer Res Treat 2008;111:113-20.  Back to cited text no. 18
[PUBMED]    
19.
Xu X, Gammon MD, Zhang Y, Cho YH, Wetmur JG, Bradshaw PT, et al. Gene promoter methylation is associated with increased mortality among women with breast cancer. Breast Cancer Res Treat 2010;121:685-92.  Back to cited text no. 19
[PUBMED]    
20.
Krasteva ME, Bozhanov SS, Antov GG, Gospodinova ZI, Angelov SG. Breast cancer patients with hypermethylation in the promoter of BRCA1 gene exhibit favorable clinical status. Neoplasma 2012;59:85-91.  Back to cited text no. 20
[PUBMED]    
21.
Chen H, Manning AK, Dupuis J. A method of moments estimator for random effect multivariate meta-analysis. Biometrics 2012;68:1278-84.  Back to cited text no. 21
[PUBMED]    
22.
Jackson D, White IR, Riley RD. Quantifying the impact of between-study heterogeneity in multivariate meta-analyses. Stat Med 2012;31:3805-20.  Back to cited text no. 22
[PUBMED]    
23.
Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Comparison of two methods to detect publication bias in meta-analysis. JAMA 2006;295:676-80.  Back to cited text no. 23
[PUBMED]    
24.
Zintzaras E, Ioannidis JP. Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol 2005;28:123-37.  Back to cited text no. 24
[PUBMED]    
25.
Wikstrom EA, Naik S, Lodha N, Cauraugh JH. Balance capabilities after lateral ankle trauma and intervention: A meta-analysis. Med Sci Sports Exerc 2009;41:1287-95.  Back to cited text no. 25
[PUBMED]    
26.
Zintzaras E, Ioannidis JP. HEGESMA: Genome search meta-analysis and heterogeneity testing. Bioinformatics 2005;21:3672-3.  Back to cited text no. 26
[PUBMED]    
27.
Cao QL, Wang ZH, Feng J, Wang G. Aberrant hypermethylation profile of BRCA1 in tissue and serum of breast carcinogensis. Med J Wuhan Univ 2010;31:640-3.  Back to cited text no. 27
    
28.
Feng J, Zhang JC, Tao JS, Lyu J, Fu P, Guo JH, et al. Detection of BRCA1 gene promoter hypermethylation in plasma of sporadic breast cancer patients. China Oncol 2005;15:442-5.  Back to cited text no. 28
    
29.
Fu DY, Wei JL, Zhu YX, Tan HS, Zhang JX. Clinical signiifcance of BRCA1, GSTP1 and MGMT gene methylation status in breast cancer. China Oncol 2014;17:487-92.  Back to cited text no. 29
    
30.
Ma GH, Hou L, Han LL. Methionine synthase and methylation of BRCA1: Their association with breast cancer morbidity. China Oncol 2011;21:256-61.  Back to cited text no. 30
    
31.
Sun Y, Li YH, Zhang P. Effect of BRCA1 promoter methylation on tumor inhibition. Hainan Med J 2014;12:1717-9.  Back to cited text no. 31
    
32.
Wang ZW, Yi J, Cang H, Gao F, Tang XM, Li T, et al. Research on development of BRCA1 promoter methylation in breast cancer. Prac Oncol J 2001;15:168-9.  Back to cited text no. 32
    
33.
Wu L, Cao WH, Chen QF, Zheng LL, Wu YY. Study in BRCA1 gene methylation status and mRNA expression level in sporadic breast cancer. J Surg Concepts Pract 2011;16:576-80.  Back to cited text no. 33
    
34.
Al-Moghrabi N, Al-Qasem AJ, Aboussekhra A. Methylation-related mutations in the BRCA1 promoter in peripheral blood cells from cancer-free women. Int J Oncol 2011;39:129-35.  Back to cited text no. 34
[PUBMED]    
35.
Ben Gacem R, Hachana M, Ziadi S, Amara K, Ksia F, Mokni M, et al. Contribution of epigenetic alteration of BRCA1 and BRCA2 genes in breast carcinomas in Tunisian patients. Cancer Epidemiol 2012;36:190-7.  Back to cited text no. 35
[PUBMED]    
36.
Birgisdottir V, Stefansson OA, Bodvarsdottir SK, Hilmarsdottir H, Jonasson JG, Eyfjord JE. Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer. Breast Cancer Res 2006;8:R38.  Back to cited text no. 36
[PUBMED]    
37.
Grushko TA, Dignam JJ, Das S, Blackwood AM, Perou CM, Ridderstråle KK, et al. MYC is amplified in BRCA1-associated breast cancers. Clin Cancer Res 2004;10:499-507.  Back to cited text no. 37
    
38.
Hsu NC, Huang YF, Yokoyama KK, Chu PY, Chen FM, Hou MF. Methylation of BRCA1 promoter region is associated with unfavorable prognosis in women with early-stage breast cancer. PLoS One 2013;8:e56256.  Back to cited text no. 38
[PUBMED]    
39.
Ren J, Jin F, Yu Z, Zhao L, Wang L, Bai X, et al. MYC overexpression and poor prognosis in sporadic breast cancer with BRCA1 deficiency. Tumour Biol 2013;34:3945-58.  Back to cited text no. 39
[PUBMED]    
40.
Singh AK, Pandey A, Tewari M, Shukla HS, Pandey HP. Epigenetic silencing of BRCA1 gene associated with demographic and pathologic factors in sporadic breast cancer: A study of an Indian population. Eur J Cancer Prev 2011;20:478-83.  Back to cited text no. 40
[PUBMED]    
41.
Wei M, Grushko TA, Dignam J, Hagos F, Nanda R, Sveen L, et al. BRCA1 promoter methylation in sporadic breast cancer is associated with reduced BRCA1 copy number and chromosome 17 aneusomy. Cancer Res 2005;65:10692-9.  Back to cited text no. 41
[PUBMED]    
42.
Yi T, Zhai B, Yu Y, Kiyotsugu Y, Raschle T, Etzkorn M, et al. Quantitative phosphoproteomic analysis reveals system-wide signaling pathways downstream of SDF-1/CXCR4 in breast cancer stem cells. Proc Natl Acad Sci U S A 2014;111:E2182-90.  Back to cited text no. 42
[PUBMED]    
43.
Smith ZD, Meissner A. DNA methylation: Roles in mammalian development. Nat Rev Genet 2013;14:204-20.  Back to cited text no. 43
[PUBMED]    
44.
Sandoval J, Heyn H, Moran S, Serra-Musach J, Pujana MA, Bibikova M, et al. Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome. Epigenetics 2011;6:692-702.  Back to cited text no. 44
[PUBMED]    
45.
Holm K, Hegardt C, Staaf J, Vallon-Christersson J, Jönsson G, Olsson H, et al. Molecular subtypes of breast cancer are associated with characteristic DNA methylation patterns. Breast Cancer Res 2010;12:R36.  Back to cited text no. 45
    
46.
Dworkin AM, Huang TH, Toland AE. Epigenetic alterations in the breast: Implications for breast cancer detection, prognosis and treatment. Semin Cancer Biol 2009;19:165-71.  Back to cited text no. 46
[PUBMED]    
47.
Caestecker KW, Van de Walle GR. The role of BRCA1 in DNA double-strand repair: Past and present. Exp Cell Res 2013;319:575-87.  Back to cited text no. 47
[PUBMED]    
48.
Zhong Q, Shi G, Zhang Y, Lu L, Levy D, Zhong S. Alteration of BRCA1 expression affects alcohol-induced transcription of RNA Pol III-dependent genes. Gene 2015;556:74-9.  Back to cited text no. 48
[PUBMED]    
49.
Galizia E, Giorgetti G, Piccinini G, Santinelli A, Loretelli C, Bianchi F, et al. BRCA1 expression in triple negative sporadic breast cancers. Anal Quant Cytol Histol 2010;32:24-9.  Back to cited text no. 49
[PUBMED]    
50.
Margeli M, Cirauqui B, Castella E, Tapia G, Costa C, Gimenez-Capitan A, et al. The prognostic value of BRCA1 mRNA expression levels following neoadjuvant chemotherapy in breast cancer. PLoS One 2010;5:e9499.  Back to cited text no. 50
[PUBMED]    
51.
Furlan D, Sahnane N, Bernasconi B, Frattini M, Tibiletti MG, Molinari F, et al. APC alterations are frequently involved in the pathogenesis of acinar cell carcinoma of the pancreas, mainly through gene loss and promoter hypermethylation. Virchows Arch 2014;464:553-64.  Back to cited text no. 51
[PUBMED]    
52.
Connolly R, Stearns V. Epigenetics as a therapeutic target in breast cancer. J Mammary Gland Biol Neoplasia 2012;17:191-204.  Back to cited text no. 52
[PUBMED]    
53.
Fiolka R, Zubor P, Janusicova V, Visnovsky J, Mendelova A, Kajo K, et al. Promoter hypermethylation of the tumor-suppressor genes RASSF1A, GSTP1 and CDH1 in endometrial cancer. Oncol Rep 2013;30:2878-86.  Back to cited text no. 53
[PUBMED]    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>Introduction>Materials and Me...>Results>Discussion>Conclusions>Article Figures>Article Tables
  In this article
>References

 Article Access Statistics
    Viewed790    
    Printed11    
    Emailed0    
    PDF Downloaded55    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]