Epigenetic silencing of BRCA1 gene associated with demographic and pathologic factors in sporadic breast cancer

Abstract

Breast cancer (BC) is a leading cause of cancer-related deaths among women worldwide, and this study further demonstrates that the women of Varanasi (north India) are not untouched by this fatal disease. During BC development, epigenetic activity plays a key role in silencing gene expression. Its widespread occurrence in the cancer genome could inactivate many cellular pathways including DNA repair, cell cycle control, apoptosis, cell adherence, and detoxification. In this study, our aim was to determine the penetrance of BRCA1 promoter methylation and its correlation with pathological and demographic factors in sporadic BC in an Indian population. Our analysis included 127 patients who were diagnosed with sporadic BC. Methylation-specific PCR for the BRCA1 promoter was used during the study and correlated with pathological and demographic factors. Methylation of the BRCA1 promoter was detected in 8.7% (11/127) of the tumors. Correlation of promoter methylation with demographic factors and clinicopathological markers revealed the following data: (i) BRCA1 methylation was more frequently observed in tumor samples taken from premenopausal or perimenopausal women (P=0.026), (ii) methylation of the BRCA1 promoter negatively correlated with estrogen receptor (P=0.040), progesterone receptor (P=0.013), and epidermal growth factor receptor-2 (P=0.002), (iii) the overall promoter methylation was higher in more advanced stages (P=0.036) of the disease. This study has immense implications for understanding epigenetic mechanisms in BC development. The result suggests that the epigenetic silencing of BRCA1 is uncommon and is associated with the triple-negative phenotype.

Association of BRCA1 promoter methylation with sporadic breast cancers: Evidence from 40 studies

“…In addition, no association between BRCA1 methylation and premenopausal status was observed in our study. This was inconsistent with a previous report 43 which showed that BRCA1 -methylated breast cancers tended to occur at an early age (<50 years) and were more frequently observed in premenopausal or perimenopausal women than postmenopausal women. Furthermore, our results showed that BRCA1 promoter methylation was strongly related to breast cancer patients with high histological grade and lymph node metastasis, revealing that aberrant methylation of BRCA1 promoter may be implicated in the invasion and metastasis of breast cancer.…”

“…As expected from previous studies 14 29 43 , we demonstrated that there was a remarkable correlation between BRCA1 promoter hypermethylation and breast tumors with lack of ER and PR expression. However, no inverse relationship was found between BRCA1 methylation and Her2 status.…”

“…Due to the different type of sample materials, we considered this study as two case-control studies. Furthermore, 30 clinical studies 3 4 6 12 13 14 16 18 27 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 with a total of 5058 breast cancer patients met our selection criteria for analyzing the association between BRCA1 promoter methylation and clinicopathological characteristics which included early age (<50 years) at diagnosis, premenopausal status, lymph node metastasis, histological grade 3, estrogen receptor (ER), progesterone receptor (PR), human epidermal receptor 2 (Her2), triple-negative phenotype and the expression of BRCA1 protein. In short, our meta-analysis included 40 eligible articles, among which 20 articles were analyzed for the frequency of BRCA1 promoter methylation in breast cancers compared with non-cancer controls, and 30 articles were analyzed for the association between BRCA1 promoter methylation and clinicopathological features.…”

The epigenetic silencing of the estrogen receptor (ER) by hypermethylation of the ESR1 promoter is seen predominantly in triple-negative breast cancers in Indian women

“…Bediaga et al and Holm et al have recently reported specific methylation patterns associated with distinct molecular subtypes of breast cancer [34,35]. Our findings are in agreement with those studies which have reported higher methylation of other genes like BRCA1 in triple-negative subtype indicating higher epigenetic dysregulation in these cancers [36,37].…”

Peroxiredoxin V: A candidate breast tumor marker of population specificity

“…Population differences in breast cancer characteristics were previously described in terms of pathological parameters (27,31,32), and in terms of the identification of mutations, intronic variant sequences and unclassified variants, as well as variated copy numbers, reporting a role in breast cancer susceptibility that remains to be clarified. For instance, mutations in the predisposition genes BRCA1 and BRCA2, known to be associated with hereditary breast cancer, were studied in different populations such as Sudanese (33,34), Tunisian (35), Indian (36) and Slovak (37), where population-specific genetic disorders were observed. Similarly, the Mspl polymorphism in the 3'-non-coding region of the CYP1A1 gene was associated with breast cancer in African-American but not in Caucasian women (38).…”