BRCA1 deficiency is a recurrent event in early-onset triple-negative breast cancer: a comprehensive analysis of germline mutations and somatic promoter methylation

Brianese, Rafael Canfield; Nakamura, Kivvi Duarte de Mello; Almeida, Fernanda Gabriella dos Santos Ramos de; Ramalho, Rodrigo F.; Barros, Bruna Durães de Figueiredo; Ferreira, Elisa Napolitano; Formiga, Maria Nirvana da Cruz; Andrade, Victor Piana de; Lima, Vladmir Cláudio Cordeiro de; Carraro, Dirce Maria

doi:10.1007/s10549-017-4552-6

Cited by 39 publications

(43 citation statements)

References 52 publications

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“…Enduring efforts made by researchers or organizations such as CIMBA demonstrate the ubiquitous perception of higher ratio of BRCA mutations in younger patients with more aggressive subgroups of breast cancer. 223 , 225 , 226 , 227 Nonetheless, the majority of these studies imply a comparable outcome among patients regardless of BRCA status, limiting the application of BRCA mutation status in prognosis prediction.…”

Section: Cancer Gene Mutations In Breast Cancermentioning

confidence: 99%

Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis

et al. 2018

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As the most commonly occurring cancer in women worldwide, breast cancer poses a formidable public health challenge on a global scale. Breast cancer consists of a group of biologically and molecularly heterogeneous diseases originated from the breast. While the risk factors associated with this cancer varies with respect to other cancers, genetic predisposition, most notably mutations in BRCA1 or BRCA2 gene, is an important causative factor for this malignancy. Breast cancers can begin in different areas of the breast, such as the ducts, the lobules, or the tissue in between. Within the large group of diverse breast carcinomas, there are various denoted types of breast cancer based on their invasiveness relative to the primary tumor sites. It is important to distinguish between the various subtypes because they have different prognoses and treatment implications. As there are remarkable parallels between normal development and breast cancer progression at the molecular level, it has been postulated that breast cancer may be derived from mammary cancer stem cells. Normal breast development and mammary stem cells are regulated by several signaling pathways, such as estrogen receptors (ERs), HER2, and Wnt/β-catenin signaling pathways, which control stem cell proliferation, cell death, cell differentiation, and cell motility. Furthermore, emerging evidence indicates that epigenetic regulations and noncoding RNAs may play important roles in breast cancer development and may contribute to the heterogeneity and metastatic aspects of breast cancer, especially for triple-negative breast cancer. This review provides a comprehensive survey of the molecular, cellular and genetic aspects of breast cancer.

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Section: Cancer Gene Mutations In Breast Cancermentioning

confidence: 99%

Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis

et al. 2018

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“…17,18 It has been suggested that promoter methylation in tumor DNA might be a mechanism of inactivation of BRCA1 gene in triple-negative BC (TNBC) patients. 19,20 In the present study, we evaluated the association of BRCA1 methylation in blood-derived DNA with the risk of BC, including TNBC. In addition, we analyzed methylation in paired tumor samples and assessed the degree of concordance between methylation in blood and breast tumor tissue.…”

Section: Introductionmentioning

confidence: 99%

“…About 75% of BC which arise in women who carry germline BRCA1 mutations are triple‐negative; however, only about 10% of patients with triple‐negative breast tumors have BRCA1 mutations . It has been suggested that promoter methylation in tumor DNA might be a mechanism of inactivation of BRCA1 gene in triple‐negative BC (TNBC) patients …”

Section: Introductionmentioning

confidence: 99%

BRCA1 promoter methylation in peripheral blood is associated with the risk of triple‐negative breast cancer

Prajzendanc

Domagała

Hybiak

et al. 2019

Intl Journal of Cancer

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Methylation of the promoter of the BRCA1 gene in DNA derived from peripheral blood cells is a possible risk factor for breast cancer. It is not clear if this association is restricted to certain types of breast cancer or is a general phenomenon. We evaluated BRCA1 methylation status in peripheral blood cells from 942 breast cancer patients and from 500 controls. We also assessed methylation status in 262 paraffin‐embedded breast cancer tissues. Methylation status was assessed using methylation‐sensitive high‐resolution melting and was categorized as positive or negative. BRCA1 methylation in peripheral blood cells was strongly associated with the risk of triple‐negative breast cancer (TNBC) (odds ratio [OR] 4.70; 95% confidence interval [CI]: 3.13–7.07; p < 0.001), but not of estrogen‐receptor positive breast cancer (OR 0.80; 95% CI: 0.46–1.42; p = 0.46). Methylation was also overrepresented among patients with high‐grade cancers (OR 4.53; 95% CI: 2.91–7.05; p < 0.001) and medullary cancers (OR 3.08; 95% CI: 1.38–6.88; p = 0.006). Moreover, we detected a significant concordance of BRCA1 promoter methylation in peripheral blood and paired tumor tissue (p < 0.001). We found that BRCA1 promoter methylation in peripheral blood cells is associated with approximately five times greater risk of TNBC. We propose that BRCA1 methylation in blood‐derived DNA could be a novel biomarker of increased breast cancer susceptibility, in particular for triple‐negative tumors.

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“…DNA promoter hypermethylation could be an alternative mechanism of inactivating BRCA1. BRCA1 promoter hypermethylation has been reported in 16-57% of TNBCs across studies [14][15][16][17][18][19][20] , superseding the frequency of germline BRCA1 alterations, however, with conflicting reports about association with prognosis (e.g. refs.…”

mentioning

confidence: 99%

Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers

et al. 2020

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Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC.

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BRCA1 deficiency is a recurrent event in early-onset triple-negative breast cancer: a comprehensive analysis of germline mutations and somatic promoter methylation

Cited by 39 publications

References 52 publications

Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis

Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis

BRCA1 promoter methylation in peripheral blood is associated with the risk of triple‐negative breast cancer

Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers

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