Hypermethylation of BRCA1 gene: implication for prognostic biomarker and therapeutic target in sporadic primary triple-negative breast cancer

Abstract

Paraffin sections from 239 cases of surgical resected mammary gland carcinomas were assessed to determine the role of BRCA1 gene methylation in sporadic triple-negative breast cancer and to evaluate the relationship between BRCA1 gene methylation and clinicopathologic features of triple-negative breast cancer in the National Cancer Center, China. Diagnostic tissues collected from patients received mastectomy in the National Cancer Center from January 1, 1999 to December 31, 2008 were reviewed. Tissue microarrays were constructed using 239 triple-negative breast cancer cases and stained with estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, cytokeratin 5/6, and epidermal growth factor receptor. Methylation status of the BRCA1 promoter was measured by methylation-specific PCR and analyzed against clinicopathologic characteristics, subtypes, and prognosis using standard statistical methods. Among the 239 triple-negative breast cancer cases, 137 (57.3 %) showed methylation of the BRCA1. According to the immunohistochemistry results, triple-negative breast cancer cases were classified into basal-like breast cancer (60.7 %) and non-basal-like breast cancer (39.3 %). The frequency of BRCA1 methylation was significantly higher in basal-like breast cancer subtype (71.7 %) than the non-basal subtype (35.1 %). Thus, BRCA1 methylation is statistically significantly correlated with basal-like breast cancer subtype (p < 0.001). Multivariate analyses further showed that BRCA1 promoter methylation is an independently predictor of overall survival (p = 0.023; HR 2.32; 95 % CI 1.12-4.81) and disease-free survival (p = 0.022; HR 2.36; 95 % CI 1.13-4.90) in triple-negative breast cancer. Here we demonstrated that epigenetic alteration of key tumor suppressor gene can be a promising biomarker for the prognosis of triple-negative breast cancer/basal-like breast cancer. Specifically our finding revealed that BRCA1 methylation is closely associated with a significant decrease in overall survival and disease-free survival, highlighting BRCA1 promoter methylation as promising and powerful biomarkers for effect and better prognosis of DNA damaging agents for triple-negative breast cancer/basal-like breast cancer.

BRCA1 Promoter Hypermethylation is Associated with Good Prognosis and Chemosensitivity in Triple-Negative Breast Cancer

“…The absence of BRCA1 nuclear expression correlates with high tumor grade and ER-negative tumors [17]. Absent or reduced BRCA1 expression in tumors without BRCA1 pathogenic variants appears to be linked to hypermethylation of the BRCA1 promoter region [18], a condition reported in 9.1-37% of sporadic BCs and associated with infiltrating ductal carcinoma type, high tumor grade (grade II-III), ER negativity, basal marker expression, younger age at diagnosis, and poor prognosis [18][19][20][21][22][23][24][25][26][27][28][29]. Thus, BRCA1 promoter hypermethylation could be a marker of BRCA1 deficiency in the absence of BRCA1 mutation, as these two events appear to be almost mutually exclusive [23,[30][31][32][33][34], outside of the recently described association between a dominantly inherited 5' UTR variant, classified as likely pathogenic, and BRCA1 promoter hypermethylation [35].…”

BET proteins regulate homologous recombination‐mediated DNA repair: BRCAness and implications for cancer therapy

“…Epigenetic BRCAness has been linked to poor outcome, but its role in respect to platinum‐based regimens or PARP inhibitors remains uncertain . Under these premises, pharmacologically induced BRCAness could represent a solid strategy to sensitize TNBC with no BRCA1 epigenetic inactivation or mutation to genotoxic agents.…”

Dysregulation of ubiquitin ligases in cancer

“…The incidence of BRCA1 promoter methylation in breast cancer tissues is significantly higher (up to 82.1%) than in non-cancerous tissues 62, 63, 64, 65 , and gene methylation status is inversely correlated with BRCA1 mRNA expression 63, 65, 66 . BRCA1 promoter methylation is also correlated with decreased overall survival and disease-free survival for triple-negative and basal-like breast cancer 62, 66 . Methylation of promoters of upstream UBLs or cooperating factors governs expression of genes including HACE1, RNF180, CHIP, KEAP1 and PARK1.…”