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Open AccessArticle

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

1
Department of Medical Oncology, Montpellier Cancer Institute Val d’Aurelle, 208 rue des Apothicaires, F-34298 Montpellier, France
2
Translational Research Unit, Montpellier Cancer Institute Val d’Aurelle, 208 rue des Apothicaires, F-34298 Montpellier, France
3
Faculty of Medicine, Montpellier University, 34090 Montpellier, France
4
Institut de Recherche en Cancérologie de Montpellier (IRCM), Inserm U1194, Université de Montpellier, Institut du Cancer Montpellier (ICM), F-34298 Montpellier, France
5
Biometrics Unit, Institut du Cancer Montpellier (ICM), Université de Montpellier, 208 rue des Apothicaires, F-34298 Montpellier, France
6
Department of Oncogenetics, APHP, GH Paris-Sud, Hôpital Paul Brousse, Inserm UMR-S 1193, Université Paris-Saclay, 14 Avenue Paul Vaillant Couturier, 94800 Villejuif, France
7
Institut d’Analyse Génomique, Imagenome-Inovie, Clinique BeauSoleil, 34070 Montpellier, France
8
Biological Resources Center, Montpellier Cancer Institute Val d’Aurelle, F-34298 Montpellier, France
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(4), 828; https://doi.org/10.3390/cancers12040828
Received: 2 March 2020 / Revised: 25 March 2020 / Accepted: 26 March 2020 / Published: 30 March 2020
(This article belongs to the Special Issue DNA Damage and Repair in Cancers)
The aberrant hypermethylation of BRCA1 promoter CpG islands induces the decreased expression of BRCA1 (Breast Cancer 1) protein. It can be detected in sporadic breast cancer without BRCA1 pathogenic variants, particularly in triple-negative breast cancers (TNBC). We investigated BRCA1 hypermethylation status (by methylation-specific polymerase chain reaction (MS-PCR) and MassARRAY® assays), and BRCA1 protein expression using immunohistochemistry (IHC), and their clinicopathological significance in 248 chemotherapy-naïve TNBC samples. Fifty-five tumors (22%) exhibited BRCA1 promoter hypermethylation, with a high concordance rate between MS-PCR and MassARRAY® results. Promoter hypermethylation was associated with reduced IHC BRCA1 protein expression (p = 0.005), and expression of Programmed death-ligand 1 protein (PD-L1) by tumor and immune cells (p = 0.03 and 0.011, respectively). A trend was found between promoter hypermethylation and basal marker staining (p = 0.058), and between BRCA1 expression and a basal-like phenotype. In multivariate analysis, relapse-free survival was significantly associated with N stage, adjuvant chemotherapy, and histological subtype. Overall survival was significantly associated with T and N stage, histology, and adjuvant chemotherapy. In addition, patients with tumors harboring BRCA1 promoter hypermethylation derived the most benefit from adjuvant chemotherapy. In conclusion, BRCA1 promoter hypermethylation is associated with TNBC sensitivity to adjuvant chemotherapy, basal-like features and PD-L1 expression. BRCA1 IHC expression is not a good surrogate marker for promoter hypermethylation and is not independently associated with prognosis. Association between promoter hypermethylation and sensitivity to Poly(ADP-ribose) polymerase PARP inhibitors needs to be evaluated in a specific series of patients. View Full-Text
Keywords: triple-negative breast cancer; BRCA1; expression; promoter hypermethylation; prognosis; basal-like triple-negative breast cancer; BRCA1; expression; promoter hypermethylation; prognosis; basal-like
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Jacot, W.; Lopez-Crapez, E.; Mollevi, C.; Boissière-Michot, F.; Simony-Lafontaine, J.; Ho-Pun-Cheung, A.; Chartron, E.; Theillet, C.; Lemoine, A.; Saffroy, R.; Lamy, P.-J.; Guiu, S. BRCA1 Promoter Hypermethylation is Associated with Good Prognosis and Chemosensitivity in Triple-Negative Breast Cancer. Cancers 2020, 12, 828.

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