Jacot William, Lopez-Crapez Evelyne, Mollevi Caroline, Boissière-Michot Florence, Simony-Lafontaine Joelle, Ho-Pun-Cheung Alexandre, Chartron Elodie, Theillet Charles, Lemoine Antoinette, Saffroy Raphael, Lamy Pierre-Jean, Guiu Séverine
Department of Medical Oncology, Montpellier Cancer Institute Val d'Aurelle, 208 rue des Apothicaires, F-34298 Montpellier, France.
Translational Research Unit, Montpellier Cancer Institute Val d'Aurelle, 208 rue des Apothicaires, F-34298 Montpellier, France.
Cancers (Basel). 2020 Mar 30;12(4):828. doi: 10.3390/cancers12040828.
The aberrant hypermethylation of promoter CpG islands induces the decreased expression of BRCA1 Breast Cancer 1 protein. It can be detected in sporadic breast cancer without pathogenic variants, particularly in triple-negative breast cancers (TNBC). We investigated 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 promoter hypermethylation, with a high concordance rate between MS-PCR and MassARRAY results. Promoter hypermethylation was associated with reduced IHC BRCA1 protein expression ( = 0.005), and expression of Programmed death-ligand 1 protein (PD-L1) by tumor and immune cells ( = 0.03 and 0.011, respectively). A trend was found between promoter hypermethylation and basal marker staining ( = 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 promoter hypermethylation derived the most benefit from adjuvant chemotherapy. In conclusion, 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.
启动子CpG岛的异常高甲基化会导致乳腺癌1（BRCA1）蛋白表达降低。在无致病变异的散发性乳腺癌中可检测到这种情况，尤其是在三阴性乳腺癌（TNBC）中。我们使用甲基化特异性聚合酶链反应（MS-PCR）和MassARRAY分析研究了248例未经化疗的TNBC样本的高甲基化状态，并通过免疫组织化学（IHC）检测了BRCA1蛋白表达，以及它们的临床病理意义。55个肿瘤（22%）表现出启动子高甲基化，MS-PCR和MassARRAY结果之间的一致性率较高。启动子高甲基化与IHC检测的BRCA1蛋白表达降低相关（P = 0.005），并且与肿瘤细胞和免疫细胞程序性死亡配体1蛋白（PD-L1）的表达相关（分别为P = 0.03和0.011）。在启动子高甲基化与基底标志物染色之间发现了一种趋势（P = 0.058），以及在BRCA1表达与基底样表型之间也发现了趋势。在多变量分析中，无复发生存与N分期、辅助化疗和组织学亚型显著相关。总生存与T和N分期、组织学以及辅助化疗显著相关。此外，具有启动子高甲基化肿瘤的患者从辅助化疗中获益最大。总之，启动子高甲基化与TNBC对辅助化疗的敏感性、基底样特征和PD-L1表达相关。BRCA1 IHC表达不是启动子高甲基化的良好替代标志物，并且与预后无独立相关性。启动子高甲基化与聚（ADP-核糖）聚合酶（PARP）抑制剂敏感性之间的关联需要在特定系列患者中进行评估。
