BRCA2 携带者的男性乳腺癌表现出肿瘤甲基化水平升高。
BRCA2 carriers with male breast cancer show elevated tumour methylation.
机构信息
Molecular Pathology Research and Development Laboratory, Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Vic, Parkville, 3010, Australia.
出版信息
BMC Cancer. 2017 Sep 11;17(1):641. doi: 10.1186/s12885-017-3632-7.
BACKGROUND
Male breast cancer (MBC) represents a poorly characterised group of tumours, the management of which is largely based on practices established for female breast cancer. However, recent studies demonstrate biological and molecular differences likely to impact on tumour behaviour and therefore patient outcome. The aim of this study was to investigate methylation of a panel of commonly methylated breast cancer genes in familial MBCs.
METHODS
60 tumours from 3 BRCA1 and 25 BRCA2 male mutation carriers and 32 males from BRCAX families were assessed for promoter methylation by methylation-sensitive high resolution melting in a panel of 10 genes (RASSF1A, TWIST1, APC, WIF1, MAL, RARβ, CDH1, RUNX3, FOXC1 and GSTP1). An average methylation index (AMI) was calculated for each case comprising the average of the methylation of the 10 genes tested as an indicator of overall tumour promoter region methylation. Promoter hypermethylation and AMI were correlated with BRCA carrier mutation status and clinicopathological parameters including tumour stage, grade, histological subtype and disease specific survival.
RESULTS
Tumours arising in BRCA2 mutation carriers showed significantly higher methylation of candidate genes, than those arising in non-BRCA2 familial MBCs (average AMI 23.6 vs 16.6, p = 0.01, 45% of genes hypermethylated vs 34%, p < 0.01). RARβ methylation and AMI-high status were significantly associated with tumour size (p = 0.01 and p = 0.02 respectively), RUNX3 methylation with invasive carcinoma of no special type (94% vs 69%, p = 0.046) and RASSF1A methylation with coexistence of high grade ductal carcinoma in situ (33% vs 6%, p = 0.02). Cluster analysis showed MBCs arising in BRCA2 mutation carriers were characterised by RASSF1A, WIF1, RARβ and GTSP1 methylation (p = 0.02) whereas methylation in BRCAX tumours showed no clear clustering to particular genes. TWIST1 methylation (p = 0.001) and AMI (p = 0.01) were prognostic for disease specific survival.
CONCLUSIONS
Increased methylation defines a subset of familial MBC and with AMI may be a useful prognostic marker. Methylation might be predictive of response to novel therapeutics that are currently under investigation in other cancer types.
背景
男性乳腺癌（MBC）代表了一组特征不明显的肿瘤，其治疗主要基于为女性乳腺癌制定的实践。然而，最近的研究表明，生物学和分子差异可能会影响肿瘤的行为，从而影响患者的预后。本研究旨在调查一组常见的乳腺癌基因在家族性 MBC 中的甲基化情况。
方法
对 3 名 BRCA1 和 25 名 BRCA2 男性突变携带者的 60 个肿瘤以及 32 名 BRCAX 家族男性的肿瘤进行了 10 个基因（RASSF1A、TWIST1、APC、WIF1、MAL、RARβ、CDH1、RUNX3、FOXC1 和 GSTP1）启动子甲基化的甲基敏感高分辨率熔解分析。计算了每个病例的平均甲基化指数（AMI），该指数由测试的 10 个基因的甲基化平均值组成，作为肿瘤启动子区域甲基化的总体指标。启动子高甲基化和 AMI 与 BRCA 携带者突变状态和临床病理参数相关，包括肿瘤分期、分级、组织学亚型和疾病特异性生存。
结果
BRCA2 突变携带者的肿瘤候选基因甲基化程度明显高于非 BRCA2 家族性 MBC 肿瘤（平均 AMI 23.6 比 16.6，p=0.01，45%的基因高甲基化比 34%，p<0.01）。RARβ 甲基化和 AMI 高状态与肿瘤大小显著相关（p=0.01 和 p=0.02），RUNX3 甲基化与非特殊类型浸润性癌相关（94%比 69%，p=0.046），RASSF1A 甲基化与高级导管原位癌共存相关（33%比 6%，p=0.02）。聚类分析显示，BRCA2 突变携带者的 MBC 以 RASSF1A、WIF1、RARβ 和 GTSP1 甲基化为特征（p=0.02），而 BRCAX 肿瘤的甲基化没有明显聚类到特定基因。TWIST1 甲基化（p=0.001）和 AMI（p=0.01）是疾病特异性生存的预后因素。
结论
高甲基化定义了家族性 MBC 的一个亚组，并且 AMI 可能是一个有用的预后标志物。甲基化可能是对目前正在其他癌症类型中进行研究的新型治疗药物的反应的预测因子。
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