Methylated genes in breast cancer Associations with clinical and histopathological features in a familial breast cancer cohort
Methylated genes in breast cancer Associations with clinical and histopathological features in a familial breast cancer cohort
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DOI：
10.4161/cbt.11.10.15177
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发表时间：
2011-05-15
影响因子：
3.6
通讯作者：
Sukumar, Saraswati
中科院分区：
文献类型：
--
作者：
Swift-Scanlan, Theresa;Vang, Russell;Sukumar, Saraswati
背景：在乳腺癌中已经发现了数百种高甲基化基因，但在非散发性乳腺癌中，这些基因在甲基化状态下对总体风险和预后的影响尚不清楚。因此，我们比较了家族性乳腺癌队列中DNA甲基化与肿瘤分期、激素/生长受体状态和临床结果的关系。由于之前很少有甲基化研究考虑其基因集的致癌或抑瘤特性，因此将这种功能状态纳入我们的相关分析。结果：我们发现癌基因甲基化与更好的预后指标相关，而肿瘤抑制基因甲基化与诊断时ER2（+）或淋巴结阳性和/或倾向于复发或发生远处转移的女性更严重的表型相关。例如，肿瘤抑制基因APC的甲基化与ER+和HER2（+）肿瘤的特定亚群密切相关，而TWIST癌基因的甲基化与未转移的乳腺癌相关。方法：这是一项回顾性的、基于医院的研究，研究对象为n = 99例来自生殖系遗传BRCA1或BRCA2突变和/或家族性乳腺癌病史的女性的乳腺肿瘤档案。采用已建立的定量多重甲基化特异性PCR （QM-MSP）方法，对福尔马林固定、石蜡包埋的肿瘤进行DNA甲基化定量。非参数统计用于分析候选基因甲基化与临床结果的关系。结论：我们报告了AP C、RASSF1A、TWIST、ER α、CDH1和Cyclin D2基因甲基化百分比与肿瘤分期、激素和生长受体状态以及复发或转移性疾病史等关键变量之间的一些新的正相关。我们的数据表明，通过功能状态和乳腺癌亚型分析基因甲基化的潜在效用。
Background: Hundreds of hypermethylated genes have been described in breast cancer, yet the nature and contribution of these genes in their methylated state to overall risk and prognosis is under-characterized in non-sporadic breast cancers. We therefore compared associations of DNA methylation with tumor stage, hormone/growth receptor status and clinical outcomes in a familial breast cancer cohort. Because few previous methylation studies have considered the oncogenic or tumor suppressor properties of their gene sets, this functional status was included as part of our correlative analysis.Results: We found methylation of oncogenes was associated with better prognostic indicators, whereas tumor suppressor gene methylation was associated with a more severe phenotype in women that were either ER2(+) or lymph node positive at diagnosis, and/or tended to recur or develop distant metastases. For example, the methylation of the tumor suppressor gene APC was strongly associated with a specific subset of tumors that were both ER+ and HER2(+), while methylation of the TWIST oncogene was associated with breast cancers that did not metastasize.Methods: This was a retrospective, hospital-based study of n = 99 archival breast tumors derived from women with a germline genetic BRCA1 or BRCA2 mutation and/or familial breast cancer history. DNA methylation was quantified from formalin fixed, paraffin embedded tumors using the established protocol of quantitative multiplex-methylation specific PCR (QM-MSP). Non-parametric statistics were used to analyze candidate gene methylation in association with clinical outcomes.Conclusion: We report several novel, positive associations between percent methylation of the AP C, RASSF1A, TWIST, ER alpha, CDH1 and Cyclin D2 genes and key variables such as tumor stage, hormone and growth receptor status, and a history of recurrent or metastatic disease. Our data suggest the potential utility of parsing gene methylation by functional status and breast tumor subtype.