Department of Pathology, University Medical Centre Utrecht, Utrecht, The Netherlands.
Mod Pathol. 2010 Jul;23(7):1029-39. doi: 10.1038/modpathol.2010.84. Epub 2010 May 14.
Several oncogenes and tumor-suppressor genes have been shown to be implicated in the development, progression and response to therapy of invasive breast cancer. The phenotypic uniqueness (and thus the heterogeneity of clinical behavior) among patients' tumors may be traceable to the underlying variation in gene copy number of these genes. To obtain a more complete view of gene copy number changes and their relation to phenotype, we analyzed 20 breast cancer-related genes in 104 invasive breast cancers with the use of multiplex ligation-dependent probe amplification (MLPA). We identified MYC gene amplification in 48% of patients, PRDM14 in 34%, topoisomerase IIalpha (TOP2A) in 32%, ADAM9 in 32%, HER2 in 28%, cyclin D1 (CCND1) in 26%, EMSY in 25%, IKBKB in 21%, AURKA in 17%, FGFR1 in 17%, estrogen receptor alpha (ESR1) in 16%, CCNE1 in 12% and EGFR in 9% of patients. There was a significant correlation between the number of amplified genes and the histological grade and mitotic index of the tumor. Gene amplifications of EGFR, CCNE1 and HER2 were negatively associated with estrogen receptor status whereas FGFR1, ADAM9, IKBKB and TOP2A revealed a positive association. Amplifications of ESR1, PRDM14, MYC and HER2 were associated with a high mitotic index, and PRDM14 and HER2 amplifications with high histological grade. MYC amplification was detected more frequently in ductal tumors and high-level MYC amplifications were significantly associated with large tumor size. HER2/MYC, HER2/CCNE1 and EGFR/MYC co-amplified tumors were significantly larger than tumors with either of these amplifications. Gene loss occurred most frequently in E-cadherin (CDH1) (20%) and FGFR1 (10%). In conclusion, MLPA analysis with this 'breast cancer kit' allowed to simultaneously assess copy numbers of 20 important breast cancer genes, providing an overview of the most frequent (co)amplifications as well as interesting phenotypic correlations, and thereby data on the potential importance of these genes in breast cancer.
已经证实，一些癌基因和抑癌基因参与了浸润性乳腺癌的发生、发展和对治疗的反应。患者肿瘤的表型独特性（因此临床行为的异质性）可能可以追溯到这些基因的基因拷贝数的潜在变化。为了更全面地了解基因拷贝数的变化及其与表型的关系，我们使用多重连接依赖性探针扩增（MLPA）分析了 104 例浸润性乳腺癌中的 20 个乳腺癌相关基因。我们发现 48%的患者存在 MYC 基因扩增，34%的患者存在 PRDM14 基因扩增，32%的患者存在拓扑异构酶 IIalpha（TOP2A）基因扩增，32%的患者存在 ADAM9 基因扩增，28%的患者存在 HER2 基因扩增，26%的患者存在 cyclin D1（CCND1）基因扩增，25%的患者存在 EMSY 基因扩增，21%的患者存在 IKBKB 基因扩增，17%的患者存在 AURKA 基因扩增，17%的患者存在 FGFR1 基因扩增，16%的患者存在雌激素受体 alpha（ESR1）基因扩增，12%的患者存在 CCNE1 基因扩增，9%的患者存在 EGFR 基因扩增。肿瘤的组织学分级和有丝分裂指数与扩增基因的数量之间存在显著相关性。EGFR、CCNE1 和 HER2 的基因扩增与雌激素受体状态呈负相关，而 FGFR1、ADAM9、IKBKB 和 TOP2A 的基因扩增则呈正相关。ESR1、PRDM14、MYC 和 HER2 的扩增与高有丝分裂指数相关，PRDM14 和 HER2 的扩增与高组织学分级相关。MYC 扩增在导管性肿瘤中更为常见，高水平的 MYC 扩增与肿瘤体积较大显著相关。HER2/MYC、HER2/CCNE1 和 EGFR/MYC 共扩增肿瘤明显大于仅存在其中一种扩增的肿瘤。E-钙黏蛋白（CDH1）（20%）和 FGFR1（10%）基因丢失最为常见。总之，使用这种“乳腺癌试剂盒”进行 MLPA 分析可以同时评估 20 个重要乳腺癌基因的拷贝数，提供最常见（共）扩增的概述以及有趣的表型相关性，从而提供这些基因在乳腺癌中潜在重要性的数据。
