Arriola Edurne, Marchio Caterina, Tan David S P, Drury Suzanne C, Lambros Maryou B, Natrajan Rachael, Rodriguez-Pinilla Socorro Maria, Mackay Alan, Tamber Narinder, Fenwick Kerry, Jones Chris, Dowsett Mitch, Ashworth Alan, Reis-Filho Jorge S
The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
Lab Invest. 2008 May;88(5):491-503. doi: 10.1038/labinvest.2008.19. Epub 2008 Mar 10.
HER2 and TOP2A are targets for the therapeutic agents trastuzumab and anthracyclines and are frequently amplified in breast cancers. The aims of this study were to provide a detailed molecular genetic analysis of the 17q12-q21 amplicon in breast cancers harbouring HER2/TOP2A co-amplification and to investigate additional recurrent co-amplifications in HER2/TOP2A-co-amplified cancers. In total, 15 breast cancers with HER2 amplification, 10 of which also harboured TOP2A amplification, as defined by chromogenic in situ hybridisation, and 6 breast cancer cell lines known to be amplified for HER2 were subjected to high-resolution microarray-based comparative genomic hybridisation analysis. This revealed that the genomes of 12 cases were characterised by at least one localised region of clustered, relatively narrow peaks of amplification, with each cluster confined to a single chromosome arm (ie 'firestorm' pattern) and 3 cases displayed many narrow segments of duplication and deletion affecting the vast majority of chromosomes (ie 'sawtooth' pattern). The smallest region of amplification (SRA) on 17q12 in the whole series extended from 34.73 to 35.48 Mb, and encompassed HER2 but not TOP2A. In HER2/TOP2A-co-amplified samples, the SRA extended from 34.73 to 36.54 Mb, spanning a region of approximately 1.8 Mb. Apart from HER2 and TOP2A, this region encompassed four additional genes whose expression levels as defined by quantitative real-time PCR are significantly higher in HER2/TOP2A-co-amplified vs HER2-amplified breast cancers: CASC3, CDC6, RARA and SMARCE1. Of the cell lines studied, SKBR3 and UACC812 showed HER2/TOP2A co-amplification. In conclusion, this is the first detailed genome-wide characterisation of HER2/TOP2A-amplified breast cancers; cell lines were identified that can be used to model these cancers in vitro. The 17q12 amplicon is complex and harbours multiple genes that may be associated with breast cancer development and progression, and potentially exploitable as therapeutic targets.
人表皮生长因子受体2（HER2）和拓扑异构酶IIα（TOP2A）是治疗药物曲妥珠单抗和蒽环类药物的作用靶点，在乳腺癌中经常出现扩增。本研究的目的是对存在HER2/TOP2A共扩增的乳腺癌中17q12 - q21扩增子进行详细的分子遗传学分析，并研究HER2/TOP2A共扩增癌症中其他复发性共扩增情况。总共对15例HER2扩增的乳腺癌（其中10例也存在TOP2A扩增，通过显色原位杂交定义）以及6种已知HER2扩增的乳腺癌细胞系进行了基于高分辨率微阵列的比较基因组杂交分析。结果显示，12例病例的基因组特征为至少有一个局部区域存在聚集的、相对较窄的扩增峰，每个簇局限于一条染色体臂（即“风暴”模式），3例表现出许多影响绝大多数染色体的狭窄重复和缺失片段（即“锯齿”模式）。整个系列中17q12上的最小扩增区域（SRA）从34.73至35.48兆碱基（Mb），包含HER2但不包含TOP2A。在HER2/TOP2A共扩增样本中，SRA从34.73至36.54 Mb，跨度约为1.8 Mb。除HER2和TOP2A外，该区域还包含另外四个基因，通过定量实时PCR定义，其在HER2/TOP2A共扩增的乳腺癌中的表达水平明显高于HER2扩增的乳腺癌：癌症易感性候选基因3（CASC3）、细胞分裂周期蛋白6（CDC6）、维甲酸受体α（RARA）和染色质重塑蛋白SMARCE1。在所研究的细胞系中，SKBR3和UACC812表现出HER2/TOP2A共扩增。总之，这是首次对HER2/TOP2A扩增的乳腺癌进行全基因组详细表征；鉴定出了可用于在体外模拟这些癌症的细胞系。17q12扩增子很复杂，包含多个可能与乳腺癌发生和进展相关的基因，并有可能作为治疗靶点加以利用。
