The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
J Pathol. 2010 Apr;220(5):562-73. doi: 10.1002/path.2675.
Cancers may be composed of multiple populations of submodal clones sharing the same initiating genetic lesions, followed by the acquisition of divergent genetic hits. Intra-tumour genetic heterogeneity has profound implications for cancer clinical management. To determine the extent of intra-tumour genetic heterogeneity in breast cancers, and whether the morphological diversity of breast cancers is underpinned by divergent genetic aberrations, we analysed the genomic profiles of microdissected, morphologically distinct components of six metaplastic breast carcinomas, tumours characterized by the presence of morphological areas with divergent differentiation. Each morphologically distinct component was separately microdissected and subjected to high-resolution microarray-based comparative genomic hybridization. Each component was also analysed by immunohistochemistry and in situ hybridization. Clonal relationship between the distinct components was tested by TP53 sequencing and human androgen receptor (HUMARA) X-chromosome inactivation assay. In the majority of cases, all morphologically distinct components from each case were clonal and displayed remarkably similar genetic profiles. In two cases, however, morphologically distinct components harboured specific genetic aberrations. In an adenosquamous carcinoma, the differences were such that only 20% of the genome harboured similar copy number changes. The squamous component displayed EGFR gene amplification, EGFR over-expression and lack of expression of hormone receptors, whereas the lobular component displayed the reverse pattern. The components of a biphasic spindle cell carcinoma harboured similar gains, losses, amplifications of 9p23 and 17q12 (HER2) and identical TP53 mutations, suggesting that these were relatively early events in the development of this tumour; however, each component displayed divergent focal amplifications. Importantly, the metastatic deposit of this case, despite harbouring a TP53 mutation identical to that found in the primary tumour, harboured additional specific focal amplifications. This proof-of-principle study provides direct evidence of intra-tumour genetic heterogeneity in breast cancers, and shows that in some cases morphological diversity may be underpinned by distinct genetic aberrations.
癌症可能由多个亚克隆群体组成，这些群体共享相同的起始遗传病变，然后获得不同的遗传打击。肿瘤内遗传异质性对癌症的临床管理具有深远的影响。为了确定乳腺癌中肿瘤内遗传异质性的程度，以及乳腺癌的形态多样性是否由不同的遗传异常支持，我们分析了六例具有形态学不同分化区域的多形性乳腺癌的微切割、形态学不同成分的基因组图谱，这些肿瘤的特征是存在形态区域具有不同的分化。每个形态学上不同的成分都被单独微切割，并进行高分辨率基于微阵列的比较基因组杂交分析。每个成分还通过免疫组织化学和原位杂交进行分析。通过 TP53 测序和人类雄激素受体（HUMARA）X 染色体失活检测来测试不同成分之间的克隆关系。在大多数情况下，来自每个病例的所有形态学上不同的成分都是克隆的，显示出非常相似的遗传谱。然而，在两种情况下，形态学上不同的成分具有特定的遗传异常。在一个腺鳞癌中，差异如此之大，以至于只有 20%的基因组具有相似的拷贝数变化。鳞状成分显示 EGFR 基因扩增、EGFR 过表达和激素受体缺乏表达，而小叶成分则显示相反的模式。双相梭形细胞癌的成分具有相似的增益、丢失、9p23 和 17q12（HER2）的扩增以及相同的 TP53 突变，这表明这些是该肿瘤发展过程中的早期事件；然而，每个成分都显示出不同的局灶性扩增。重要的是，该病例的转移沉积物虽然具有与原发性肿瘤相同的 TP53 突变，但还存在其他特定的局灶性扩增。这项初步研究提供了乳腺癌中肿瘤内遗传异质性的直接证据，并表明在某些情况下，形态多样性可能由不同的遗传异常支持。
