Genetic and phenotypic diversity in breast tumor metastases.
Genetic and phenotypic diversity in breast tumor metastases.
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DOI：
10.1158/0008-5472.can-13-2357-t
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发表时间：
2014-03-01
期刊：
影响因子：
11.2
通讯作者：
Polyak K
中科院分区：
文献类型：
--
作者：
Almendro V;Kim HJ;Cheng YK;Gönen M;Itzkovitz S;Argani P;van Oudenaarden A;Sukumar S;Michor F;Polyak K
由于几乎普遍的治疗耐药性，转移性疾病是癌症相关死亡的主要原因。尽管其临床相关性很高，但我们对癌细胞群在转移进展过程中如何变化的了解仍然有限。在这里，我们研究了乳腺癌转移进展过程中的肿瘤内遗传和表型异质性。我们通过对来自快速尸检病例以及全身治疗前收集的原发肿瘤和匹配淋巴结转移瘤的远处转移肿瘤的完整组织切片进行免疫-FISH，在单细胞水平上分析了细胞基因型和表型。我们计算了所有癌细胞和表型不同的细胞群内肿瘤内多样性的香农指数。我们发现，无论分析的染色体区域如何，肿瘤内遗传多样性的程度都是相似的，这意味着它可能反映了肿瘤的固有特性。我们观察到，远处转移灶的遗传多样性最高，并且同一患者内的各个病变通常是一致的，而未经治疗的原发肿瘤和匹配的淋巴结转移灶在遗传上往往更加不同。相反，远处转移瘤之间的细胞表型比原发肿瘤和匹配的淋巴结转移瘤之间更加不一致。与其他亚型相比，HER2+ 肿瘤中 8q24 的多样性始终较高，三阴性肿瘤转移灶相对于原发部位的多样性也始终较高。我们的结论是，我们的综合方法将生态模型与人体组织样本的实验数据相结合，可用于改善癌症患者的预后，并为进展性疾病设计更有效的疗法。通过定义原发性和转移性乳腺肿瘤的瘤内细胞遗传和表型异质性的定量测量，并通过评估肿瘤拓扑结构，我们确定远处转移性肿瘤是最多样化的，这可以解释晚期疾病常见的治疗耐药性。
Metastatic disease is the main cause of cancer-related mortality due to almost universal therapeutic resistance. Despite its high clinical relevance our knowledge of how cancer cell populations change during metastatic progression is limited. Here we investigated intratumor genetic and phenotypic heterogeneity during metastatic progression of breast cancer. We analyzed cellular genotypes and phenotypes at the single cell level by performing immuno-FISH in intact tissue sections of distant metastatic tumors from rapid autopsy cases and from primary tumors and matched lymph node metastases collected prior to systemic therapy. We calculated Shannon index of intratumor diversity in all cancer cells and within phneotypically distinct cell populations. We found that the extent of intratumor genetic diversity was similar regardless of the chromosomal region analyzed, implying that it may reflect an inherent property of the tumors. We observed that genetic diversity was highest in distant metastases and was generally concordant across lesions within the same patient, whereas treatment-naïve primary tumors and matched lymph node metastases were frequently genetically more divergent. In contrast, cellular phenotypes were more discordant between distant metastases than primary tumors and matched lymph node metastases. Diversity for 8q24 was consistently higher in HER2+ tumors compared to other subtypes and in metastases of triple negative tumors relative to primary sites. We conclude that our integrative method that couples ecologic models with experimental data in human tissue samples, could be used for the improved prognostication of cancer patients and for the design of more effective therapies for progressive disease. By defining quantitative measures of intratumor cellular genetic and phenotypic heterogeneity in primary and metastatic breast tumors and by assessing tumor topology, we determined that distant metastatic tumors are the most diverse, which can explain the frequent therapy-resistance of advanced stage disease.