Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer
Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer
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DOI：
10.1016/s0140-6736(02)09838-0
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发表时间：
2002-08-31
期刊：
影响因子：
168.9
通讯作者：
Riethmüller, G
中科院分区：
文献类型：
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作者：
Klein, CA;Blankenstein, TJF;Riethmüller, G
背景由于小肿瘤患者尽管接受局部和全身治疗仍经常复发，我们研究了微小残留病阶段远处转移前体的遗传变异。播散的肿瘤细胞可以检测到上皮标记间充质组织和代表目标的辅助therapy.Methods我们筛选了525骨髓，血液和淋巴结样本474例乳腺癌，前列腺癌，胃肠道癌的单个播散的癌细胞免疫细胞化学与上皮特异性标记。71（14%）的样本含有两个或更多个肿瘤细胞，我们通过单细胞基因组杂交研究了其基因组组织。此外，我们测试了TP53是否突变。分层聚类算法被用来确定的程度克隆相关的姐妹细胞，从个别patients.Findings分离的癌症类型无关，我们看到了一个意想不到的高遗传分化的微小残留癌，特别是在染色体不平衡的水平。虽然在疾病的这个阶段很少有播散性细胞携带TP53突变，但我们也看到了TP53基因型的微观异质性。的遗传异质性显着降低与临床上明显的metastasis.Interpretation的出现虽然原发性肿瘤的异质性早已被称为，我们在这里显示，早期播散的癌细胞基因组是非常不稳定的。选择克隆扩增的细胞导致转移，似乎发生在扩散发生后。因此，辅助治疗面临着一个非常大的变异细胞库，从中可以选择耐药肿瘤细胞。
Background Because cancer patients with small tumours often relapse despite local and systemic treatment, we investigated the genetic variation of the precursors of distant metastasis at the stage of minimal residual disease. Disseminated tumour cells can be detected by epithelial markers in mesenchymal tissues and represent targets for adjuvant therapies.Methods We screened 525 bone-marrow, blood, and lymphnode samples from 474 patients with breast, prostate, and gastrointestinal cancers for single disseminated cancer cells by immunocytochemistry with epithelial-specific markers. 71 (14%) of the samples contained two or more tumour cells whose genomic organisation we studied by single cell genomic hybridisation. In addition, we tested whether TP53 was mutated. Hierarchical clustering algorithms were used to determine the degree of clonal relatedness of sister cells that were isolated from individual patients.Findings Irrespective of cancer type, we saw an unexpectedly high genetic divergence in minimal residual cancer, particularly at the level of chromosomal imbalances. Although few disseminated cells harboured TP53 mutations at this stage of disease, we also saw microheterogeneity of the TP53 genotype. The genetic heterogeneity was strikingly reduced with the emergence of clinically evident metastasis.Interpretation Although the heterogeneity of primary tumours has long been known, we show here that early disseminated cancer cells are genomically very unstable as well. Selection of clonally expanding cells leading to metastasis, seems to occur after dissemination has taken place. Therefore, adjuvant therapies are confronted with an extremely large reservoir of variant cells from which resistant tumour cells can be selected.