Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center UTHealth, Houston, TX, USA.
Nature. 2021 Apr;592(7853):302-308. doi: 10.1038/s41586-021-03357-x. Epub 2021 Mar 24.
Our knowledge of copy number evolution during the expansion of primary breast tumours is limited. Here, to investigate this process, we developed a single-cell, single-molecule DNA-sequencing method and performed copy number analysis of 16,178 single cells from 8 human triple-negative breast cancers and 4 cell lines. The results show that breast tumours and cell lines comprise a large milieu of subclones (7-22) that are organized into a few (3-5) major superclones. Evolutionary analysis suggests that after clonal TP53 mutations, multiple loss-of-heterozygosity events and genome doubling, there was a period of transient genomic instability followed by ongoing copy number evolution during the primary tumour expansion. By subcloning single daughter cells in culture, we show that tumour cells rediversify their genomes and do not retain isogenic properties. These data show that triple-negative breast cancers continue to evolve chromosome aberrations and maintain a reservoir of subclonal diversity during primary tumour growth.
我们对原发性乳腺癌扩张过程中拷贝数进化的了解有限。在这里，为了研究这个过程，我们开发了一种单细胞、单分子 DNA 测序方法，并对 8 个人类三阴性乳腺癌和 4 个细胞系的 16178 个单细胞进行了拷贝数分析。结果表明，乳腺癌和细胞系包含大量亚克隆（7-22 个），这些亚克隆组织成少数（3-5 个）主要超克隆。进化分析表明，在克隆性 TP53 突变、多次杂合性丢失事件和基因组加倍之后，原发性肿瘤扩张过程中有一个短暂的基因组不稳定期，随后持续进行拷贝数进化。通过在培养中对单个子细胞进行亚克隆，我们表明肿瘤细胞重新多样化其基因组，并且不保留同基因性质。这些数据表明，三阴性乳腺癌在原发性肿瘤生长过程中继续进化染色体异常，并维持亚克隆多样性的储备。
