三阴性乳腺癌生长期间仍可变化多端
染色体拷贝数非整倍性是人类乳腺癌的显著特征，尤其携带抑癌基因TP53突变的三阴性乳腺癌。虽然体外细胞模型和动物体内模型已经阐明非整倍性的潜在分子机制，但是我们对于人类原发肿瘤生长期间何时以及如何出现并维持染色体重排的了解仍然有限。
2021年3月24日，全球自然科学三大期刊之首、英国《自然》正刊在线发表美国德克萨斯大学MD安德森癌症中心、哈佛大学达纳法伯癌症研究所、哈佛大学陈曾熙公共卫生学院、哈佛大学医学院路德维希中心、麻省理工学院哈佛布罗德研究所、英国弗朗西斯克里克研究所的研究报告，对1万多个人类三阴性乳腺癌细胞生长期间拷贝数变化进行了分析。
该研究首先开发了一种单细胞单分子脱氧核糖核酸（DNA）测序方法，并对来自8例人类三阴性乳腺癌患者和4种人类三阴性乳腺癌细胞系的1万6178个细胞进行了拷贝数分析。
结果表明，乳腺肿瘤和细胞系存在大量亚克隆（7～22）并组成几个（3～5）主要的超级克隆。根据原发肿瘤生长期间的演化分析，在克隆TP53突变、多个杂合性丢失事件和基因组倍增之后，存在一段短暂的基因组不稳定期，随后出现拷贝数变化。通过亚克隆培养单个子代细胞，可见肿瘤细胞使其基因组多样化，并且不保持等基因特性。
因此，该研究结果表明，三阴性乳腺癌原发肿瘤生长期间，仍然继续染色体变化，并且保持亚克隆多样性能力，为进一步探索三阴性乳腺癌患者染色体变化及其对策奠定了基础。
Nature. 2021 Mar 24. Online ahead of print.
Breast tumours maintain a reservoir of subclonal diversity during expansion.
Darlan C. Minussi, Michael D. Nicholson, Hanghui Ye, Alexander Davis, Kaile Wang, Toby Baker, Maxime Tarabichi, Emi Sei, Haowei Du, Mashiat Rabbani, Cheng Peng, Min Hu, Shanshan Bai, Yu-wei Lin, Aislyn Schalck, Asha Multani, Jin Ma, Thomas O. McDonald, Anna Casasent, Angelica Barrera, Hui Chen, Bora Lim, Banu Arun, Funda Meric-Bernstam, Peter Van Loo, Franziska Michor, Nicholas E. Navin.
The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Harvard T.H. Chan School of Public Health, Boston, MA, USA; Harvard University, Cambridge, MA, USA; The Ludwig Center at Harvard, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; The Francis Crick Institute, London, UK.
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.
DOI: 10.1038/s41586-021-03357-x