Cancer Ageing and Somatic Mutations Programme, Wellcome Trust Sanger Insitute, Hinxton, UK.
Hubrecht Institute, University Medical Center Utrecht and Princess Maxima Center, Utrecht, The Netherlands.
Nature. 2018 Apr;556(7702):457-462. doi: 10.1038/s41586-018-0024-3. Epub 2018 Apr 11.
Every cancer originates from a single cell. During expansion of the neoplastic cell population, individual cells acquire genetic and phenotypic differences from each other. Here, to investigate the nature and extent of intra-tumour diversification, we characterized organoids derived from multiple single cells from three colorectal cancers as well as from adjacent normal intestinal crypts. Colorectal cancer cells showed extensive mutational diversification and carried several times more somatic mutations than normal colorectal cells. Most mutations were acquired during the final dominant clonal expansion of the cancer and resulted from mutational processes that are absent from normal colorectal cells. Intra-tumour diversification of DNA methylation and transcriptome states also occurred; these alterations were cell-autonomous, stable, and followed the phylogenetic tree of each cancer. There were marked differences in responses to anticancer drugs between even closely related cells of the same tumour. The results indicate that colorectal cancer cells experience substantial increases in somatic mutation rate compared to normal colorectal cells, and that genetic diversification of each cancer is accompanied by pervasive, stable and inherited differences in the biological states of individual cancer cells.
每种癌症都起源于单个细胞。在肿瘤细胞群体的扩张过程中，个别细胞彼此之间获得了遗传和表型上的差异。在这里，为了研究肿瘤内多样化的本质和程度，我们对源自三个结直肠癌的多个单细胞以及相邻正常肠隐窝的类器官进行了表征。结直肠癌细胞表现出广泛的突变多样化，携带的体细胞突变比正常结直肠细胞多几倍。大多数突变是在癌症最终的主导克隆扩张过程中获得的，并且源自正常结直肠细胞中不存在的突变过程。DNA 甲基化和转录组状态的肿瘤内多样化也发生了；这些改变是细胞自主的、稳定的，并遵循每个癌症的系统发育树。即使是同一肿瘤中密切相关的细胞对抗癌药物的反应也有明显的差异。结果表明，与正常结直肠细胞相比，结直肠癌细胞的体细胞突变率显著增加，并且每个癌症的遗传多样化伴随着单个癌细胞生物学状态的普遍、稳定和遗传差异。
