小柯机器人

英国癌症研究所Trevor A. Graham和Andrea Sottoriva共同合作近期取得重要工作进展，他们的研究发现了结直肠癌进化中的表型可塑性和遗传控制。相关论文2022年10月26日在线发表于《自然》杂志上。

研究人员发现肿瘤内基因祖先很少影响结直肠癌（CRC）的基因表达特征和亚克隆进化。利用空间分辨率配对的全基因组和转录组测序，研究人员发现大多数肿瘤内的基因表达变异不是强烈的遗传，而是 "可塑性"。体细胞表达数量性状位点分析确定了一些由顺式编码和非编码突变控制表达的假定遗传，其中大多数是在肿瘤内的克隆，同时还有频繁的结构改变。一致的是，对肿瘤系统发育的空间模式的计算推断发现，相当一部分CRC没有显示出亚克隆选择的证据，只有一部分假定的遗传驱动因素与亚克隆扩增有关。克隆的空间混杂是很常见的，一些肿瘤呈指数增长，而另一些只在外围增长。

这些数据表明，CRC的大多数瘤内遗传变异没有主要的表型后果，相反，转录可塑性在肿瘤内是广泛存在的。

据介绍，遗传和表观遗传变异，加上转录可塑性，有助于肿瘤内异质性的形成。这些生物过程的相互作用以及它们各自对肿瘤进化的贡献仍然未知。

附：英文原文

Title: Phenotypic plasticity and genetic control in colorectal cancer evolution

Author: Househam, Jacob, Heide, Timon, Cresswell, George D., Spiteri, Inmaculada, Kimberley, Chris, Zapata, Luis, Lynn, Claire, James, Chela, Mossner, Maximilian, Fernandez-Mateos, Javier, Vinceti, Alessandro, Baker, Ann-Marie, Gabbutt, Calum, Berner, Alison, Schmidt, Melissa, Chen, Bingjie, Lakatos, Eszter, Gunasri, Vinaya, Nichol, Daniel, Costa, Helena, Mitchinson, Miriam, Ramazzotti, Daniele, Werner, Benjamin, Iorio, Francesco, Jansen, Marnix, Caravagna, Giulio, Barnes, Chris P., Shibata, Darryl, Bridgewater, John, Rodriguez-Justo, Manuel, Magnani, Luca, Sottoriva, Andrea, Graham, Trevor A.

Issue&Volume: 2022-10-26

Abstract: Genetic and epigenetic variation, together with transcriptional plasticity, contribute to intratumour heterogeneity1. The interplay of these biological processes and their respective contributions to tumour evolution remain unknown. Here we show that intratumour genetic ancestry only infrequently affects gene expression traits and subclonal evolution in colorectal cancer (CRC). Using spatially resolved paired whole-genome and transcriptome sequencing, we find that the majority of intratumour variation in gene expression is not strongly heritable but rather ‘plastic’. Somatic expression quantitative trait loci analysis identified a number of putative genetic controls of expression by cis-acting coding and non-coding mutations, the majority of which were clonal within a tumour, alongside frequent structural alterations. Consistently, computational inference on the spatial patterning of tumour phylogenies finds that a considerable proportion of CRCs did not show evidence of subclonal selection, with only a subset of putative genetic drivers associated with subclone expansions. Spatial intermixing of clones is common, with some tumours growing exponentially and others only at the periphery. Together, our data suggest that most genetic intratumour variation in CRC has no major phenotypic consequence and that transcriptional plasticity is, instead, widespread within a tumour.

DOI: 10.1038/s41586-022-05311-x

Source: https://www.nature.com/articles/s41586-022-05311-x

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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