Assessment of the evolutionary consequence of putative driver mutations in colorectal cancer with spatial multiomic data-猫眼课题宝

DOI：

10.1101/2021.07.14.451265

发表时间：

2021-07

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Timon Heide;J. Househam;George D. Cresswell;I. Spiteri;Claire Lynn;C. Kimberley;M. Mossner;L. Zapata;C. Gabbutt;Daniele Ramazzotti;Bingjie Chen;J. Fernández-Mateos;C. James;A. Vinceti;A. Berner;Melissa Schmidt;E. Lakatos;A. Baker;D. Nichol;Helena Costa;Miriam Mitchinson;B. Werner;F. Iorio;M. Jansen;Chris P. Barnes;G. Caravagna;D. Shibata;J. Bridgewater;M. Rodríguez-Justo;L. Magnani;T. Graham;A. Sottoriva

癌症基因组医学依赖于靶向驱动基因。然而，目前的癌症驱动因素目录大多基于突变频率、位置或类型的间接测量，而不是它们对体内克隆扩增的影响。此外，非遗传驱动因素很大程度上是未知的，遗传驱动因素的表观遗传和转录组效应也是如此。在这里，我们通过匹配的全基因组测序、ATAC-seq 和 RNA-seq 对多组数据进行空间计算推理。使用 436 个样本，我们直接量化了推定驱动基因对 30 例结直肠癌体内亚克隆扩增的贡献或缺乏（每个患者 4-33 个样本，中位数 = 15）。尽管亚克隆中性进化很普遍（13/26例有足够的数据），但在某些情况下有明确的亚克隆选择证据（6/26），我们在体内测量了亚克隆之间的表观遗传和转录组差异。在 7/26 的情况下，我们无法利用现有数据区分中性进化和选择性进化。我们发现了不受已知遗传改变驱动的扩展亚克隆，并提出了候选表观遗传驱动因素。我们确定了快速呈指数增长的肿瘤（7/26）与仅在外围生长的肿瘤（19/26）产生的基因组异质性的区别模式，并确定了克隆混合性（16/28病例有足够的数据）与分离的恶性肿瘤（10/28）。我们基于模型的方法在空间和时间上测量遗传和非遗传亚克隆选择或缺乏亚克隆选择，并允许在体内比较人类肿瘤内亚克隆的新表型特性。

Cancer genomic medicine relies on targeting driver genes. However, current catalogues of cancer drivers are mostly based on indirect measurements of mutation frequencies, positions or types, rather than their effect on clonal expansions in vivo. Moreover, non-genetic drivers are largely unknown, as are the epigenetic and transcriptomic effects of genetic drivers. Here we perform spatial computational inference on multiomic data with matched whole-genome sequencing, ATAC-seq and RNA-seq. Using 436 samples, we directly quantify the contribution, or lack thereof, of putative driver genes to subclonal expansions in vivo in 30 colorectal carcinomas (4-33 samples per patient, median=15). Although subclonal neutral evolution was widespread (13/26 cases with sufficient data), there were cases with clear evidence of subclonal selection (6/26) in which we measured epigenetic and transcriptomic differences between subclones in vivo. In 7/26 cases we could not distinguish between neutral or selective evolution with the available data. We identified expanding subclones that were not driven by known genetic alterations, and propose candidate epigenetic drivers. We identified the distinguishing patterns of genomic heterogeneity produced in fast, exponentially growing tumours (7/26) versus neoplasms growing only at the periphery (19/26), as well as identifying clonally intermixed (16/28 cases with sufficient data) versus segregated malignancies (10/28). Our model-based approach measures genetic and non-genetic subclonal selection, or lack thereof, in space and time and allows in vivo comparisons of the emergent phenotypic properties of subclones within human tumours.

Assessment of the evolutionary consequence of putative driver mutations in colorectal cancer with spatial multiomic data

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