State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
China National Center for Bioinformation, Beijing, China.
Mol Biol Evol. 2022 Jan 7;39(1). doi: 10.1093/molbev/msab335.
Spatial genetic and phenotypic diversity within solid tumors has been well documented. Nevertheless, how this heterogeneity affects temporal dynamics of tumorigenesis has not been rigorously examined because solid tumors do not evolve as the standard population genetic model due to the spatial constraint. We therefore, propose a neutral spatial (NS) model whereby the mutation accumulation increases toward the periphery; the genealogical relationship is spatially determined and the selection efficacy is blunted (due to kin competition). In this model, neutral mutations are accrued and spatially distributed in manners different from those of advantageous mutations. Importantly, the distinctions could be blurred in the conventional model. To test the NS model, we performed a three-dimensional multiple microsampling of two hepatocellular carcinomas. Whole-genome sequencing (WGS) revealed a 2-fold increase in mutations going from the center to the periphery. The operation of natural selection can then be tested by examining the spatially determined clonal relationships and the clonal sizes. Due to limited migration, only the expansion of highly advantageous clones can sweep through a large part of the tumor to reveal the selective advantages. Hence, even multiregional sampling can only reveal a fraction of fitness differences in solid tumors. Our results suggest that the NS patterns are crucial for testing the influence of natural selection during tumorigenesis, especially for small solid tumors.
实体瘤内的空间遗传和表型多样性已有充分的文献记载。然而，由于实体瘤的空间限制，其不会像标准的群体遗传模型那样进化，因此这种异质性如何影响肿瘤发生的时间动态尚未得到严格检查。为此，我们提出了一个中性空间（NS）模型，其中突变积累朝着外围增加；系统发育关系是空间确定的，选择效果变钝（由于亲缘竞争）。在这个模型中，中性突变以不同于有利突变的方式积累和空间分布。重要的是，在传统模型中，这些区别可能会变得模糊。为了验证 NS 模型，我们对两个肝细胞癌进行了三维多次微采样。全基因组测序（WGS）显示，从中心到外围，突变增加了两倍。然后可以通过检查空间确定的克隆关系和克隆大小来测试自然选择的作用。由于迁移受限，只有高度有利的克隆的扩张才能席卷肿瘤的大部分，从而揭示出选择优势。因此，即使是多区域采样也只能揭示实体瘤中部分适应性差异。我们的结果表明，NS 模式对于测试肿瘤发生过程中自然选择的影响至关重要，特别是对于小的实体瘤。
