Dept. Biological Physics, Eötvös University, Pázmány P. stny. 1A., H-1117, Budapest, Hungary.
ELTE-MTA "Lendület" Evolutionary Genomics Research Group, Pázmány P. stny. 1A., H-1117, Budapest, Hungary.
Nat Commun. 2022 Mar 29;13(1):1666. doi: 10.1038/s41467-022-29004-1.
Species-specific differences control cancer risk across orders of magnitude variation in body size and lifespan, e.g., by varying the copy numbers of tumor suppressor genes. It is unclear, however, how different tissues within an organism can control somatic evolution despite being subject to markedly different constraints, but sharing the same genome. Hierarchical differentiation, characteristic of self-renewing tissues, can restrain somatic evolution both by limiting divisional load, thereby reducing mutation accumulation, and by increasing cells' commitment to differentiation, which can "wash out" mutants. Here, we explore the organization of hierarchical tissues that have evolved to limit their lifetime incidence of cancer. Estimating the likelihood of cancer in the presence of mutations that enhance self-proliferation, we demonstrate that a trade-off exists between mutation accumulation and the strength of washing out. Our results explain differences in the organization of widely different hierarchical tissues, such as colon and blood.
物种特异性差异控制着体型和寿命跨度极大的癌症风险，例如通过改变肿瘤抑制基因的拷贝数。然而，不同组织尽管受到明显不同的限制，但共享相同的基因组，那么它们如何控制体细胞进化尚不清楚。自我更新组织的特征是分层分化，可以通过限制分裂负荷来限制体细胞进化，从而减少突变积累，并且通过增加细胞向分化的分化来“淘汰”突变体。在这里，我们探索了进化以限制其终生癌症发生率的分层组织的组织。在存在增强自我增殖的突变的情况下估计癌症的可能性，我们证明突变积累和“淘汰”突变体的强度之间存在权衡。我们的结果解释了广泛不同的分层组织之间的组织差异，例如结肠和血液。
