Department of Cancer Biology and Evolution, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
Department of Bioinformatics, Moffitt Cancer Center, Tampa, USA.
Med Oncol. 2024 May 5;41(6):135. doi: 10.1007/s12032-024-02344-2.
Somatic evolution selects cancer cell phenotypes that maximize survival and proliferation in dynamic environments. Although cancer cells are molecularly heterogeneous, we hypothesized convergent adaptive strategies to common host selection forces can be inferred from patterns of epigenetic and genetic evolutionary selection in similar tumors. We systematically investigated gene mutations and expression changes in lung adenocarcinomas with no common driver genes (n = 313). Although 13,461 genes were mutated in at least one sample, only 376 non-synonymous mutations evidenced positive evolutionary selection with conservation of 224 genes, while 1736 and 2430 genes exhibited ≥ two-fold increased and ≥ 50% decreased expression, respectively. Mutations under positive selection are more frequent in genes with significantly altered expression suggesting they often "hardwire" pre-existing epigenetically driven adaptations. Conserved genes averaged 16-fold higher expression in normal lung tissue compared to those with selected mutations demonstrating pathways necessary for both normal cell function and optimal cancer cell fitness. The convergent LUAD phenotype exhibits loss of differentiated functions and cell-cell interactions governing tissue organization. Conservation with increased expression is found in genes associated with cell cycle, DNA repair, p53 pathway, epigenetic modifiers, and glucose metabolism. No canonical driver gene pathways exhibit strong positive selection, but extensive down-regulation of membrane ion channels suggests decreased transmembrane potential may generate persistent proliferative signals. NCD LUADs perform niche construction generating a stiff, immunosuppressive microenvironment through selection of specific collagens and proteases. NCD LUADs evolve to a convergent phenotype through a network of interconnected genetic, epigenetic, and ecological pathways.
体细胞进化选择了最大限度地提高在动态环境中生存和增殖能力的癌细胞表型。尽管癌细胞在分子上是异质的，但我们假设，从类似肿瘤中观察到的表观遗传和遗传进化选择模式中，可以推断出针对常见宿主选择压力的趋同适应策略。我们系统地研究了无共同驱动基因的肺腺癌（n = 313）中的基因突变和表达变化。尽管至少有一个样本中存在 13461 个基因突变，但只有 376 个非同义突变具有正向进化选择的证据，其中 224 个基因得到了保守，而 1736 个和 2430 个基因分别表现出两倍以上的增加和 50%以上的减少表达。正向选择下的突变在表达发生显著改变的基因中更为常见，这表明它们经常“硬连线”预先存在的表观遗传驱动适应性。与具有选择突变的基因相比，保守基因在正常肺组织中的表达平均高出 16 倍，这表明它们是正常细胞功能和最佳癌细胞适应性所必需的途径。趋同的 LUAD 表型表现出分化功能丧失和控制组织组织的细胞-细胞相互作用。在与细胞周期、DNA 修复、p53 途径、表观遗传修饰剂和葡萄糖代谢相关的基因中发现了保守且表达增加的现象。没有经典的驱动基因途径表现出强烈的正向选择，但膜离子通道的广泛下调表明，跨膜电位的降低可能产生持续的增殖信号。NCD LUAD 通过选择特定的胶原蛋白和蛋白酶，通过一系列相互关联的遗传、表观遗传和生态途径，来构建生态位，从而产生坚硬、免疫抑制的微环境。NCD LUAD 通过相互关联的遗传、表观遗传和生态途径，进化为趋同表型。
