有害乘客突变对癌症进展的影响
The impact of deleterious passenger mutations on cancer progression
摘要：
癌症进展是由肿瘤中积累的少量遗传改变驱动的。这几个驱动改变存在于癌症基因组中，与成千上万的其他突变一起存在，这些突变被广泛认为在癌症中没有作用，并被称为乘客。然而，许多乘客属于蛋白质编码基因和其他功能元件，可能对癌细胞产生有害影响。在这里，我们调查了潜在的轻度有害乘客积累和改变过程中的肿瘤进展。我们的方法将癌症进展的进化模拟与癌症测序数据的分析相结合。在我们的模拟中，单个细胞随机分裂，获得有利的驱动突变和有害的乘客突变，或者死亡。令人惊讶的是，尽管选择对他们不利，乘客积累，并在很大程度上逃避选择过程中的进展。虽然个别弱，乘客的集体负担改变了进展的过程，导致肿瘤学中观察到的几种现象，不能用传统的以司机为中心的观点来解释。我们使用癌症基因组数据测试了模型的预测。我们发现，许多乘客突变可能是有害的，并且与模型一致，它们在很大程度上逃避了净化选择。最后，我们使用我们的模型来探索癌症治疗，通过1）增加突变率或2）加剧其有害影响来利用乘客的负载。虽然这两种方法都导致癌症消退，但后者导致复发频率较低。我们的研究结果为理解癌症进展提供了一个新的框架，即驾驶员和乘客突变的平衡。
英文摘要：
Cancer progression is driven by a small number of genetic alterations accumulating in a neoplasm. These few driver alterations reside in a cancer genome alongside tens of thousands of other mutations that are widely believed to have no role in cancer and termed passengers. Many passengers, however, fall within protein coding genes and other functional elements and can possibly have deleterious effects on cancer cells. Here we investigate a potential of mildly deleterious passengers to accumulate and alter the course of neoplastic progression. Our approach combines evolutionary simulations of cancer progression with the analysis of cancer sequencing data. In our simulations, individual cells stochastically divide, acquire advantageous driver and deleterious passenger mutations, or die. Surprisingly, despite selection against them, passengers accumulate and largely evade selection during progression. Although individually weak, the collective burden of passengers alters the course of progression leading to several phenomena observed in oncology that cannot be explained by a traditional driver-centric view. We tested predictions of the model using cancer genomic data. We find that many passenger mutations are likely to be damaging and that, in agreement with the model, they have largely evaded purifying selection. Finally, we used our model to explore cancer treatments that exploit the load of passengers by either 1) increasing the mutation rate; or 2) exacerbating their deleterious effects. While both approaches lead to cancer regression, the later leads to less frequent relapse. Our results suggest a new framework for understanding cancer progression as a balance of driver and passenger mutations.
机构、总结、中文摘要均由AI分析而来，可能存在错误，请以论文正文为准。
