Ancient genes establish stress-induced mutation as a hallmark of cancer.
Ancient genes establish stress-induced mutation as a hallmark of cancer.
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DOI：
10.1371/journal.pone.0176258
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Davies P
中科院分区：
文献类型：
--
作者：
Cisneros L;Bussey KJ;Orr AJ;Miočević M;Lineweaver CH;Davies P
癌症有时被描述为适应于生活在多细胞组装中的细胞中的单细胞行为的逆转。如果是这样的话，人们会认为癌症中的突变破坏了抑制细胞水平特征的功能机制，这些特征对多细胞性有害。这种机制应该是随着多细胞生物的出现而进化的，或者是在多细胞生物出现之后进化的。这就引出了两个相关但又截然不同的假设：1）癌症的体细胞突变会发生在比多细胞性出现更年轻的基因上（10亿年[MY]）;和2）在癌症中频繁突变并且其突变对于在过去10亿年中进化的癌症表型的出现在功能上重要的基因，因此会呈现出偏向年轻基因的年龄分布。为了研究这些假设，我们估计了所有人类基因的进化年龄，然后研究了正常生殖系和癌症背景下突变的概率及其与年龄和基因组位置相关的生物学功能。我们观察到，在基因组均匀随机突变的模型下，控制基因大小，小于500 MY的基因在两种情况下都更频繁地突变。巧合的是，COSMIC癌症基因普查中定义的致病基因在这个年龄组中被耗尽。当我们使用功能富集分析来解释这个意想不到的结果时，我们发现具有隐性疾病表型的COSMIC基因富集用于DNA修复和细胞周期控制。这些途径中的非突变基因与细菌中胁迫诱导突变的潜在基因是正交的，这导致单核苷酸变异的聚集。COSMIC基因在观察突变簇的概率高的区域中不太常见，尽管与其他人类基因相比，它们携带突变簇的可能性大约高2倍。我们的研究结果表明，这种在原核生物中进化的古老的应激突变反应被用来维持种系和免疫系统的多样性，而原始的表型在癌症中被恢复。回复到应激诱导的突变反应是癌症的标志，其允许有效地搜索“受保护的”基因组空间，在该基因组空间中定位与癌症有因果关系的基因，并且是癌症特征的高适应性潜力和伴随的治疗抗性的基础。
Cancer is sometimes depicted as a reversion to single cell behavior in cells adapted to live in a multicellular assembly. If this is the case, one would expect that mutation in cancer disrupts functional mechanisms that suppress cell-level traits detrimental to multicellularity. Such mechanisms should have evolved with or after the emergence of multicellularity. This leads to two related, but distinct hypotheses: 1) Somatic mutations in cancer will occur in genes that are younger than the emergence of multicellularity (1000 million years [MY]); and 2) genes that are frequently mutated in cancer and whose mutations are functionally important for the emergence of the cancer phenotype evolved within the past 1000 million years, and thus would exhibit an age distribution that is skewed to younger genes. In order to investigate these hypotheses we estimated the evolutionary ages of all human genes and then studied the probability of mutation and their biological function in relation to their age and genomic location for both normal germline and cancer contexts. We observed that under a model of uniform random mutation across the genome, controlled for gene size, genes less than 500 MY were more frequently mutated in both cases. Paradoxically, causal genes, defined in the COSMIC Cancer Gene Census, were depleted in this age group. When we used functional enrichment analysis to explain this unexpected result we discovered that COSMIC genes with recessive disease phenotypes were enriched for DNA repair and cell cycle control. The non-mutated genes in these pathways are orthologous to those underlying stress-induced mutation in bacteria, which results in the clustering of single nucleotide variations. COSMIC genes were less common in regions where the probability of observing mutational clusters is high, although they are approximately 2-fold more likely to harbor mutational clusters compared to other human genes. Our results suggest this ancient mutational response to stress that evolved among prokaryotes was co-opted to maintain diversity in the germline and immune system, while the original phenotype is restored in cancer. Reversion to a stress-induced mutational response is a hallmark of cancer that allows for effectively searching “protected” genome space where genes causally implicated in cancer are located and underlies the high adaptive potential and concomitant therapeutic resistance that is characteristic of cancer.