Table_4_Natural Selection on Exonic SNPs Shapes Allelic Expression Imbalance (AEI) Adaptability in Lung Cancer Progression.XLS

Tumors are driven by a sequence of genetic and epigenetic alterations. Previous studies have mostly focused on the roles of somatic mutations in tumorigenesis, but how germline variants act is largely unknown. In this study, we hypothesized that allelic expression imbalance (AEI) participated in the process of germline variants on tumorigenesis. We screened single-nucleotide polymorphisms (SNPs) as representative germline variants. By using 127 patients’ RNA sequencing data from paired lung cancer and adjacent normal tissues from public databases, we analyzed the effects of the functional consequence of SNPs, function and conservativeness on genes with AEI. We found that natural selection can affect AEI. Functional adaptability of genes with a high frequency of AEI and a correlation of the incidence of AEI with conservativeness were observed in both adjacent tissues and tumor tissues. Moreover, we observed a higher incidence of AEI in genes with non-synonymous SNPs than in those with synonymous SNPs. However, we also found that AEI was affected by allele expression noise, especially in tumor tissues, which led to an increased proportion of AEI, weakened the effect of natural selection and eliminated the influence of the functional consequence of SNPs on AEI. We unveiled a previously unknown adaptive regulatory mechanism in which the effect of natural selection on SNPs can be reflected in allelic expression, which provides insight into a better understanding of cancer evolution.

肿瘤的发生由一系列遗传与表观遗传改变驱动。既往研究多聚焦于体细胞突变在肿瘤发生过程中的作用，而生殖系变异的具体作用机制仍未得到充分阐释。本研究提出假说：等位基因表达失衡（allelic expression imbalance, AEI）参与了生殖系变异介导的肿瘤发生过程。本研究以单核苷酸多态性（single-nucleotide polymorphisms, SNPs）作为代表性生殖系变异进行筛选。本研究借助公共数据库收录的127例肺癌患者的配对癌组织与癌旁正常组织RNA测序数据，分析了单核苷酸多态性的功能效应、基因功能与保守性对携带等位基因表达失衡的基因的影响。研究发现自然选择能够影响等位基因表达失衡。在癌旁组织与肿瘤组织中，均观察到高频率等位基因表达失衡基因的功能适应性，以及等位基因表达失衡发生率与基因保守性之间的相关性。此外，本研究发现携带非同义单核苷酸多态性的基因的等位基因表达失衡发生率显著高于携带同义单核苷酸多态性的基因。但本研究同时发现，等位基因表达噪声可对等位基因表达失衡产生影响，尤其在肿瘤组织中：这一效应会提升等位基因表达失衡的比例、削弱自然选择的调控作用，并消除单核苷酸多态性功能效应对等位基因表达失衡的影响。本研究揭示了一种此前未被报道的适应性调控机制——自然选择对单核苷酸多态性的作用可通过等位基因表达得以体现，这为深入理解癌症演化过程提供了新的研究视角。