Abstract
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.
Highlights
Tumorigenesis is a process in which normal cells transform into cancer cells, manifesting as a cellular accumulation of changes at the genetic and epigenetic levels and eventually leading to uncontrolled proliferation
To reduce the false rate caused by systematic mismatches of next-generation sequencing and to reduce the effect of somatic mutation and RNA editing, we downloaded the annotation file from the ftp servers of dbSNP (Sherry et al, 2001) and retained the single-nucleotide polymorphisms (SNPs) from our analysis that overlapped with the dbSNP
The results from the gene function cluster analysis displayed the differences in the functional adaptation of allelic expression imbalance (AEI) in tumor tissues and adjacent tissues, with immune-related genes being enriched in the adjacent tissues and DNA-repair-related and stress response genes being enriched in the tumor tissues
Summary
Tumorigenesis is a process in which normal cells transform into cancer cells, manifesting as a cellular accumulation of changes at the genetic and epigenetic levels and eventually leading to uncontrolled proliferation. This process is similar to evolution, which acts through mutation accumulation and selection (Nowell, 1976). AEI refers to the phenomenon that the two alleles of genes exhibit unbalanced expression (Reinius and Sandberg, 2015). Previous studies have shown that expression quantitative trait loci (eQTLs) (Pickrell et al, 2010) and epigenetics (Shoemaker et al, 2010) can cause AEI. We hypothesized that in the absence of new mutations as “the second hit,” allele dosage changes can directly reflect the effects of heterozygous SNPs
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