Abstract
The functional relevancy of mutations occurring in the regulatory regions in cancers remains mostly elusive. Here, we identified and analyzed regulatory mutations having transcriptional consequences in lung adenocarcinoma-derived cell lines. We phased the mutations in the regulatory regions to the downstream heterozygous SNPs in the coding regions and examined whether the ChIP-Seq variant tags of the regulatory SNVs and the RNA-Seq variant tags of their target transcripts showed biased frequency between the mutant and reference alleles. We identified 137 potential regulatory mutations affecting the transcriptional regulation of 146 RefSeq transcripts with at least 84 SNVs that create and/or disrupt potential transcription factor binding sites. For example, in the regulatory region of NFATC1 gene, a novel and active binding site for the ETS transcription factor family was created. Further examination revealed that 31 of these disruptions were presented in clinical lung adenocarcinoma samples and were associated with prognosis of patients.
Highlights
In this study, using a series of lung adenocarcinoma cell lines, we identified a total of 137 SNVs or indels that are likely to have transcriptional consequences in the potential regulatory regions of 146 RefSeq transcripts
We identified several regulatory aberrations that may occur in clinical samples using TCGA datasets and a number of these aberrations associated with prognosis of patients
We found that the GemCode Long Ranger software is not optimized for phasing non-diploid genomes as described in their original publication[12]
Summary
10x GemCode synthetic long read sequencing enables phasing of lung adenocarcinoma cell lines. A427 cell line had an SNV in the promoter region (chr17:5191978 C > G) of the ZNF594 gene and the mutant allele was transcriptionally silent (Supplementary Fig. S9). This regulatory SNV overlapped with several TF ChIP-Seq peaks including POLR2A, TAF1 and MYC, according to the ENCODE dataset. The mutant allele was transcriptionally silenced; this newly acquired TF binding might work as a transcriptional repressor In another example, in RERF-LC-Ad1 cell line, a regulatory SNV (chr18:79395018 C > G) was found in the region of NFATC1 gene. Overall survival and disease-free survival were shown in the left and right panels, respectively
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