Impact of SNPs on CpG Islands in the MYC and HRAS oncogenes and in a wide variety of tumor suppressor genes: A multi-cancer approach

Abstract

Single nucleotide polymorphisms (SNPs) that occur within CpG Islands may lead to increased hypermethylation if a SNP allele has the potential to form a CpG dinucleotide, as well as potentially lead to hypomethylation if a SNP allele eliminates a CpG dinucleotide. We analyzed CpG-related SNP allele frequencies in whole genome sequences (WGS) across 5 TCGA cancer datasets, thereby exploiting a more recent appreciation for signaling pathway degeneracy in cancer. The cancer data sets were analyzed for SNPs in CpG islands associated with the oncogenes, HRAS and MYC, and in the CpG islands associated with the tumor suppressor genes, APC, DCC, and RB1. We determined that one SNP allele (rs3824120) in a CpG island associated with MYC which eliminated a CpG was more common in the cancer datasets than in the 100Genomes databases (p < 0.01). For HRAS, 2 SNP alleles (rs112690925, rs7939028) that created CpG's occurred significantly less frequently in the cancer data sets than in the general SNP databases (e.g., rs7939028, p < 0.0002, in comparison with AllSNPs (142)). Also, one SNP allele (rs4940177) that created a CpG in a CpG island associated with the DCC tumor suppressor gene, was more common in the cancer datasets (p < 0.0007). To understand a broader picture of the potential of SNP alleles to create CpG's in CpG islands of tumor suppressor genes, we developed a scripted algorithm to assess the SNP alleles associated with the CpG islands of 43 tumor suppressor genes. The following tumor suppressor genes have the possibility of significant, percent increases in their CpG counts, depending on which SNP allele(s) is present: VHL, BRCA1, BRCA2, CHEK2, PTEN and RB1.

Global DNA methylation in placental tissues from pregnant with preeclampsia: A systematic review and pathway analysis

“…However, SNPs that occur within CpG dinucleotide (CpG-SNPs) may lead to alteration of methylation in a region and thereby affect gene expression [46]. The correlation of CpG-SNPs with complex diseases is well-described [47], including type 2 diabetes [48] and cancer [49]. However, the association between CpG-SNPs and PE has not been examined.…”

LncRBase V.2: an updated resource for multispecies lncRNAs and ClinicLSNP hosting genetic variants in lncRNAs for cancer patients

“…CpG-SNP rs7766585 has been found to have a strong association with breast cancer risk [63]. The impact of SNPs within the CpG Islands in oncogenes and tumor suppressor genes has also been documented [64]. Our analysis revealed chr15:100554315-100559288, chr21:8431968-8441142 and chr14:19300376-19302642, within lncRNA loci to be SNP enriched CGI regions.…”

Familial analysis reveals rare risk variants for migraine in regulatory regions

“…Variations within CpG islands have been shown to influence DNA methylation patterns. Depending on the increase or elimination of CpG dinucleotides, the mutations may lead to hyper-or hypomethylation and, therefore, an altered transcriptional activity [38]. If CpG islands are hypermethylated, they may cause a stable silencing of the gene.…”