Further Confirmation of Germline Glioma Risk Variant rs78378222 in TP53 and Its Implication in Tumor Tissues via Integrative Analysis of TCGA Data

Abstract

We confirmed strong association of rs78378222:A>C (per allele odds ratio [OR] = 3.14; P = 6.48 × 10(-11) ), a germline rare single-nucleotide polymorphism (SNP) in TP53, via imputation of a genome-wide association study of glioma (1,856 cases and 4,955 controls). We subsequently performed integrative analyses on the Cancer Genome Atlas (TCGA) data for GBM (glioblastoma multiforme) and LUAD (lung adenocarcinoma). Based on SNP data, we imputed genotypes for rs78378222 and selected individuals carrying rare risk allele (C). Using RNA sequencing data, we observed aberrant transcripts with ∼3 kb longer than normal for those individuals. Using exome sequencing data, we further showed that loss of haplotype carrying common protective allele (A) occurred somatically in GBM but not in LUAD. Our bioinformatic analysis suggests rare risk allele (C) disrupts mRNA termination, and an allelic loss of a genomic region harboring common protective allele (A) occurs during tumor initiation or progression for glioma.

Keywords: TCGA; TP53; glioma; rare SNP.

Figure 1

17p13.1 regional plot. Results of trend test for association for genotyped (blue diamond) and imputed (gray diamond) SNPs were plotted on a negative log scale (left y-axis) against genomic coordinates (x-axis, 17p13.1:7487108–7685748, hg19). Blue line graph depicts recombination hotspots inferred from the 1000 Genomes Project phase 1 European data (100 random sampled) in likelihood ratio statistics (right y-axis). Lower panel depicts linkage disequilibrium heat map based on r² using the 1000 Genomes Project phase 1 European data (n = 379).