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

Wang Z1,2, Rajaraman P1, Melin BS3, Chung CC1,2, Zhang W4, McKean-Cowdin R5, Michaud D6,7, Yeager M1,2, Ahlbom A8, Albanes D1, Andersson U3,Freeman LE1, Buring JE9, Butler MA10, Carreón T10, Feychting M8, Gapstur SM11, Gaziano JM9,12, Giles GG13,14, Hallmans G15, Henriksson R3, Hoffman-Bolton J16, Inskip PD1, Kitahara CM1, Marchand LL17, Linet MS1, Li S1,2, Peters U18,19, Purdue MP1, Rothman N1, Ruder AM10, Sesso HD9, Severi G13,14,Stampfer M20,21, Stevens VL11, Visvanathan K16,22, Wang SS23, White E18,19, Zeleniuch-Jacquotte A24, Hoover R1, Fraumeni JF1, Chatterjee N1, Hartge P1,Chanock SJ1.

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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.