Further Confirmation of Germline Glioma Risk Variant rs78378222 in TP53 and Its Implication in Tumor Tissues via Integrative Analysis of TCGA Data.
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.
['Wang|Zhaoming|Z|', 'Rajaraman|Preetha|P|', 'Melin|Beatrice S|BS|', 'Chung|Charles C|CC|', 'Zhang|Weijia|W|', 'McKean-Cowdin|Roberta|R|', 'Michaud|Dominique|D|', 'Yeager|Meredith|M|', 'Ahlbom|Anders|A|', 'Albanes|Demetrius|D|', 'Andersson|Ulrika|U|', 'Freeman|Laura E Beane|LE|', 'Buring|Julie E|JE|', 'Butler|Mary Ann|MA|', 'Carreón|Tania|T|', 'Feychting|Maria|M|', 'Gapstur|Susan M|SM|', 'Gaziano|J Michael|JM|', 'Giles|Graham G|GG|', 'Hallmans|Goran|G|', 'Henriksson|Roger|R|', 'Hoffman-Bolton|Judith|J|', 'Inskip|Peter D|PD|', 'Kitahara|Cari M|CM|', 'Marchand|Loic Le|LL|', 'Linet|Martha S|MS|', 'Li|Shengchao|S|', 'Peters|Ulrike|U|', 'Purdue|Mark P|MP|', 'Rothman|Nathaniel|N|', 'Ruder|Avima M|AM|', 'Sesso|Howard D|HD|', 'Severi|Gianluca|G|', 'Stampfer|Meir|M|', 'Stevens|Victoria L|VL|', 'Visvanathan|Kala|K|', 'Wang|Sophia S|SS|', 'White|Emily|E|', 'Zeleniuch-Jacquotte|Anne|A|', 'Hoover|Robert|R|', 'Fraumeni|Joseph F|JF|', 'Chatterjee|Nilanjan|N|', 'Hartge|Patricia|P|', 'Chanock|Stephen J|SJ|']
D000230:Adenocarcinoma D000077192:Adenocarcinoma of Lung D000328:Adult D016543:Central Nervous System Neoplasms D019295:Computational Biology D030561:Databases, Nucleic Acid D055106:Genome-Wide Association Study D005909:Glioblastoma D005910:Glioma D006801:Humans D008175:Lung Neoplasms D008875:Middle Aged D020641:Polymorphism, Single Nucleotide D012306:Risk D016159:Tumor Suppressor Protein p53
glioma TP53 TCGA rare SNP