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Further Confirmation of Germline Glioma Risk Variant rs78378222 in TP53 and Its Implication in Tumor Tissues via Integrative Analysis of TCGA Data
Author(s) -
Wang Zhaoming,
Rajaraman Preetha,
Melin Beatrice S.,
Chung Charles C.,
Zhang Weijia,
McKeanCowdin Roberta,
Michaud Dominique,
Yeager Meredith,
Ahlbom Anders,
Albanes Demetrius,
Andersson Ulrika,
Freeman Laura E. Beane,
Buring Julie E.,
Butler Mary Ann,
Carreón Tania,
Feychting Maria,
Gapstur Susan M.,
Gaziano J. Michael,
Giles Graham G.,
Hallmans Goran,
Henriksson Roger,
HoffmanBolton Judith,
Inskip Peter D.,
Kitahara Cari M.,
Marchand Loic Le,
Linet Martha S.,
Li Shengchao,
Peters Ulrike,
Purdue Mark P.,
Rothman Nathaniel,
Ruder Avima M.,
Sesso Howard D.,
Severi Gianluca,
Stampfer Meir,
Stevens Victoria L.,
Visvanathan Kala,
Wang Sophia S.,
White Emily,
ZeleniuchJacquotte Anne,
Hoover Robert,
Fraumeni Joseph F.,
Chatterjee Nilanjan,
Hartge Patricia,
Chanock Stephen J.
Publication year - 2015
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22799
Subject(s) - biology , germline , glioma , genetics , cancer research , computational biology , medicine , gene
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.