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

Zhaoming Wang, Preetha Rajaraman, Beatrice S. Melin, Charles C. Chung, Weijia Zhang, Roberta McKean-Cowdin, Dominique S. Michaud, Meredith Yeager, Anders Ahlbom, Demetrius Albanes, Ulrika Andersson, Laura E.Beane Freeman, Julie E Buring, Mary Ann Butler, Tania Carreón, Maria Feychting, Susan M. Gapstur, J. Michael Gaziano, Graham G. Giles, Goran HallmansRoger Henriksson, Judith Hoffman-Bolton, Peter D. Inskip, Cari M. Kitahara, Loic Le Marchand, Martha S. Linet, Shengchao Li, Ulrike Peters, Mark P. Purdue, Nathaniel Rothman, Avima M. Ruder, Howard D. Sesso, Gianluca Severi, Meir Jonathan Stampfer, Victoria L. Stevens, Kala Visvanathan, Sophia S. Wang, Emily White, Anne Zeleniuch-Jacquotte, Robert N Hoover, Joseph F. Fraumeni, Nilanjan Chatterjee, Patricia Hartge, Stephen J Chanock

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17 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)684-688
Number of pages5
JournalHuman Mutation
Issue number7
Publication statusPublished - Jul 2015
Externally publishedYes


  • Glioma
  • Rare SNP
  • TCGA
  • TP53

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