title: 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.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.|Cancer Genomics Research Laboratory, Leidos Biomedical Research Inc, Gaithersburg, Maryland.
authors.forename: Zhaoming
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
authors.forename: Preetha
authors.initials: P
authors.lastname: Rajaraman
authors.affiliation: Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
authors.forename: Beatrice S
authors.initials: BS
authors.lastname: Melin
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.|Cancer Genomics Research Laboratory, Leidos Biomedical Research Inc, Gaithersburg, Maryland.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Chung
authors.affiliation: Department of Medicine Bioinformatics Core, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Roberta
authors.initials: R
authors.lastname: McKean-Cowdin
authors.affiliation: Department of Epidemiology, Division of Biology and Medicine, Brown University, Providence, Rhode Island.|School of Public Health, Imperial College London, London, UK.
authors.forename: Dominique
authors.initials: D
authors.lastname: Michaud
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.|Cancer Genomics Research Laboratory, Leidos Biomedical Research Inc, Gaithersburg, Maryland.
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.affiliation: Division of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Ahlbom
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
authors.affiliation: Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Andersson
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
authors.forename: Laura E Beane
authors.initials: LE
authors.lastname: Freeman
authors.affiliation: Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Buring
authors.affiliation: National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Cincinnati, Ohio.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Butler
authors.affiliation: National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Cincinnati, Ohio.
authors.forename: Tania
authors.initials: T
authors.lastname: Carreón
authors.affiliation: Division of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Feychting
authors.affiliation: Epidemiology Research Program, American Cancer Society, Atlanta, Georgia.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Gapstur
authors.affiliation: Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.|Massachusetts Veteran's Epidemiology, Research and Information Center, Geriatric Research Education and Clinical Center, VA Boston Healthcare System, Boston, Massachusetts.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Gaziano
authors.affiliation: Cancer Epidemiology Centre, Cancer Council of Victoria, Melbourne, Australia.|Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, University of Melbourne, Melbourne, Australia.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.affiliation: Department of Public Health and Clinical Medicine/Nutritional Research, Umeå University, Umeå, Sweden.
authors.forename: Goran
authors.initials: G
authors.lastname: Hallmans
authors.affiliation: Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
authors.forename: Roger
authors.initials: R
authors.lastname: Henriksson
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Judith
authors.initials: J
authors.lastname: Hoffman-Bolton
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Inskip
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
authors.forename: Cari M
authors.initials: CM
authors.lastname: Kitahara
authors.affiliation: Cancer Research Center, University of Hawaii, Honolulu, Hawaii.
authors.forename: Loic Le
authors.initials: LL
authors.lastname: Marchand
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
authors.forename: Martha S
authors.initials: MS
authors.lastname: Linet
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.|Cancer Genomics Research Laboratory, Leidos Biomedical Research Inc, Gaithersburg, Maryland.
authors.forename: Shengchao
authors.initials: S
authors.lastname: Li
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.|Department of Epidemiology, University of Washington, Seattle, Washington.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Peters
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Purdue
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.affiliation: National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Cincinnati, Ohio.
authors.forename: Avima M
authors.initials: AM
authors.lastname: Ruder
authors.affiliation: Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Howard D
authors.initials: HD
authors.lastname: Sesso
authors.affiliation: Cancer Epidemiology Centre, Cancer Council of Victoria, Melbourne, Australia.|Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, University of Melbourne, Melbourne, Australia.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Severi
authors.affiliation: Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.|Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Meir
authors.initials: M
authors.lastname: Stampfer
authors.affiliation: Epidemiology Research Program, American Cancer Society, Atlanta, Georgia.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Stevens
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.|Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Kala
authors.initials: K
authors.lastname: Visvanathan
authors.affiliation: Division of Cancer Etiology, Department of Population Sciences, City of Hope and the Beckman Research Institute, Duarte, California.
authors.forename: Sophia S
authors.initials: SS
authors.lastname: Wang
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.|Department of Epidemiology, University of Washington, Seattle, Washington.
authors.forename: Emily
authors.initials: E
authors.lastname: White
authors.affiliation: Division of Epidemiology, Department of Environmental Medicine, NYU School of Medicine, New York, New York.
authors.forename: Anne
authors.initials: A
authors.lastname: Zeleniuch-Jacquotte
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
authors.forename: Robert
authors.initials: R
authors.lastname: Hoover
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Fraumeni
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Chatterjee
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
authors.forename: Patricia
authors.initials: P
authors.lastname: Hartge
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000077192:Adenocarcinoma of Lung; D000328:Adult; D016543:Central Nervous System Neoplasms / Q000235:genetics*; D019295:Computational Biology; D030561:Databases, Nucleic Acid; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data; D005909:Glioblastoma / Q000235:genetics; D005910:Glioma / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53
keywords: TCGA; TP53; glioma; rare SNP