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Hum Mutat. 2015 Jul;36(7):684-8. doi: 10.1002/humu.22799. Epub 2015 May 18.

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

Author information

1
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
2
Cancer Genomics Research Laboratory, Leidos Biomedical Research Inc, Gaithersburg, Maryland.
3
Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
4
Department of Medicine Bioinformatics Core, Icahn School of Medicine at Mount Sinai, New York, New York.
5
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
6
Department of Epidemiology, Division of Biology and Medicine, Brown University, Providence, Rhode Island.
7
School of Public Health, Imperial College London, London, UK.
8
Division of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
9
Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
10
National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Cincinnati, Ohio.
11
Epidemiology Research Program, American Cancer Society, Atlanta, Georgia.
12
Massachusetts Veteran's Epidemiology, Research and Information Center, Geriatric Research Education and Clinical Center, VA Boston Healthcare System, Boston, Massachusetts.
13
Cancer Epidemiology Centre, Cancer Council of Victoria, Melbourne, Australia.
14
Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, University of Melbourne, Melbourne, Australia.
15
Department of Public Health and Clinical Medicine/Nutritional Research, Umeå University, Umeå, Sweden.
16
Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
17
Cancer Research Center, University of Hawaii, Honolulu, Hawaii.
18
Fred Hutchinson Cancer Research Center, Seattle, Washington.
19
Department of Epidemiology, University of Washington, Seattle, Washington.
20
Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
21
Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Massachusetts.
22
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
23
Division of Cancer Etiology, Department of Population Sciences, City of Hope and the Beckman Research Institute, Duarte, California.
24
Division of Epidemiology, Department of Environmental Medicine, NYU School of Medicine, New York, New York.

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.

KEYWORDS:

TCGA; TP53; glioma; rare SNP

PMID:
25907361
PMCID:
PMC4750473
DOI:
10.1002/humu.22799
[Indexed for MEDLINE]
Free PMC Article

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