Integrative genomic analysis reveals extended germline homozygosity with lung cancer risk in the PLCO cohort

Susceptibility to common cancers is multigenic resulting from low-to-high penetrance predisposition-factors and environmental exposure. Genomic studies suggest germline homozygosity as a novel low-penetrance factor contributing to common cancers. We hypothesized that long homozygous regions (tracts-...

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Bibliographic Details
Published in:PloS one 2012-02, Vol.7 (2), p.e31975-e31975
Main Authors: Orloff, Mohammed S, Zhang, Li, Bebek, Gurkan, Eng, Charis
Format: Article
Language:English
Subjects:
Age Factors
Alleles
Apoptosis
Bioinformatics
Biology
Bone marrow
Cancer
Cancer genetics
Cancer prevention
Cancer research
Cluster Analysis
Cohort Studies
Cytokines
Demographics
Demography
Disease susceptibility
Exposure
Female
Filtration
Gene expression
Genes
Genetic aspects
Genetic Predisposition to Disease
Genome-Wide Association Study
Genomes
Genomic analysis
Genomics
Genotype
Health aspects
Health risks
Homozygosity
Homozygote
Humans
Hypotheses
Lung cancer
Lung diseases
Lung Neoplasms - genetics
Lung Neoplasms - pathology
Male
Medical screening
Medicine
Microsatellite Repeats - genetics
Models, Genetic
Polymorphism, Single Nucleotide
Prostate
Regression Analysis
Risk
Risk Factors
Risk management
Single-nucleotide polymorphism
Smoking
Smoking - adverse effects
Studies
Tobacco
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Summary:Susceptibility to common cancers is multigenic resulting from low-to-high penetrance predisposition-factors and environmental exposure. Genomic studies suggest germline homozygosity as a novel low-penetrance factor contributing to common cancers. We hypothesized that long homozygous regions (tracts-of-homozygosity [TOH]) harbor tobacco-dependent and independent lung-cancer predisposition (or protection) genes. We performed in silico genome-wide SNP-array-based analysis of lung-cancer patients of European-ancestry from the PLCO screening-trial cohort to identify TOH regions amongst 788 cancer-cases and 830 ancestry-matched controls. Association analyses was then performed between presence of lung cancer and common(c)TOHs (operationally defined as 10 or more subjects sharing ≥100 identical homozygous calls), aTOHs (allelically-matched groups within a cTOH), demographics and tobacco-exposure. Finally, integration of significant c/aTOH with transcriptome was performed to functionally-map lung-cancer risk-genes. After controlling for demographics and smoking, we identified 7 cTOHs and 5 aTOHs associated with lung cancer (adjusted p
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0031975