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

ABSTRACT: 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<0.01). Three cTOHs were over-represented in cases over controls (OR?=?1.75-2.06, p?=?0.007-0.001), whereas 4 were under-represented (OR?=?0.28-0.69, p?=?0.006-0.001). Interaction between smoking status and cTOH3/aTOH2 (2p16.3-2p16.1) was observed (adjusted p<0.03). The remaining significant aTOHs have ORs 0.23-0.50 (p?=?0.004-0.006) and 2.95-3.97 (p?=?0.008-0.001). After integrating significant cTOH/aTOHs with publicly-available lung-cancer transcriptome datasets followed by filtering based on lung cancer and its relevant pathways revealed 9 putative predisposing genes (p<0.0001). In conclusion, differentially-distributed cTOH/aTOH genomic variants between cases and controls harbor sets of plausible differentially-expressed genes accounting for the complexity of lung-cancer predisposition.

SUBMITTER: Orloff MS

PROVIDER: S-EPMC3288062 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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

Orloff Mohammed S MS Zhang Li L Bebek Gurkan G Eng Charis C

PloS one 20120227 2

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 ...[more]

PMID: 22384118

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Project description:BackgroundThe incidence and mortality of lung cancer are the highest among all cancers. Patients with systemic sclerosis show a four-fold greater risk of lung cancer than the general population. However, the underlying mechanism remains poorly understood.MethodsThe expression profiles of 355 peripheral blood samples were integratedly analyzed, including 70 cases of lung cancer, 61 cases of systemic sclerosis, and 224 healthy controls. After data normalization and cleaning, differentially expressed genes (DEGs) between disease and control were obtained and deeply analyzed by bioinformatics methods. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed online by DAVID and KOBAS. The protein-protein interaction (PPI) networks were constructed from the STRING database.ResultsFrom a total of 14,191 human genes, 299 and 1644 genes were identified as DEGs in systemic sclerosis and lung cancer, respectively. Among them, 64 DEGs were overlapping, including 36 co-upregulated, 10 co-downregulated, and 18 counter-regulated DEGs. Functional and enrichment analysis showed that the two diseases had common changes in immune-related genes. The expression of innate immune response and response to virus-related genes increased significantly, while the expression of negative regulation of cell cycle-related genes decreased notably. In contrast, the expression of mitophagy regulation, chromatin binding and fatty acid metabolism-related genes showed distinct trends.ConclusionsStable differences and similarities between systemic sclerosis and lung cancer were revealed. In peripheral blood, enhanced innate immunity and weakened negative regulation of cell cycle may be the common mechanisms of the two diseases, which may be associated with the high risk of lung cancer in systemic sclerosis patients. On the other hand, the counter-regulated DEGs can be used as novelbiomarkers of pulmonary diseases. In addition, fat metabolism-related DEGs were consideredto be associated with clinical blood lipid data.

Dataset Information

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

Publications

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

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