NDLI: Integrative Genomic Analysis Reveals Extended Germline Homozygosity with Lung Cancer Risk in the PLCO Cohort

Content Provider	PubMed Central
Author	Orloff, Md. S. Zhang, Li Bebek, Gurkan Eng, Charis
Editor	Toland, Amanda Ewart
Copyright Year	2012
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.
Related Links	http://dx.doi.org/10.1371/journal.pone.0031975
Starting Page	31975
File Format	PDF
ISSN	19326203
e-ISSN	19326203
Journal	PLoS ONE
Issue Number	2
Volume Number	7
Language	English
Publisher	Public Library of Science
Publisher Date	2012-02-01
Access Restriction	Open
Rights Holder	Public Library of Science
Subject Keyword	Biochemistry, Genetics and Molecular Biology(all) Agricultural and Biological Sciences(all) Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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