title: 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.
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: Orloff
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Gurkan
authors.initials: G
authors.lastname: Bebek
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D000367:Age Factors; D000483:Alleles; D016000:Cluster Analysis; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D012306:Risk; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects