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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 i n 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.

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