Genetic variants cis-regulating Xrn2 expression contribute to the risk of spontaneous lung tumor

Gene expression variation is an important mechanism underlying susceptibility to complex disease. In comparison with tobacco-related lung carcinogenesis, lung cancer in nonsmokers may involve important and etiologically distinct causal pathways. In this study, we conducted a genome-wide association study on spontaneous lung tumor incidence in inbred mice and identified a major susceptibility locus on mouse chromosome 2 (rs27328255, P=6.68 × 10−7). We then evaluated the correlations of polymorphisms with the transcription of positional candidate genes in normal lungs. Single-nucleotide polymorphism rs27328255 was consistently and strongly associated (P=7.42 × 10−9) in cis with transcript levels of Xrn2. We further showed that Xrn2 promotes proliferation and inhibits squamous differentiation in human lung epithelial cells and polymorphisms in human homolog XRN2 are associated with human lung cancer (rs2025811, P=1.90 × 10−3, OR=1.20). We conclude that genetic variants regulating Xrn2 expression in cis are determinants of spontaneous lung tumor susceptibility in mice and have genetic equivalents in lung cancer susceptibility in human beings. Identifying Xrn2 as a major candidate for spontaneous lung cancer has important implications for the diagnosis and treatment of lung cancer as well as delineation of the mechanisms underlying the genesis of lung cancer in nonsmokers.