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

Oncogene volume 29, pages 1041–1049 (2010)Cite this article

Abstract

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.

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Acknowledgements

We thank the Broad Institute of Harvard/Massachusetts General Hospital and Massachusetts Institute of Technology, the Wellcome Trust Center for Human Genetics at Oxford University, and Perlegen Sciences for releasing inbred laboratory mouse SNP data. We thank the Mouse Phenome Project for collecting mouse SNP data. We thank the International Agency for Research on Cancer (Lyon, France) for releasing lung cancer GWAS data. We also thank investigators for generating spontaneous lung tumor data in inbred mice. The mouse SNP and phenotype data were crucial for the key findings described in this paper. We thank the staff of The Vanderbilt Microarray Shared Resource for microarray processing. MY was supported by grants from the US National Institutes of Health (CA099187, CA099147, ES012063, and ES013340). We thank Dr Jay W Tichelaar for his critical comments on the manuscript.

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  1. Department of Surgery and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA

    Y Lu, P Liu, M James, H G Vikis, H Liu, W Wen, A Franklin & M You

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Correspondence to M You.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Lu, Y., Liu, P., James, M. et al. Genetic variants cis-regulating Xrn2 expression contribute to the risk of spontaneous lung tumor. Oncogene 29, 1041–1049 (2010). https://doi.org/10.1038/onc.2009.396

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