Genetic variants cis-regulating Xrn2 expression contribute to the risk of spontaneous lung tumor. Oncogene 2010 Feb 18;29(7):1041-9
Date
11/17/2009Pubmed ID
19915612Pubmed Central ID
PMC6019621DOI
10.1038/onc.2009.396Scopus ID
2-s2.0-77149169733 (requires institutional sign-in at Scopus site) 21 CitationsAbstract
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 x 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 x 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 x 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.
Author List
Lu Y, Liu P, James M, Vikis HG, Liu H, Wen W, Franklin A, You MMESH terms used to index this publication - Major topics in bold
AnimalsCell Differentiation
Cell Line
Cell Proliferation
Epithelial Cells
Exoribonucleases
Female
Gene Expression Regulation
Genetic Predisposition to Disease
Genetic Variation
Genome-Wide Association Study
Humans
Lung Neoplasms
Male
Mice
Polymorphism, Single Nucleotide
RNA Interference
RNA, Messenger
