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Genetic variants cis-regulating Xrn2 expression contribute to the risk of spontaneous lung tumor. Oncogene 2010 Feb 18;29(7):1041-9 PMID: 19915612 PMCID: PMC6019621

Pubmed ID

19915612

DOI

10.1038/onc.2009.396

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 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 M

Authors

Michael James PhD Assistant Professor in the Surgery department at Medical College of Wisconsin
Pengyuan Liu PhD Adjunct Associate Professor in the Physiology department at Medical College of Wisconsin
Ming You MD, PhD Associate Provost, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




Scopus

2-s2.0-77149169733   13 Citations

MESH terms used to index this publication - Major topics in bold

Animals
Cell 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
jenkins-FCD Prod-353 9ccd8489072cb19f5b9f808bb23ed672c582f41e