Variants in Inflammation Genes Are Implicated in Risk of Lung Cancer in Never Smokers Exposed to Second-hand Smoke

作者：Spitz Margaret R^*; Gorlov Ivan P; Amos Christopher I; Dong Qiong; Chen Wei; Etzel Carol J; Gorlova Olga Y; Chang David W; Pu Xia; Zhang Di; Wang Liang; Cunningham Julie M; Yang Ping; Wu Xifeng

来源：Cancer Discovery, 2011, 1(5): 420-429.

DOI：10.1158/2159-8290.CD-11-0080

Lung cancer in lifetime never smokers is distinct from that in smokers, but the role of separate or overlapping carcinogenic pathways has not been explored. We therefore evaluated a comprehensive panel of 11,737 single-nucleotide polymorphisms (SNP) in inflammatory-pathway genes in a discovery phase (451 lung cancer cases, 508 controls from Texas). SNPs that were significant were evaluated in a second external population (303 cases, 311 controls from the Mayo Clinic). An intronic SNP in the ACVR1B gene, rs12809597, was replicated with significance and restricted to those reporting adult exposure to environmental tobacco smoke. Another promising candidate was a SNP in NR4A1, although the replication OR did not achieve statistical significance. ACVR1B belongs to the TGFR-beta superfamily, contributing to resolution of inflammation and initiation of airway remodeling. An inflammatory microenvironment (second-hand smoking, asthma, or hay fever) is necessary for risk from these gene variants to be expressed. These findings require further replication, followed by targeted resequencing, and functional validation.
SIGNIFICANCE: Beyond passive smoking and family history of lung cancer, little is known about the etiology of lung cancer in lifetime never smokers that accounts for about 15% of all lung cancers in the United States. Our two-stage candidate pathway approach examined a targeted panel of inflammation genes and has identified novel structural variants that appear to contribute to risk in patients who report prior exposure to sidestream smoking. Cancer Discovery;1(5):420-9.

• 出版日期2011-10