TY - JOUR
T1 - Variants in inflammation genes are implicated in risk of lung cancer in never smokers exposed to second-hand smoke
AU - Spitz, Margaret R.
AU - Gorlov, Ivan P.
AU - Amos, Christopher I.
AU - Dong, Qiong
AU - Chen, Wei
AU - Etzel, Carol J.
AU - Gorlova, Olga Y.
AU - Chang, David W.
AU - Pu, Xia
AU - Zhang, Di
AU - Wang, Liang
AU - Cunningham, Julie M.
AU - Yang, Ping
AU - Wu, Xifeng
PY - 2011/10
Y1 - 2011/10
N2 - 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 inflammatorypathway 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-β 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.
AB - 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 inflammatorypathway 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-β 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.
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U2 - 10.1158/2159-8290.CD-11-0080
DO - 10.1158/2159-8290.CD-11-0080
M3 - Article
C2 - 22586632
AN - SCOPUS:84863575098
SN - 2159-8274
VL - 1
SP - 420
EP - 429
JO - Cancer discovery
JF - Cancer discovery
IS - 5
ER -