title: Variants in inflammation genes are implicated in risk of lung cancer in never smokers exposed to second-hand smoke.
abstract: 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 an 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.
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. spitz@bcm.edu
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Spitz
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Gorlov
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Qiong
authors.initials: Q
authors.lastname: Dong
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Etzel
authors.forename: Olga Y
authors.initials: OY
authors.lastname: Gorlova
authors.forename: David W
authors.initials: DW
authors.lastname: Chang
authors.forename: Xia
authors.initials: X
authors.lastname: Pu
authors.forename: Di
authors.initials: D
authors.lastname: Zhang
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics; D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics; D000077192:Adenocarcinoma of Lung; D056151:Airway Remodeling / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000209:etiology / Q000235:genetics; D016022:Case-Control Studies; D003043:Cocarcinogenesis; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D014028:Tobacco Smoke Pollution; C498932:ACVR1B protein, human; D030201:Activin Receptors, Type I