Gene Summary

Gene:CHRNA5; cholinergic receptor nicotinic alpha 5 subunit
Aliases: LNCR2
Summary:The protein encoded by this gene is a nicotinic acetylcholine receptor subunit and a member of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. These receptors are thought to be heteropentamers composed of separate but similar subunits. Defects in this gene have been linked to susceptibility to lung cancer type 2 (LNCR2).[provided by RefSeq, Jun 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:neuronal acetylcholine receptor subunit alpha-5
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (16)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Chromosome 15
  • Stomach Cancer
  • African Americans
  • Up-Regulation
  • Lung Cancer
  • Linkage Disequilibrium
  • Odds Ratio
  • DNA Sequence Analysis
  • Messenger RNA
  • Lung
  • Genetic Variation
  • Adolescents
  • Tobacco Use Disorder
  • Pulmonary Disease, Chronic Obstructive
  • Surveys and Questionnaires
  • Sequence Alignment
  • Single Nucleotide Polymorphism
  • Genetic Association Studies
  • Adenocarcinoma
  • Logistic Models
  • Proportional Hazards Models
  • Nerve Tissue Proteins
  • Case-Control Studies
  • Smoking and Smoking Cessation
  • Squamous Cell Carcinoma
  • Haplotypes
  • European Continental Ancestry Group
  • Multigene Family
  • Non-Small Cell Lung Cancer
  • Genome-Wide Association Study
  • Cohort Studies
  • Genotype
  • Genetic Predisposition
  • Asian Continental Ancestry Group
  • Phenotype
  • Risk Assessment
  • p53 Protein
  • Alleles
  • Polymorphism
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CHRNA5 (cancer-related)

Rajesh D, Azeem Mohiyuddin SM, Balakrishna S, Kutty AVM
Nicotinic acetylcholine receptor gene polymorphism is not associated with tobacco-related oral squamous cell carcinoma.
Indian J Cancer. 2018 Oct-Dec; 55(4):399-403 [PubMed] Related Publications
BACKGROUND: Nicotinic acetylcholine receptor is implicated in carcinogenesis indirectly through increasing nicotine dependence and directly through its impact on cell-cycle regulation. Functional polymorphism in nicotinic acetylcholine receptor alpha-5 subunit gene (CHRNA5 c.1192G>A; rs16969968) is associated with nicotine dependence and risk of lung cancer.
AIM: The aim of this study was to evaluate the association of CHRNA5 c.1192G>A polymorphism with the risk of oral squamous cell carcinoma (OSCC).
SETTINGS AND DESIGN: This was a rural teaching hospital-based case-control study.
MATERIALS AND METHODS: A total of 100 histopathologically confirmed cases of OSCC patients and 100 age- and gender-matched healthy individuals were genotyped for CHRNA5 c.1192G>A polymorphism by polymerase chain reaction-restriction fragment length polymorphism method. Allele and genotype frequencies among case and control groups were compared by Chi-squared test (Fisher's exact).
RESULTS: The frequency of CHRNA5 c.1192A allele was 22% in OSCC patients and 26% in control individuals. The difference in the distribution of alleles and genotypes between case and control groups was not significant (P > 0.05).
CONCLUSIONS: CHRNA5 c.1192G>A polymorphism is not associated with the risk of developing OSCC.

Cingir Koker S, Jahja E, Shehwana H, et al.
Cholinergic Receptor Nicotinic Alpha 5 (CHRNA5) RNAi is associated with cell cycle inhibition, apoptosis, DNA damage response and drug sensitivity in breast cancer.
PLoS One. 2018; 13(12):e0208982 [PubMed] Free Access to Full Article Related Publications
Cholinergic Receptor Nicotinic Alpha 5 (CHRNA5) is an important susceptibility locus for nicotine addiction and lung cancer. Depletion of CHRNA5 has been associated with reduced cell viability, increased apoptosis and alterations in cellular motility in different cancers yet not in breast cancer. Herein we first showed the expression of CHRNA5 was variable and positively correlated with the fraction of total genomic alterations in breast cancer cell lines and tumors indicating its potential role in DNA damage response (DDR). Next, we demonstrated that silencing of CHRNA5 expression in MCF7 breast cancer cell line by RNAi affected expression of genes involved in cytoskeleton, TP53 signaling, DNA synthesis and repair, cell cycle, and apoptosis. The transcription profile of CHRNA5 depleted MCF7 cells showed a significant positive correlation with that of A549 lung cancer cell line while exhibiting a negative association with the CHRNA5 co-expression profile obtained from Cancer Cell Line Encylopedia (CCLE). Moreover, it exhibited high similarities with published MCF7 expression profiles obtained from exposure to TP53 inducer nutlin-3a and topoisomerase inhibitors. We then demonstrated that CHRNA5 siRNA treatment reduced cell viability and DNA synthesis indicating G1 arrest while it significantly increased apoptotic sub-G1 cell population. Accordingly, we observed lower levels of phosphorylated RB (Ser807/811) and an increased BAX/BCL2 ratio in RNAi treated MCF7 cells. We also showed that CHRNA5 RNAi transcriptome correlated negatively with DDR relevant gene expression profile in breast cancer gene expression datasets while the coexposure to topoisomerase inhibitors in the presence of CHRNA5 RNAi enhanced chemosensitivity potentially due to reduced DDR. CHRNA5 RNAi consistently lowered total CHEK1 mRNA and protein levels as well as phosphorylated CHEK1 (Ser345) in MCF7 cells. We also detected a significant positive correlation between the expression levels of CHRNA5 and CHEK1 in CCLE, TCGA and METABRIC breast cancer datasets. Our study suggests CHRNA5 RNAi is associated with cell cycle inhibition, apoptosis as well as reduced DDR and increased drug sensitivity in breast cancer yet future studies are warranted since dose- and cell line-specific differences exist in response to CHRNA5 depletion. Gene expression microarray data can be accessed from GEO database under the accession number GSE89333.

Pérez-Morales R, González-Zamora A, González-Delgado MF, et al.
CHRNA3 rs1051730 and CHRNA5 rs16969968 polymorphisms are associated with heavy smoking, lung cancer, and chronic obstructive pulmonary disease in a mexican population.
Ann Hum Genet. 2018; 82(6):415-424 [PubMed] Related Publications
BACKGROUND AND PURPOSE: Smoking is a major public health problem worldwide. Polymorphisms in CHRNA3, CHRNA5, and CHRNB4 receptors play a critical role in nicotine dependence, lung cancer (LC) risk, and chronic obstructive pulmonary disease (COPD). This study characterized the CHRNA3 rs1051730 and CHRNA5 rs16969968 polymorphisms in a Mexican population and its association with nicotine dependence, LC, and COPD.
METHODS: The study included 312 healthy individuals, 74 LC cases and 117 COPD cases. Genotyping was performed using TaqMan probes, and the data were analyzed using logistic regression adjusted for covariates.
RESULTS: The polymorphism CHRNA3 rs1051730 and CHRNA5 rs16969968 were in the Hardy-Weinberg equilibrium and the allelic frequency of the A allele was 0.15, for both polymorphisms. The smokers were stratified in heavy smokers and moderate/light smokers, and we found in A alleles an OR = 2.86 (P = 0.01) to CHRNA3 rs1051730 and OR = 3.12 (P = 0.03) to CHRNA5 rs16969968. In addition, the A alleles in CHRNA3 rs1051730 and CHRNA5 rs16969968 were associated with the risk for LC (OR = 1.66, P = 0.07 and OR = 1.57, P = 0.1, respectively) and for COPD (OR = 2.04, P = 0.01 and OR = 1.91, P = 0.02, respectively).
CONCLUSION: CHRNA3/5 polymorphisms are associated with nicotine dependence, LC, and COPD in Mexicans.

Byun J, Schwartz AG, Lusk C, et al.
Genome-wide association study of familial lung cancer.
Carcinogenesis. 2018; 39(9):1135-1140 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
To identify genetic variation associated with lung cancer risk, we performed a genome-wide association analysis of 685 lung cancer cases that had a family history of two or more first or second degree relatives compared with 744 controls without lung cancer that were genotyped on an Illumina Human OmniExpressExome-8v1 array. To ensure robust results, we further evaluated these findings using data from six additional studies that were assembled through the Transdisciplinary Research on Cancer of the Lung Consortium comprising 1993 familial cases and 33 690 controls. We performed a meta-analysis after imputation of all variants using the 1000 Genomes Project Phase 1 (version 3 release date September 2013). Analyses were conducted for 9 327 222 SNPs integrating data from the two sources. A novel variant on chromosome 4p15.31 near the LCORL gene and an imputed rare variant intergenic between CDKN2A and IFNA8 on chromosome 9p21.3 were identified at a genome-wide level of significance for squamous cell carcinomas. Additionally, associations of CHRNA3 and CHRNA5 on chromosome 15q25.1 in sporadic lung cancer were confirmed at a genome-wide level of significance in familial lung cancer. Previously identified variants in or near CHRNA2, BRCA2, CYP2A6 for overall lung cancer, TERT, SECISPB2L and RTEL1 for adenocarcinoma and RAD52 and MHC for squamous carcinoma were significantly associated with lung cancer.

Ayesh BM, Al-Masri R, Abed AA
CHRNA5 and CHRNA3 polymorphism and lung cancer susceptibility in Palestinian population.
BMC Res Notes. 2018; 11(1):218 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
OBJECTIVE: The genetic polymorphism (rs16969968 in CHRNA5, and rs1051730 in CHRNA3 genes) were recently shown to be associated with risk of LC. The aim of this study is to elucidate whether they predispose Palestinian individuals to lung cancer, and how is this related to smoking.
RESULTS: Frequency of the rs16969968-A allele was significantly higher in the case group (36.7%) than in normal controls (17.5%; P = 0.022; OR = 6.83 for AA and 2.81 for AG genotypes). The frequency of rs1051730-T allele was also significantly higher in the case group (46.7%) than in the control group (22.5%; P = 0.001; OR = 2.20 for TC and 13.22 for TT genotypes). Frequency of rs16969968-A allele was higher in smokers (29.1%) than nonsmokers (15.7%) regardless of lung cancer; similarly, frequency of rs1051730-T allele was also higher in smokers than in smokers (46.7% vs 22.5%, respectively). The higher the proportion of the risk allele (rs16969968-A and rs1051730-T), the higher the mean number of daily consumed cigarettes (P = 0.006). Carrying rs16969968-A and/or rs1051730-T alleles results in an increased risk to lung cancer probably by increasing the individual's tendency for heavy smoking. The allelic frequency of the rs16969968-A and rs1051730-T alleles among normal Palestinian controls is similar to different populations worldwide.

O'Brien TD, Jia P, Caporaso NE, et al.
Weak sharing of genetic association signals in three lung cancer subtypes: evidence at the SNP, gene, regulation, and pathway levels.
Genome Med. 2018; 10(1):16 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
BACKGROUND: There are two main types of lung cancer: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC has many subtypes, but the two most common are lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). These subtypes are mainly classified by physiological and pathological characteristics, although there is increasing evidence of genetic and molecular differences as well. Although some work has been done at the somatic level to explore the genetic and biological differences among subtypes, little work has been done that interrogates these differences at the germline level to characterize the unique and shared susceptibility genes for each subtype.
METHODS: We used single-nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS) of European samples to interrogate the similarity of the subtypes at the SNP, gene, pathway, and regulatory levels. We expanded these genotyped SNPs to include all SNPs in linkage disequilibrium (LD) using data from the 1000 Genomes Project. We mapped these SNPs to several lung tissue expression quantitative trait loci (eQTL) and enhancer datasets to identify regulatory SNPs and their target genes. We used these genes to perform a biological pathway analysis for each subtype.
RESULTS: We identified 8295, 8734, and 8361 SNPs with moderate association signals for LUAD, LUSC, and SCLC, respectively. Those SNPs had p < 1 × 10
CONCLUSIONS: Our results suggest that the three lung cancer subtypes do not share much genetic signal at the SNP, gene, pathway, or regulatory level, which differs from the common subtype classification based upon histology. However, three (CHRNA5, IDH3A, and PSMA4) of the five genes shared between the subtypes are well-known lung cancer genes that may act as general lung cancer genes regardless of subtype.

Wang Y, Wu W, Zhu M, et al.
Integrating expression-related SNPs into genome-wide gene- and pathway-based analyses identified novel lung cancer susceptibility genes.
Int J Cancer. 2018; 142(8):1602-1610 [PubMed] Related Publications
Traditional pathway analysis map single nucleotide polymorphisms (SNPs) to genes according to physical position, which lacks sufficient biological bases. Here, we incorporated genetics of gene expression into gene- and pathway-based analysis to identify genes and pathways associated with lung cancer risk. We identified expression-related SNPs (eSNPs) in lung tissues and integrated these eSNPs into three lung cancer genome-wide association studies (GWASs), including 12,843 lung cancer cases and 12,639 controls. We used SKAT-C for gene-based analysis, and conditional analysis to identify independent eSNPs of each gene. ARTP algorithm was used for pathway analysis. A total of 374,382 eSNPs in the GWAS datasets survived quality control, which were mapped to 5,084 genes and 2,752 pathways. In the gene-based analysis, nine genes showed significant associations with lung cancer risk. Among them, TP63 (3q28), RP11-650L12.2 (15q25.1) and CHRNA5 (15q25.1) were located in known lung cancer susceptibility loci. We also validated two newly identified susceptibility loci (RNASET2 and AL133458.1 in 6q27, and MPZL3 in 11q23.3). Besides, DVL3 (3q27.1), RP11-522I20.3 (9q21.32) and CCDC116 (22q11.21) were identified as novel lung cancer susceptibility genes. Pathway analysis showed that pathways involved in protein structure, the Notch signaling pathway and the nicotinic acetylcholine receptor-related pathways were associated with lung cancer risk. Combing eSNPs, gene- and pathway-based analysis identifies novel lung cancer susceptibility genes, which serves as a powerful approach to decipher biological mechanisms underlying GWAS findings.

Wang J, Liu Q, Yuan S, et al.
Genetic predisposition to lung cancer: comprehensive literature integration, meta-analysis, and multiple evidence assessment of candidate-gene association studies.
Sci Rep. 2017; 7(1):8371 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
More than 1000 candidate-gene association studies on genetic susceptibility to lung cancer have been published over the last two decades but with few consensuses for the likely culprits. We conducted a comprehensive review, meta-analysis and evidence strength evaluation of published candidate-gene association studies in lung cancer up to November 1, 2015. The epidemiological credibility of cumulative evidence was assessed using the Venice criteria. A total of 1018 publications with 2910 genetic variants in 754 different genes or chromosomal loci were eligible for inclusion. Main meta-analyses were performed on 246 variants in 138 different genes. Twenty-two variants from 21 genes (APEX1 rs1130409 and rs1760944, ATM rs664677, AXIN2 rs2240308, CHRNA3 rs6495309, CHRNA5 rs16969968, CLPTM1L rs402710, CXCR2 rs1126579, CYP1A1 rs4646903, CYP2E1 rs6413432, ERCC1 rs11615, ERCC2 rs13181, FGFR4 rs351855, HYKK rs931794, MIR146A rs2910164, MIR196A2 rs11614913, OGG1 rs1052133, PON1 rs662, REV3L rs462779, SOD2 rs4880, TERT rs2736098, and TP53 rs1042522) showed significant associations with lung cancer susceptibility with strong cumulative epidemiological evidence. No significant associations with lung cancer risk were found for other 150 variants in 98 genes; however, seven variants demonstrated strong cumulative evidence. Our findings provided the most updated summary of genetic risk effects on lung cancer and would help inform future research direction.

Zhang Y, Jia Y, Li P, et al.
Reciprocal activation of α5-nAChR and STAT3 in nicotine-induced human lung cancer cell proliferation.
J Genet Genomics. 2017; 44(7):355-362 [PubMed] Related Publications
Cigarette smoking is the top environmental risk factor for lung cancer. Nicotine, the addictive component of cigarettes, induces lung cancer cell proliferation, invasion and migration via the activation of nicotinic acetylcholine receptors (nAChRs). Genome-wide association studies (GWAS) show that CHRNA5 gene encoding α5-nAChR is especially relevant to lung cancer. However, the mechanism of this subunit in lung cancer is not clear. In the present study, we demonstrate that the expression of α5-nAChR is correlated with phosphorylated STAT3 (pSTAT3) expression, smoking history and lower survival of non-small cell lung cancer (NSCLC) samples. Nicotine increased the levels of α5-nAChR mRNA and protein in NSCLC cell lines and activated the JAK2/STAT3 signaling cascade. Nicotine-induced activation of JAK2/STAT3 signaling was inhibited by the silencing of α5-nAChR. Characterization of the CHRNA5 promoter revealed four STAT3-response elements. ChIP assays confirmed that the CHRNA5 promoter contains STAT3 binding sites. By silencing STAT3 expression, nicotine-induced upregulation of α5-nAChR was suppressed. Downregulation of α5-nAChR and/or STAT3 expression inhibited nicotine-induced lung cancer cell proliferation. These results suggest that there is a feedback loop between α5-nAChR and STAT3 that contributes to the nicotine-induced tumor cell proliferation, which indicates that α5-nAChR is an important therapeutic target involved in tobacco-associated lung carcinogenesis.

Chianello Nicolau M, Pinto LF, Nicolau-Neto P, et al.
Nicotinic cholinergic receptors in esophagus: Early alteration during carcinogenesis and prognostic value.
World J Gastroenterol. 2016; 22(31):7146-56 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
AIM: To compare expression of nicotinic cholinergic receptors (CHRNs) in healthy and squamous cell carcinoma-affected esophagus and determine the prognostic value.
METHODS: We performed RT-qPCR to measure the expression of CHRNs in 44 esophageal samples from healthy individuals and in matched normal surrounding mucosa, and in tumors from 28 patients diagnosed with esophageal squamous cell carcinoma (ESCC). Next, we performed correlation analysis for the detected expression of these receptors with the habits and clinico-pathological characteristics of all study participants. In order to investigate the possible correlations between the expression of the different CHRN subunits in both healthy esophagus and tissues from ESCC patients, correlation matrices were generated. Subsequently, we evaluated whether the detected alterations in expression of the various CHRNs could precede histopathological modifications during the esophageal carcinogenic processes by using receiver operating characteristic curve analysis. Finally, we evaluated the impact of CHRNA5 and CHRNA7 expression on overall survival by using multivariate analysis.
RESULTS: CHRNA3, CHRNA5, CHRNA7 and CHRNB4, but not CHRNA1, CHRNA4, CHRNA9 or CHRNA10, were found to be expressed in normal (healthy) esophageal mucosa. In ESCC, CHRNA5 and CHRNA7 were overexpressed as compared with patient-matched surrounding non-tumor mucosa (ESCC-adjacent mucosa; P < 0.0001 and P = 0.0091, respectively). Positive correlations were observed between CHRNA3 and CHRNB4 expression in all samples analyzed. Additionally, CHRNB4 was found to be differentially expressed in the healthy esophagus and the normal-appearing ESCC-adjacent mucosa, allowing for distinguishment between these tissues with a sensitivity of 75.86% and a specificity of 78.95% (P = 0.0002). Finally, CHRNA5 expression was identified as an independent prognostic factor in ESCC; patients with high CHRNA5 expression showed an increased overall survival, in comparison with those with low expression. The corresponding age- and tumor stage-adjusted hazard ratio was 0.2684 (95%CI: 0.075-0.97, P = 0.0448).
CONCLUSION: Expression of CHRNs is homogeneous along healthy esophagus and deregulated in ESCC, suggesting a pathogenic role for these receptors in ESCC development and progression.

Chen LS, Baker T, Hung RJ, et al.
Genetic Risk Can Be Decreased: Quitting Smoking Decreases and Delays Lung Cancer for Smokers With High and Low CHRNA5 Risk Genotypes - A Meta-Analysis.
EBioMedicine. 2016; 11:219-226 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
BACKGROUND: Recent meta-analyses show that individuals with high risk variants in CHRNA5 on chromosome 15q25 are likely to develop lung cancer earlier than those with low-risk genotypes. The same high-risk genetic variants also predict nicotine dependence and delayed smoking cessation. It is unclear whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not.
METHODS: Meta-analyses examined the association between smoking cessation and lung cancer risk in 15 studies of individuals with European ancestry who possessed varying rs16969968 genotypes (N=12,690 ever smokers, including 6988 cases of lung cancer and 5702 controls) in the International Lung Cancer Consortium.
RESULTS: Smoking cessation (former vs. current smokers) was associated with a lower likelihood of lung cancer (OR=0.48, 95%CI=0.30-0.75, p=0.0015). Among lung cancer patients, smoking cessation was associated with a 7-year delay in median age of lung cancer diagnosis (HR=0.68, 95%CI=0.61-0.77, p=4.9∗10
CONCLUSION: We demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7years for those who develop it. These results: 1) underscore the potential value of smoking cessation for all smokers, 2) suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3) have potential value for framing preventive interventions for those who smoke.

Zanetti KA, Wang Z, Aldrich M, et al.
Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population.
Lung Cancer. 2016; 98:33-42 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
OBJECTIVES: Genome-wide association studies (GWAS) of lung cancer have identified regions of common genetic variation with lung cancer risk in Europeans who smoke and never-smoking Asian women. This study aimed to conduct a GWAS in African Americans, who have higher rates of lung cancer despite smoking fewer cigarettes per day when compared with Caucasians. This population provides a different genetic architecture based on underlying African ancestry allowing the identification of new regions and exploration of known regions for finer mapping.
MATERIALS AND METHODS: We genotyped 1,024,001 SNPs in 1737 cases and 3602 controls in stage 1, followed by a replication phase of 20 SNPs (p<1.51×10(-5)) in an independent set of 866 cases and 796 controls in stage 2.
RESULTS AND CONCLUSION: In the combined analysis, we confirmed two loci to be associated with lung cancer that achieved the threshold of genome-wide significance: 15q25.1 marked by rs2036527 (p=1.3×10(-9); OR=1.32; 95% CI=1.20-1.44) near CHRNA5, and 5p15.33 marked by rs2853677 (p=2.8×10(-9); OR=1.28; 95% CI=1.18-1.39) near TERT. The association with rs2853677 is driven by the adenocarcinoma subtype of lung cancer (p=1.3×10(-8); OR=1.37; 95% CI=1.23-1.54). No SNPs reached genome-wide significance for either of the main effect models examining smoking - cigarettes per day and current or former smoker. Our study was powered to identify strong risk loci for lung cancer in African Americans; we confirmed results previously reported in African Americans and other populations for two loci near plausible candidate genes, CHRNA5 and TERT, on 15q25.1 and 5p15.33 respectively, are associated with lung cancer. Additional work is required to map and understand the biological underpinnings of the strong association of these loci with lung cancer risk in African Americans.

Wu W, Liu H, Song F, et al.
Associations between smoking behavior-related alleles and the risk of melanoma.
Oncotarget. 2016; 7(30):47366-47375 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
Several studies have reported that cigarette smoking is inversely associated with the risk of melanoma. This study further tested whether incorporating genetic factors will provide another level of evaluation of mechanisms underlying the association between smoking and risk of melanoma. We investigated the association between SNPs selected from genome-wide association studies (GWAS) on smoking behaviors and risk of melanoma using 2,298 melanoma cases and 6,654 controls. Among 16 SNPs, three (rs16969968 [A], rs1051730 [A] and rs2036534 [C] in the 15q25.1 region) reached significance for association with melanoma risk in men (0.01 < = P values < = 0.02; 0.85 < = Odds Ratios (ORs) <= 1.20). There was association between the genetic scores based on the number of smoking behavior-risk alleles and melanoma risk with P-trend = 0.005 among HPFS. Further association with smoking behaviors indicating those three SNPs (rs16969968 [A], rs1051730 [A] and rs2036534 [C]) significantly associated with number of cigarettes smoked per day, CPD, with P = 0.009, 0.011 and 0.001 respectively. The SNPs rs215605 in the PDE1C gene and rs6265 in the BDNF gene significantly interacted with smoking status on melanoma risk (interaction P = 0.005 and P = 0.003 respectively). Our study suggests that smoking behavior-related SNPs are likely to play a role in melanoma development and the potential public health importance of polymorphisms in the CHRNA5-A3-B4 gene cluster. Further larger studies are warranted to validate the findings.

Gao X, Zhang Y, Breitling LP, Brenner H
Tobacco smoking and methylation of genes related to lung cancer development.
Oncotarget. 2016; 7(37):59017-59028 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
Lung cancer is a leading cause of cancer-related mortality worldwide, and cigarette smoking is the major environmental hazard for its development. This study intended to examine whether smoking could alter methylation of genes at lung cancer risk loci identified by genome-wide association studies (GWASs). By systematic literature review, we selected 75 genomic candidate regions based on 120 single-nucleotide polymorphisms (SNPs). DNA methylation levels of 2854 corresponding cytosine-phosphate-guanine (CpG) candidates in whole blood samples were measured by the Illumina Infinium Human Methylation450 Beadchip array in two independent subsamples of the ESTHER study. After correction for multiple testing, we successfully confirmed associations with smoking for one previously identified CpG site within the KLF6 gene and identified 12 novel sites located in 7 genes: STK32A, TERT, MSH5, ACTA2, GATA3, VTI1A and CHRNA5 (FDR <0.05). Current smoking was linked to a 0.74% to 2.4% decrease of DNA methylation compared to never smoking in 11 loci, and all but one showed significant associations (FDR <0.05) with life-time cumulative smoking (pack-years). In conclusion, our study demonstrates the impact of tobacco smoking on DNA methylation of lung cancer related genes, which may indicate that lung cancer susceptibility genes might be regulated by methylation changes in response to smoking. Nevertheless, this mechanism warrants further exploration in future epigenetic and biomarker studies.

Wang Y, Peng X, Zhu L, et al.
Genetic variants of CHRNA5-A3 and CHRNB3-A6 predict survival of patients with advanced non-small cell lung cancer.
Oncotarget. 2016; 7(18):26436-43 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
Nicotinic acetylcholine receptors (nAChRs) play a key role in carcinogenesis and progression of lung cancer; and polymorphisms in CHRNA5-A3 and CHRNB3-A6, two gene clusters encoding nAChR subunits, have been associated with lung cancer risk. In this study, we investigated whether variants in the two gene clusters were associated with prognosis of advanced non-small cell lung cancer (NSCLC). A total of 165 stage IIIB-IV NSCLC patients were enrolled in this study. Three polymorphisms (rs667282 and rs3743073 in CHRNA5-A3 and rs13280604 in CHRNB3-A6) were genotyped using the TaqMan method. Overall survival (OS) was estimated using the log-rank test and the Cox models. Our results showed that patients with CHRNA5-A3 rs667282 TT or TC genotypes had a significantly shorter OS than those carrying the CC genotype (Log-rank, P = 0.043). Furthermore, multivariate Cox regression analysis showed that rs667282 TT/TC genotypes are significantly associated with increased risk of overall deaths (adjusted hazard ratio, 1.7; 95% CI, 1.1-2.7). However, the similar results were not observed for other two polymorphisms. Furthermore, no evident association was found between these variants and clinicopathologic features of advanced NSCLC. Our present study suggested that rs667282 in CHRNA5-A3 may modify the prognosis of patients with advanced NSCLC.

David SP, Wang A, Kapphahn K, et al.
Gene by Environment Investigation of Incident Lung Cancer Risk in African-Americans.
EBioMedicine. 2016; 4:153-61 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
BACKGROUND: Genome-wide association studies have identified polymorphisms linked to both smoking exposure and risk of lung cancer. The degree to which lung cancer risk is driven by increased smoking, genetics, or gene-environment interactions is not well understood.
METHODS: We analyzed associations between 28 single nucleotide polymorphisms (SNPs) previously associated with smoking quantity and lung cancer in 7156 African-American females in the Women's Health Initiative (WHI), then analyzed main effects of top nominally significant SNPs and interactions between SNPs, cigarettes per day (CPD) and pack-years for lung cancer in an independent, multi-center case-control study of African-American females and males (1078 lung cancer cases and 822 controls).
FINDINGS: Nine nominally significant SNPs for CPD in WHI were associated with incident lung cancer (corrected p-values from 0.027 to 6.09 × 10(-5)). CPD was found to be a nominally significant effect modifier between SNP and lung cancer for six SNPs, including CHRNA5 rs2036527[A](betaSNP*CPD = - 0.017, p = 0.0061, corrected p = 0.054), which was associated with CPD in a previous genome-wide meta-analysis of African-Americans.
INTERPRETATION: These results suggest that chromosome 15q25.1 variants are robustly associated with CPD and lung cancer in African-Americans and that the allelic dose effect of these polymorphisms on lung cancer risk is most pronounced in lighter smokers.

Zhang Y, Jiang M, Li Q, et al.
Chromosome 15q25 (CHRNA3-CHRNB4) Variation Indirectly Impacts Lung Cancer Risk in Chinese Males.
PLoS One. 2016; 11(3):e0149946 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
INTRODUCTION: Recently, genome-wide association studies (GWAS) in Caucasian populations have identified an association between single nucleotide polymorphisms (SNPs) in the CHRNA5-A3-B4 nicotinic acetylcholine receptor subunit gene cluster on chromosome 15q25, lung cancer risk and smoking behaviors. However, these SNPs are rare in Asians, and there is currently no consensus on whether SNPs in CHRNA5-A3-B4 have a direct or indirect carcinogenic effect through smoking behaviors on lung cancer risk. Though some studies confirmed rs6495308 polymorphisms to be associated with smoking behaviors and lung cancer, no research was conducted in China. Using a case-control study, we decided to investigate the associations between CHRNA3 rs6495308, CHRNB4 rs11072768, smoking behaviors and lung cancer risk, as well as explore whether the two SNPs have a direct or indirect carcinogenic effect on lung cancer.
METHODS: A total of 1025 males were interviewed using a structured questionnaire (204 male lung cancer patients and 821 healthy men) to acquire socio-demographic status and smoking behaviors. Venous blood samples were collected to measure rs6495308 and rs11072768 gene polymorphisms. All subjects were divided into 3 groups: non-smokers, light smokers (1-15 cigarettes per day) and heavy smokers (>15 cigarettes per day).
RESULTS: Compared to wild genotype, rs6495308 and rs11072768 variant genotypes reported smoking more cigarettes per day and a higher pack-years of smoking (P<0.05). More importantly, among smokers, both rs6495308 CT/TT and rs11072768 GT/GG had a higher risk of lung cancer compared to wild genotype without adjusting for potential confounding factors (OR = 1.36, 95%CI = 1.09-1.95; OR = 1.11, 95%CI = 1.07-1.58 respectively). Furthermore, heavy smokers with rs6495308 or rs11072768 variant genotypes have a positive interactive effect on lung cancer after adjustment for potential confounding factors (OR = 1.13, 95%CI = 1.01-3.09; OR = 1.09, 95%CI = 1.01-3.41 respectively). However, No significant associations were found between lung cancer risk and both rs6495308 and rs11072768 genotypes among non-smokers and smokers after adjusting for age, occupation, and education.
CONCLUSION: This study confirmed both rs6495308 and rs11072768 gene polymorphisms association with smoking behaviors and had an indirect link between gene polymorphisms and lung cancer risk.

Liu Y, Kheradmand F, Davis CF, et al.
Focused Analysis of Exome Sequencing Data for Rare Germline Mutations in Familial and Sporadic Lung Cancer.
J Thorac Oncol. 2016; 11(1):52-61 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
INTRODUCTION: The association between smoking-induced chronic obstructive pulmonary disease (COPD) and lung cancer (LC) is well documented. Recent genome-wide association studies (GWAS) have identified 28 susceptibility loci for LC, 10 for COPD, 32 for smoking behavior, and 63 for pulmonary function, totaling 107 nonoverlapping loci. Given that common variants have been found to be associated with LC in genome-wide association studies, exome sequencing of these high-priority regions has great potential to identify novel rare causal variants.
METHODS: To search for disease-causing rare germline mutations, we used a variation of the extreme phenotype approach to select 48 patients with sporadic LC who reported histories of heavy smoking-37 of whom also exhibited carefully documented severe COPD (in whom smoking is considered the overwhelming determinant)-and 54 unique familial LC cases from families with at least three first-degree relatives with LC (who are likely enriched for genomic effects).
RESULTS: By focusing on exome profiles of the 107 target loci, we identified two key rare mutations. A heterozygous p.Arg696Cys variant in the coiled-coil domain containing 147 (CCDC147) gene at 10q25.1 was identified in one sporadic and two familial cases. The minor allele frequency (MAF) of this variant in the 1000 Genomes database is 0.0026. The p.Val26Met variant in the dopamine β-hydroxylase (DBH) gene at 9q34.2 was identified in two sporadic cases; the minor allele frequency of this mutation is 0.0034 according to the 1000 Genomes database. We also observed three suggestive rare mutations on 15q25.1: iron-responsive element binding protein neuronal 2 (IREB2); cholinergic receptor, nicotinic, alpha 5 (neuronal) (CHRNA5); and cholinergic receptor, nicotinic, beta 4 (CHRNB4).
CONCLUSIONS: Our results demonstrated highly disruptive risk-conferring CCDC147 and DBH mutations.

Kupiainen H, Kuokkanen M, Kontto J, et al.
CHRNA5/CHRNA3 Locus Associates with Increased Mortality among Smokers.
COPD. 2016; 13(4):464-70 [PubMed] Related Publications
Polymorphisms in the nicotinic acetylcholine receptor gene (CHRNA5/CHRNA3 locus) have been associated with several smoking related traits such as nicotine dependence, cigarette consumption, smoking cessation, lung cancer, and COPD. The aim of this candidate gene study was to study the locus among the Finnish COPD patients and long-term smokers with regard to COPD risk, smoking behavior, cancer, and all-cause mortality. Genotyping of rs1051730, the locus tagging SNP was done in two longitudinal cohorts: Finnish COPD patients (N = 575, 74% men) and long-term smokers, all men (N = 1911). Finnish population sample (N = 1730) was used as controls. The analyses were done using logistic and Cox regression. The main findings were that the minor allele increased the risk of COPD when compared to the Finnish population at large (OR = 1.4, 95% CI 1.2-1.7, p = 3.2 × 10-5). Homozygosity for the risk allele was associated in both cohorts with all-cause mortality (crude HR 2.2, 95% CI 1.2-3.8 and 1.3, 95% CI 1.1-1.5, respectively), with any type of cancer (crude OR 2.3, 95% CI 1.0-5.1) among the COPD patients and with the number of pack-years (crude OR 1.4, 95% CI 1.1-1.9) among the male smokers. CHRNA5/CHRNA3 locus tagged by rs1051730, which has been previously associated with several smoking related diseases was now shown to be associated also with increased all-cause mortality among long-term smokers with or without clinical COPD further emphasizing the clinical importance of the finding.

Halldén S, Sjögren M, Hedblad B, et al.
Gene variance in the nicotinic receptor cluster (CHRNA5-CHRNA3-CHRNB4) predicts death from cardiopulmonary disease and cancer in smokers.
J Intern Med. 2016; 279(4):388-98 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
BACKGROUND: Genetic variation in the cluster on chromosome 15, encoding the nicotinic acetylcholine receptor subunits (CHRNA5-CHRNA3-CHRNB4), has shown strong associations with tobacco consumption and an additional risk increase in smoking-related diseases such as chronic obstructive pulmonary disease (COPD), peripheral artery disease and lung cancer.
OBJECTIVES: To test whether rs1051730 (C/T), a tag for multiple variants in the CHRNA5-CHRNA3-CHRNB3 cluster, is associated with a change in risk of smoking-related mortality and morbidity in the Malmö Diet and Cancer study, a population-based prospective cohort study.
METHODS: At baseline participants were classified as current (n = 6951), previous (n = 8426) or never (n = 9417) smokers. Cox-proportional hazards models were used to determine the correlation between rs1051730 and incidence of first COPD, tobacco-related cancer, other cancer and cardiovascular disease (CVD), and total mortality due to these causes, during approximately 14 years of follow-up.
RESULTS: Amongst current smokers there were 480 first incident COPD events, 852 tobacco-related cancers, 810 other cancers and 1022 CVD events. A total of 1508 deaths occurred, including 500 due to CVD, 102 due to respiratory diseases and 677 due to cancer. In adjusted additive models, an increasing number of T alleles were associated with a gradual increase in total mortality, incident COPD and tobacco-related cancer, even after adjustment for smoking quantity. No significant associations were observed amongst never smokers.
CONCLUSION: Our data suggest that gene variance in the CHRNA5-CHRNA3-CHRNB4 cluster is associated with an increased risk of death, incidence of COPD and tobacco-related cancer in smokers. These findings indicate an individual susceptibility to tobacco use and its complications; this may be important when targeting and designing smoking cessation therapies.

Rennert G, Kremer R, Rennert HS, et al.
Lower lung cancer rates in Jewish smokers in Israel and the USA.
Int J Cancer. 2015; 137(9):2155-62 [PubMed] Related Publications
Lung cancer rates in Israeli Jews have remained stable over the last five decades and are much lower than in most developed countries despite high historical smoking rates. We compared lung cancer risk in Jews and non-Jews in Israel and in the United States. Data were derived from a population-based, case-control study in Israel (638 cases, 496 controls) to estimate lung cancer risk associated with smoking. Data were also acquired from a case-control study in the United States with information on religious affiliation (5,093 cases, 4,735 controls). Smoking was associated with lung cancer risk in all religion/gender groups in both studies. However, major differences in risk magnitude were noted between Jews and non-Jews; ever smoking was associated with a moderately elevated risk of lung cancer in Jewish men and women in Israel (OR = 4.61, 2.90-7.31 and OR = 2.10, 1.36-3.24, respectively), and in Jewish men and women in the United States (OR = 7.63, 5.34-10.90 and OR = 8.50, 5.94-12.17) but were significantly higher in Israeli non-Jewish men (OR = 12.96, 4.83-34.76) and US non-Jewish men and women (OR = 11.33, 9.09-14.12 and OR = 12.78, 10.45-15.63). A significant interaction between smoking and religion was evident in light, moderate and heavy male and female smokers. The differences in risk level between Israeli Jews and non-Jews could not be explained by lung cancer genetic risk variants which were identified in GWAS (genes in the CHRNA5, TERT and CLPTM1L regions). Data from the two studies support the notion of a reduced risk of lung cancer in Jewish compared to non-Jewish smokers in different areas of the world.

Tseng TS, Park JY, Zabaleta J, et al.
Role of nicotine dependence on the relationship between variants in the nicotinic receptor genes and risk of lung adenocarcinoma.
PLoS One. 2014; 9(9):e107268 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
Several variations in the nicotinic receptor genes have been identified to be associated with both lung cancer risk and smoking in the genome-wide association (GWA) studies. However, the relationships among these three factors (genetic variants, nicotine dependence, and lung cancer) remain unclear. In an attempt to elucidate these relationships, we applied mediation analysis to quantify the impact of nicotine dependence on the association between the nicotinic receptor genetic variants and lung adenocarcinoma risk. We evaluated 23 single nucleotide polymorphisms (SNPs) in the five nicotinic receptor related genes (CHRNB3, CHRNA6, and CHRNA5/A3/B4) previously reported to be associated with lung cancer risk and smoking behavior and 14 SNPs in the four 'control' genes (TERT, CLPTM1L, CYP1A1, and TP53), which were not reported in the smoking GWA studies. A total of 661 lung adenocarcinoma cases and 1,347 controls with a smoking history, obtained from the Environment and Genetics in Lung Cancer Etiology case-control study, were included in the study. Results show that nicotine dependence is a mediator of the association between lung adenocarcinoma and gene variations in the regions of CHRNA5/A3/B4 and accounts for approximately 15% of this relationship. The top two CHRNA3 SNPs associated with the risk for lung adenocarcinoma were rs1051730 and rs12914385 (p-value = 1.9×10(-10) and 1.1×10(-10), respectively). Also, these two SNPs had significant indirect effects on lung adenocarcinoma risk through nicotine dependence (p = 0.003 and 0.007). Gene variations rs2736100 and rs2853676 in TERT and rs401681 and rs31489 in CLPTM1L had significant direct associations on lung adenocarcinoma without indirect effects through nicotine dependence. Our findings suggest that nicotine dependence plays an important role between genetic variants in the CHRNA5/A3/B4 region, especially CHRNA3, and lung adenocarcinoma. This may provide valuable information for understanding the pathogenesis of lung adenocarcinoma and for conducting personalized smoking cessation interventions.

Nguyen JD, Lamontagne M, Couture C, et al.
Susceptibility loci for lung cancer are associated with mRNA levels of nearby genes in the lung.
Carcinogenesis. 2014; 35(12):2653-9 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
Recent studies identified three genetic loci reproducibly associated with lung cancer in populations of European ancestry, namely 15q25, 5p15 and 6p21. The goals of this study are first to confirm whether these loci are associated with lung cancer in a French Canadian population and second to identify disease-associated single nucleotide polymorphisms (SNPs) influencing messenger RNA (mRNA) expression levels of genes in the lung, that is expression quantitative trait loci (eQTLs). SNPs were genotyped in 420 patients undergoing lung cancer surgery and compared with 3151 controls of European ancestry. Genome-wide gene expression levels in non-tumor lung tissues of the same 420 patients were also measured to identify eQTLs. Significant eQTLs were then followed-up in two replication sets (n = 339 and 363). SNPs found in the three susceptibility loci were associated with lung cancer in the French Canadian population. Strong eQTLs were found on chromosome 15q25 with the expression levels of CHRNA5 (P = 2.23 × 10(-) (22) with rs12907966). The CHRNA5-rs12907966 eQTL was convincingly validated in the two replication sets (P = 3.46 × 10(-) (16) and 2.01 × 10(-) (15)). On 6p21, a trend was observed for rs3131379 to be associated with the expression of APOM (P = 3.58 × 10(-) (4)) and validated in the replication sets (P = 1.11 × 10(-) (8) and 6.84 × 10(-) (4)). On 5p15, no significant eQTLs were found. This study confirmed that chromosomes 15q25, 5p15 and 6p21 harbored susceptibility loci for lung cancer in French Canadians. Most importantly, this study suggests that the risk alleles at 15q25 and 6p21 may mediate their effect by regulating the mRNA expression levels of CHRNA5 and APOM in the lung.

Anantharaman D, Chabrier A, Gaborieau V, et al.
Genetic variants in nicotine addiction and alcohol metabolism genes, oral cancer risk and the propensity to smoke and drink alcohol: a replication study in India.
PLoS One. 2014; 9(2):e88240 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
BACKGROUND: Genetic variants in nicotinic acetylcholine receptor and alcohol metabolism genes have been associated with propensity to smoke tobacco and drink alcohol, respectively, and also implicated in genetic susceptibility to head and neck cancer. In addition to smoking and alcohol, tobacco chewing is an important oral cancer risk factor in India. It is not known if these genetic variants influence propensity or oral cancer susceptibility in the context of this distinct etiology.
METHODS: We examined 639 oral and pharyngeal cancer cases and 791 controls from two case-control studies conducted in India. We investigated six variants known to influence nicotine addiction or alcohol metabolism, including rs16969968 (CHRNA5), rs578776 (CHRNA3), rs1229984 (ADH1B), rs698 (ADH1C), rs1573496 (ADH7), and rs4767364 (ALDH2).
RESULTS: The CHRN variants were associated with the number of chewing events per day, including in those who chewed tobacco but never smoked (P =  0.003, P =  0.01 for rs16969968 and rs578776 respectively). Presence of the variant allele contributed to approximately 13% difference in chewing frequency compared to non-carriers. While no association was observed between rs16969968 and oral cancer risk (OR =  1.01, 95% CI =  0.83- 1.22), rs578776 was modestly associated with a 16% decreased risk of oral cancer (OR =  0.84, 95% CI =  0.72- 0.98). There was little evidence for association between polymorphisms in genes encoding alcohol metabolism and oral cancer in this population.
CONCLUSION: The association between rs16969968 and number of chewing events implies that the effect on smoking propensity conferred by this gene variant extends to the use of smokeless tobacco.

Li R, Qian J, Wang YY, et al.
Long noncoding RNA profiles reveal three molecular subtypes in glioma.
CNS Neurosci Ther. 2014; 20(4):339-43 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
BACKGROUND: Gliomas are the most lethal type of primary brain tumor in adult. Long noncoding RNAs (lncRNAs), which are involved in the progression of various cancers, may offer a potential gene therapy target in glioma.
METHODS AND FINDINGS: We first classified gliomas into three molecular subtypes (namely LncR1, LncR2 and LncR3) in Rembrandt dataset using consensus clustering. Survival analysis indicated that LncR3 had the best prognosis, while the LncR1 subtype showed the poorest overall survival rate. The results were further validated in an independent glioma dataset GSE16011. Additionally, we collected and merged data of the two databases (Rembrandt and GSE16011 dataset) and analyzed prognosis of each subtype in WHO II, III and IV gliomas. The similar results were obtained. Gene Set Variation Analysis (GSVA) demonstrated that LncR1 subtype enriched cultured astroglia's gene signature, while LncR2 subtype was characterized by neuronal gene signature. Oligodendrocytic was rich in LncR3. In addition, IDH1 mutation and 1p/19q LOH were found rich with LncR3, and EGFR amplification showed high percentage in LncR1 in GSE16011 dataset.
CONCLUSIONS: We report a novel molecular classification of glioma based on lncRNA expression profiles and believe that it would provide a potential platform for future studies on gene treatment for glioma and lead to more individualized therapies to improve survival rates.

Wang Y, Wu H, Liu Q, et al.
Association of CHRNA5-A3-B4 variation with esophageal squamous cell carcinoma risk and smoking behaviors in a Chinese population.
PLoS One. 2013; 8(7):e67664 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
BACKGROUND: CHRNA5-A3-B4, the gene cluster encoding nicotinic acetylcholine receptor subunits, is associated with lung cancer risk and smoking behaviors in people of European descent. Because cigarette smoking is also a major risk factor for esophageal squamous cell carcinoma (ESCC), we investigated the associations between variants in CHRNA5-A3-B4 and ESCC risk, as well as smoking behaviors, in a Chinese population.
METHODS: A case-control study of 866 ESCC patients and 952 healthy controls was performed to study the association of polymorphisms (rs667282 and rs3743073) in CHRNA5-A3-B4 with cancer risk using logistic regression models. The relationships between CHRNA5-A3-B4 polymorphisms and smoking behaviors that can be quantified by cigarettes smoked per day (CPD) and pack-years of smoking were separately estimated with Kruskal-Wallis tests among all 840 smokers.
RESULTS: CHRNA5-A3-B4 rs667282 TT/TG genotypes were associated with significantly increased risk of ESCC [adjusted odds ratio (OR) = 1.32, 95% confidence interval (CI) = 1.03 - 1.69, P = 0.029]. The increased ESCC risk was even higher among younger subjects (≤60 years) (OR = 1.44, 95% CI = 1.04 - 1.98, P = 0.024). These effects were not found in another polymorphism rs3743073. No evident association between the two polymorphisms and smoking behaviors was observed.
CONCLUSIONS: These results support the hypothesis that CHRNA5-A3-B4 is a susceptibility gene cluster for ESCC. The relationship between CHRNA5-A3-B4 and smoking behaviors in a Chinese population needs further investigation.

Eggert M, Aichinger E, Pfaffl MW, et al.
Nicotinic acetylcholine receptor subunits α4 and α5 associated with smoking behaviour and lung cancer are regulated by upstream open reading frames.
PLoS One. 2013; 8(7):e66157 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
Nicotinic acetylcholine receptor subunits (nAChR) are associated with different aspects of smoking behaviour as well as with smoking related disorders. Several of these subunits have been found to be upregulated in smokers or differentially expressed in lung tumor cells. The mechanisms behind these observations are not known but assumed to be mainly post-transcriptional. Many post-transcriptional mechanisms are initiated by functionally relevant sequence motifs within untranslated gene regions, such as upstream open reading frames (uORFs). We performed a systematic search in all smoking-associated neuronal nAChR subunits and identified functionally relevant uORFs in CHRNA4 and CHRNA5. Luciferase experiments showed that these uORFs are able to significantly decrease protein expression. Our quantitative real-time PCR (qPCR) results strongly suggest that the observed effects originate at the translation rather than at the transcription level. Interestingly, the CHRNA4 uORF was only functionally relevant when expressed in the shorter isoform of this gene. Therefore, the data presented in this study strongly points towards an important role of uORFs within the 5'UTR of CHRNA4-isoform 1 and CHRNA5 as regulators of protein translation. Moreover, the shared uORF of CHRNA4-isoform 1/isoform 2 represents the first example of a sequence context-dependent uORF.

Wassenaar CA, Dong Q, Amos CI, et al.
Pilot study of CYP2B6 genetic variation to explore the contribution of nitrosamine activation to lung carcinogenesis.
Int J Mol Sci. 2013; 14(4):8381-92 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
We explored the contribution of nitrosamine metabolism to lung cancer in a pilot investigation of genetic variation in CYP2B6, a high-affinity enzymatic activator of tobacco-specific nitrosamines with a negligible role in nicotine metabolism. Previously we found that variation in CYP2A6 and CHRNA5-CHRNA3-CHRNB4 combined to increase lung cancer risk in a case-control study in European American ever-smokers (n = 860). However, these genes are involved in the pharmacology of both nicotine, through which they alter smoking behaviours, and carcinogenic nitrosamines. Herein, we separated participants by CYP2B6 genotype into a high- vs. low-risk group (*1/*1 + *1/*6 vs. *6/*6). Odds ratios estimated through logistic regression modeling were 1.25 (95% CI 0.68-2.30), 1.27 (95% CI 0.89-1.79) and 1.56 (95% CI 1.04-2.31) for CYP2B6, CYP2A6 and CHRNA5-CHRNA3-CHRNB4, respectively, with negligible differences when all genes were evaluated concurrently. Modeling the combined impact of high-risk genotypes yielded odds ratios that rose from 2.05 (95% CI 0.39-10.9) to 2.43 (95% CI 0.47-12.7) to 3.94 (95% CI 0.72-21.5) for those with 1, 2 and 3 vs. 0 high-risk genotypes, respectively. Findings from this pilot point to genetic variation in CYP2B6 as a lung cancer risk factor supporting a role for nitrosamine metabolic activation in the molecular mechanism of lung carcinogenesis.

Wu H, Wang Y, Wang S, et al.
Is susceptibility locus for lung cancer in the 15q25 nicotinic acetylcholine receptor gene cluster CHRNA5-A3-B4 associated with risk of gastric cancer?
Med Oncol. 2013; 30(2):576 [PubMed] Related Publications
An association between common variants in the 15q25 nicotinic acetylcholine receptor (nAChR) gene cluster CHRNA5-A3-B4 (responsible for encoding nAChR subunits) and lung cancer risk has recently been reported in both Caucasian and Chinese population. Cigarette smoking is one of the major risk factors for both lung and gastric cancer. Moreover, nAChR plays an important role in cigarette smoke-related lung carcinogenesis as well as gastric cancer. Nevertheless, no study has evaluated the association between CHRNA5-A3-B4 gene cluster variants (rs667282 and rs3743073, two variants modifying lung cancer risk) and risk of gastric cancer. We genotyped these two single nucleotide polymorphisms(SNPs) and analyzed their associations with risk of gastric cancer in a case-control study of 637 gastric cancer patients and 855 healthy individuals matched by age and sex in a Chinese Han population. The differences in genotype distribution of the two SNPs (rs667282, rs3743073) between the cases and controls were not statistically significant (p = 0.468 and p = 0.495, respectively). Overall, we did not observe a significant association of each genotype of the two SNPs with risk of gastric cancer (TT/CT vs. CC: adjusted OR = 1.12,95 % CI = 0.86-1.45; p = 0.401 for rs667282 and GG/TG vs. TT: adjusted OR = 1.13,95 % CI = 0.90-1.43; p = 0.300 for rs3743073).The results of our study indicated that these two SNPs at the 15q25 locus did not modify gastric cancer risk and the reported risk SNP at 15q25 may be specific to lung cancer. Additional larger studies are needed to further confirm our findings.

Gabrielsen ME, Romundstad P, Langhammer A, et al.
Association between a 15q25 gene variant, nicotine-related habits, lung cancer and COPD among 56,307 individuals from the HUNT study in Norway.
Eur J Hum Genet. 2013; 21(11):1293-9 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
Genetic studies have shown an association between single-nucleotide polymorphisms on chromosome 15q25 and smoking-related traits and diseases, such as quantity of smoking, lung cancer and chronic obstructive pulmonary disease (COPD). A discussion has centred on the variants and their effects being directly disease related or indirect via nicotine addiction. To address these discrepancies, we genotyped the single-nucleotide polymorphism rs16969968 in the CHRNA5/A3/B4 gene cluster at chromosome 15q25, in 56 307 individuals from a large homogenous population-based cohort, the North Trøndelag Health Study (HUNT) in Norway. The variant was examined in relation to four different outcomes: lung cancer, loss of lung function equivalent to that of COPD, smoking behaviour and the use of smokeless tobacco (snus). Novel associations were found between rs16969968 and the motivational factor for starting to use snus, and the quantity of snus used. Our results also confirm and extend previous findings for associations between rs16969968 and lung cancer, loss of lung function equivalent to that of COPD, and smoking quantity. Our data suggest a role for rs16969968 in nicotine addiction, and the novel association with snus strengthens this observation.

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