Bryan A. Hay

Lung cancer gene associated with COPD: triple whammy or possible confounding effect?

Recently, several large genome-wide association studies have identified a putative “lung cancer” locus in the nicotinic acetylcholine receptor subunit genes (nAChR) on 15q25. However, these findings may be confounded by the presence of chronic obstructive pulmonary disease (COPD), which is also strongly associated with smoking exposure and lung cancer. This is likely as the prevalence of COPD in lung cancer cohorts is as much as two-fold greater than that reported in smoking control populations (50 versus 20%). The present authors compared the genotype frequencies of the most strongly associated single nucleotide polymorphism (rs16969968) in the α5 subunit of the nAChR gene cluster between three matched smoking cohorts. The AA genotype was found to be more frequent and was seen in 437 (16%) lung cancer cases and 445 (14%) COPD cases compared with 475 (9%) healthy smoking controls. More importantly, when 429 lung cancer cases were divided according to spirometry results (performed within 3 months of diagnosis, prior to surgery and in the absence of effusions or collapse), the AA genotype was present in 19 and 11% of cases with and without COPD, respectively. These findings suggest that the association between the α5 subunit nicotinic acetylcholine receptor single nucleotide polymorphism and lung cancer may, in part, be confounded by chronic obstructive pulmonary disease.

Individual and Cumulative Effects of GWAS Susceptibility Loci in Lung Cancer: Associations after Sub-Phenotyping for COPD

Epidemiological studies show that approximately 20–30% of chronic smokers develop chronic obstructive pulmonary disease (COPD) while 10–15% develop lung cancer. COPD pre-exists lung cancer in 50–90% of cases and has a heritability of 40–77%, much greater than for lung cancer with heritability of 15–25%. These data suggest that smokers susceptible to COPD may also be susceptible to lung cancer. This study examines the association of several overlapping chromosomal loci, recently implicated by GWA studies in COPD, lung function and lung cancer, in (n = 1400) subjects sub-phenotyped for the presence of COPD and matched for smoking exposure. Using this approach we show; the 15q25 locus confers susceptibility to lung cancer and COPD, the 4q31 and 4q22 loci both confer a reduced risk to both COPD and lung cancer, the 6p21 locus confers susceptibility to lung cancer in smokers with pre-existing COPD, the 5p15 and 1q23 loci both confer susceptibility to lung cancer in those with no pre-existing COPD. We also show the 5q33 locus, previously associated with reduced FEV1, appears to confer susceptibility to both COPD and lung cancer. The 6p21 locus previously linked to reduced FEV1 is associated with COPD only. Larger studies will be needed to distinguish whether these COPD-related effects may reflect, in part, associations specific to different lung cancer histology. We demonstrate that when the “risk genotypes” derived from the univariate analysis are incorporated into an algorithm with clinical variables, independently associated with lung cancer in multivariate analysis, modest discrimination is possible on receiver operator curve analysis (AUC = 0.70). We suggest that genetic susceptibility to lung cancer includes genes conferring susceptibility to COPD and that sub-phenotyping with spirometry is critical to identifying genes underlying the development of lung cancer.

Chromosome 4q31 locus in COPD is also associated with lung cancer.

Chronic obstructive pulmonary disease (COPD) is the single greatest risk factor for lung cancer in smokers and is found in 50–90% of lung cancer cases. The link between COPD and lung cancer may stem in part from the matrix remodelling and repair processes underlying COPD, and the development of epithelial–mesenchymal transition (EMT) that underlies lung carcinogenesis. The Hedgehog-interacting protein (HHIP), which mediates the epithelial response (EMT) to smoking, has been implicated in COPD and lung cancer. Recent genome-wide and candidate gene studies of COPD implicate genetic variants on the chromosomal 4q31 (HHIP/glycophorin A (GYPA)) locus. In a case–control study of smokers with normal lung function, COPD and lung cancer (subphenotyped for COPD), we show the GG genotype of the rs 1489759 HHIP single-nucleotide polymorphism (SNP) and the CC genotype of the rs 2202507 GYPA SNP confers a “protective” effect on COPD (OR 0.59, p = 0.006 for HHIP and OR = 0.65, p = 0.006 for GYPA) and lung cancer (OR = 0.70 (p = 0.05) for HHIP and OR 0.70 (p = 0.02) for GYPA). This study suggests that, in smokers, genetic variants of the 4q31 locus conferring a protective effect for COPD are also protective in lung cancer. We conclude that genetic susceptibility to lung cancer includes COPD-related gene variants.

A gene-based risk score for lung cancer susceptibility in smokers and ex-smokers.

Background: Epidemiological and family studies suggest that lung cancer results from the combined effects of age, smoking and genetic factors. Chronic obstructive pulmonary disease (COPD) is also an independent risk factor for lung cancer and coexists in 40–60% of lung cancer cases. Methods: In a two-stage case–control association study, genetic markers associated with either susceptibility or protection against lung cancer were identified. In a test cohort of 439 Caucasian smokers or ex-smokers, consisting of healthy smokers and lung cancer cases, 157 candidate single nucleotide polymorphisms (SNPs) were screened. From this, 30 SNPs were identified, the genotypes (codominant or recessive model) of which were associated with either the healthy smokers (protective) or lung cancer (susceptibility) phenotype. After genotyping of this 30-SNP panel in a second validation cohort of 491 subjects and using the same protective and susceptibility genotypes from our test cohort, a 20-SNP panel was selected on the basis of independent univariate analyses. Results: Using multivariate logistic regression, including the 20 SNPs, it was also found that age, history of COPD, family history of lung cancer and gender were significantly and independently associated with lung cancer. Conclusions: When numeric scores were assigned to both the SNP and demographic data, and sequentially combined by a simple algorithm in a risk model, the composite score was found to be linearly related to lung cancer risk with a bimodal distribution. Genetic data may therefore be combined with other risk variables from smokers or ex-smokers to identify individuals who are most susceptible to developing lung cancer.

Lung Cancer Susceptibility Model Based on Age, Family History and Genetic Variants

Background Epidemiological and pedigree studies suggest that lung cancer results from the combined effects of age, smoking, impaired lung function and genetic factors. In a case control association study of healthy smokers and lung cancer cases, we identified genetic markers associated with either susceptibility or protection to lung cancer. Methodology/Principal Findings We screened 157 candidate single nucleotide polymorphisms (SNP) in a discovery cohort of 439 subjects (200 controls and 239 lung cancer cases) and identified 30 SNPs associated with either the healthy smokers (protective) or lung cancer (susceptibility) phenotype. After genotyping this 30 SNP panel in a validation cohort of 491 subjects (248 controls and 207 lung cancers) and, using the same protective and susceptibility genotypes from our discovery cohort, a 20 SNP panel was selected based on replication of SNP associations in the validation cohort. Following multivariate logistic regression analyses, including the selected SNPs from runs 1 and 2, we found age and family history of lung cancer to be significantly and independently associated with lung cancer. Numeric scores were assigned to both the SNP and demographic data, and combined to form a simple algorithm of risk. Conclusions/Significance Significant differences in the distribution of the lung cancer susceptibility score was found between normal controls and lung cancer cases, which remained after accounting for differences in lung function. Validation in other case-control and prospective cohorts are underway to further define the potential clinical utility of this model.

FAM13A locus in COPD is independently associated with lung cancer – evidence of a molecular genetic link between COPD and lung cancer

Recent genome-wide association studies have reported a FAM13A variant on chromosome 4q22.1 is associated with lung function and COPD. We examined this variant in a case-control study of current or former smokers with chronic obstructive pulmonary disease (COPD, n = 458), lung cancer (n = 454), or normal lung function (n = 488). Sex, age, and smoking history were comparable between groups. We confirmed the FAM13A variant (rs7671167) confers a protective effect on smoking-related COPD alone (C allele odds ratio [OR] = 0.79, P = 0.013, and CC genotype OR = 0.71, P = 0.024) and those with COPD, both with and without lung cancer (C allele OR = 0.80, P = 0.008, and CC genotype OR = 0.70, P = 0.007). The FAM13A variant also confers a protective effect on lung cancer overall (C allele OR = 0.75, P = 0.002, and CC genotype OR = 0.64, P = 0.003) even after excluding those with co-existing COPD (C allele OR = 0.67, P = 0.0007, and CC genotype OR = 0.58, P = 0.006). This was independent of age, sex, height, lung function, and smoking history. This protective effect was confined to those with nonsmall cell lung cancer (C allele OR = 0.72, P = 0.0009, and CC genotype OR = 0.61, P = 0.003). This study suggests that genetic predisposition to COPD is shared with lung cancer through shared pathogenetic factors such as the 4q22.1 locus implicating the Rho-kinase pathway.

Does RAGE protect smokers from COPD

To the Editors: We read with interest the article by Smith et al . [1], which showed a positive correlation between plasma soluble receptor for advanced glycation end-products (sRAGE) and forced expiratory volume in 1 s (FEV1) in patients with chronic obstructive pulmonary disease (COPD). Here, we outline the results of recent genetic epidemiological studies that suggest the advanced glycosylation end product-specific receptor ( AGER ) gene, which encodes sRAGE, may also have a role in the development of COPD. Two recent large genome-wide association (GWA) studies conclude that a locus on chromosome 6p21 is associated with lung function (FEV1 and FEV1/forced vital capacity) [2, 3], directly implicating the AGER gene, which is known to be expressed in alveolar epithelial cells [2]. However, this association was made in populations dominated by nonsmokers and did not specifically examine the effect in chronic smokers. We and others have …

GSTM1 null genotype in COPD and lung cancer: evidence of a modifier or confounding effect?

BACKGROUND Studies over the past two decades have reported associations between GSTM1 (glutathione S-transferase mu 1) null genotype and chronic obstructive pulmonary disease (COPD) or lung cancer. However, a modifier or confounding effect from COPD mediating the GSTM1 association with lung cancer has not been previously explored. AIM AND METHODS This variant was examined in a case-control study of current or former smokers with COPD (n = 669), lung cancer (n = 454), or normal lung function (n = 488). Sex, age, and smoking history were comparable between groups. RESULTS The GSTM1 null genotype was found to be more frequent in smokers with COPD alone (odds ratio [OR] 1.30, 95% confidence interval [CI] 1.02-1.66, P = 0.031) and lung cancer (OR 1.26, 95% CI 0.96-1.65, P = 0.083) than in matched smokers with normal lung function (62%, 61%, and 56%, respectively). However, when smokers with lung cancer were subgrouped according to the presence of COPD, then the association with all COPD subjects (OR 1.34, 95% CI 1.07-1.70, P = 0.010) and with COPD and lung cancer (OR 1.50, 95% CI 1.06-2.12, P = 0.018) continued to be significant while that with lung cancer only was reduced (OR 1.11, 95% CI 0.78-1.56, P = 0.55). These associations were independent of age, sex, height, lung function, and smoking history. CONCLUSION Findings suggest that COPD is an important subphenotype of lung cancer and may underlie previously reported associations with the GSTM1 null genotype.

Abstract A65: Gene-based test for lung cancer risk motivates smoking cessation in randomly selected smokers

Personalized risk assessment has been successfully used in coronary heart disease prevention to motivate lifestyle change and target drug therapy. In the Tension, Trigger and Treatment (3Ts) paradigm of smoking cessation, smokers quit smoking when the perceived harms outweigh benefits (or when motivational tension outweighs optimistic bias). Using a gene-based test for lung cancer risk, recently validated in a prospective study, we examined the effect of risk assessment on smoker9s attitudes and actions to quitting. In this pilot study, 28 smokers were randomly recruited from a hospital database (eligibility: ≥40 years old, current smoker, and 20+ pack year smoking history). Through a telephone questionnaire, baseline smoking history and recent quit attempts were documented. Smokers were also offered a gene-based risk test for lung cancer risk. 25 (90%) accepted and were followed. On visit 1, smokers were counseled, consented and a cheek swab was taken for genotyping. On visit 2, the lung cancer risk test result was given along with materials on smoking cessation services and medications. Based on a telephone questionnaire at 6 months after genetic testing (n=25) we found the following; 32% had quit smoking while 48% had reduced their smoking consumption (overall 80% had taken positive steps toward reducing smoking), 48% had used a smoking cessation service or product and only 4% of smokers appeared less committed to quitting. Quit rates were comparable in moderate- and high-risk groups. We conclude from this pilot study that personalized risk assessment using a gene-based test of lung cancer susceptibility appears to confer a positive effect on quitting smoking. The quit rates achieved in this study occurred in randomly selected smokers and compares favorably with other approaches. We suggest that the risk test provides a teachable moment and enhances motivational tension towards quitting. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A65.

Abstract B31: Gene-based lung cancer risk test (Respiragene), identifies high-risk smokers for early detection of lung cancer

Lung cancer results from the combined effects of smoking and genetic susceptibility. Recent studies show that between 50-90% of lung cancer cases have preexisting COPD and reduced FEV1 has been shown to be the single most important risk factor for lung cancer among smokers. Given the heritability for COPD and lung cancer is 40-75% and 15-25% respectively, it is clear genes conferring risk of COPD also underlies lung cancer susceptibility. In a study of 930 subjects, we have developed a gene-based lung cancer susceptibility model that combines genetic markers (SNPs) associated with COPD and lung cancer, with non-genetic variables (age and family history), to derive a score that helps to distinguish those smokers (and ex-smokers) at greatest risk of lung cancer. The panel includes SNPs validated in candidate and GWAS studies. In a prospective study of 1212 smokers we identified 52 new lung cancers and show their lung cancer scores are very similar to that of the original lung cancer cases (n=446). In a 2nd cross-sectional study of 606 lung cancer cases from the United Kingdom, the lung cancer score was also similarly distributed and showed similar performance in an ROC analysis. In a CT study of 25 lung cancer detected through CT screening in Spain, a similar high score was shown. Current CT screening programs for lung cancer generally target smokers over 50 years with a minimum 20 pack year history and achieve pick up rates of 1%. Using our gene-based model, where age, family history, COPD and genetic variants are combined, lung cancer detection rates maybe even higher. Citation Information: Cancer Prev Res 2010;3(12 Suppl):B31.