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

Abstract

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.Approximately 90% of people with lung cancer have a smoking history, yet only 10-15% of chronic smokers get lung cancer, suggesting that factors in addition to smoking exposure must be relevant.1 Epidemiological studies have identified age, smoking exposure, impaired lung function and family history as key risk factors for lung cancer.

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

“…First, predictive risk models for lung cancer should include COPD as a risk variable and/or incorporate these overlapping genetic markers [13,14]. Second, chemopreventive therapy targeting pathogenic pathways common to both COPD and lung cancer might confer considerable benefit to smokers and/or ex-smokers.…”

“…The heritability of COPD and lung cancer is estimated to be 40-77% and 15-25%, respectively [11,12]. These findings suggest some smokers susceptible to COPD might also be susceptible to lung cancer and that some of the genetic factors conferring this dual susceptibility might overlap [13][14][15]. Recent interest in lung cancer has focused on the role of smoking in epithelial-mesenchymal transition (EMT) [16], a process driven by release of growth factors and matrix metalloproteinases during lung remodelling and repair [17,18].…”

“…In the absence of spirometry, 50-80% of COPD cases remain undiagnosed [29]. In order to better explore associations between single nucleotide polymorphisms (SNPs), COPD and/or lung cancer, the COPD phenotype requires identification through spirometry assessment [13,14]. Secondly, to better examine SNP associations with lung cancer and/or COPD, three study populations should be employed: smokers with normal lung function (resistant smokers with no evidence of COPD); smokers with COPD; and smokers with lung cancer in whom spirometry has been performed to identify coexisting COPD [13,14].…”

“…In order to better explore associations between single nucleotide polymorphisms (SNPs), COPD and/or lung cancer, the COPD phenotype requires identification through spirometry assessment [13,14]. Secondly, to better examine SNP associations with lung cancer and/or COPD, three study populations should be employed: smokers with normal lung function (resistant smokers with no evidence of COPD); smokers with COPD; and smokers with lung cancer in whom spirometry has been performed to identify coexisting COPD [13,14]. Using such an approach, we identified that the chromosome 15q25 locus, originally associated with lung cancer in GWA studies [20][21][22], is also associated with COPD [30].…”

Lung Cancer Risk Prediction to Select Smokers for Screening CT—Letter

“…This is currently undergoing further validation in the NLST. We conclude that the optimal target population for CT screening of lung cancer can be identified by risk models that include clinical variables indicative of COPD (1,3,5). …”