30 March 2010
In the UK, lung cancer is the second most common diagnosed cancer and the most common cause of cancer death accounting for more than 1 in 5 cancer-related deaths (according to Cancer Research UK). Although smoking is the single largest risk factor for lung cancer, and causes almost 90% of lung cancer deaths, around a quarter of lung cancer cases worldwide have no history of smoking.
Using a “four-stage” case-control study design, Li et al. have investigated the genetic basis for lung cancer in non-smokers [Li et al. Lancet Oncol (2010) doi.10.1016/S1470-2045(10)70042-5]. The first stage used a genome-wide association study design to genotype more than 300,000 SNPs across the genomes of 754 ‘never smokers’, i.e. people who have smoked less than 100 cigarettes during their lifetime, which yielded 44 SNPs for further investigation. In order to validate these initial findings, the second stage involved genotyping these 44 SNPs in a further almost 1000 never smokers from two different study populations. Combining the data from all three study populations strengthened the association observed for two SNPs in complete linkage disequilibrium (rs2352028 and rs2352029) on chromosome 13. Based on the third stage results, just rs2352028 was genotyped in a fourth study population comprising of 530 never smokers, and when all four study populations were combined in a meta-analysis, the association between rs2352028 and lung cancer in never smokers produced an odds ratio of 1.46 (95% CI 1.26-1.70; p=5.94 x 10-6).
In the fourth stage of the study authors investigation, they identified 36 genes surrounding the 44 top SNP results from the first stage, and conducted a gene expression study involving normal lung tissue samples from 70 cases. Only the two replicated SNPs (rs2352028 and rs2352029) showed a strong association with the expression level of a nearby gene (GPC5). Individuals with a high risk allele at rs2352028 had a substantially lower expression of GPC5 than those individuals with the more common allele. When looking at only adenocarcinoma (a clinical subtype of lung cancer) cells, the GPC5 expression levels were half that of normal lung tissue. The authors therefore speculate that the two genetic variants on chromosome 13 (located within intron 5 of the GPC5 gene) might affect regulation of GPC5 expression.
Comment: Very little is known about the molecular genetics of lung cancer in non-smokers. By incorporating both GWAS with validation samples as well as a gene expression study, this study takes an important first step in improving this understanding. However, there are several important limitations to this research. First, as the authors acknowledge, the sample sizes used in their study did not provide enough statistical power to reach genome-wide significance, and so the findings need repeating in larger studies. Second, the authors note that identifying so called “pure” never smokers from multiple study sites in several countries is a very difficult task. Finally, even if the finding is robust, it is currently unclear how it will directly improve the diagnosis or treatment of patients with lung cancer.