Elsevier

The Lancet Oncology

Volume 11, Issue 4, April 2010, Pages 321-330
The Lancet Oncology

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Genetic variants and risk of lung cancer in never smokers: a genome-wide association study

https://doi.org/10.1016/S1470-2045(10)70042-5Get rights and content

Summary

Background

Lung cancer in individuals who have never smoked tobacco products is an increasing medical and public-health issue. We aimed to unravel the genetic basis of lung cancer in never smokers.

Methods

We did a four-stage investigation. First, a genome-wide association study of single nucleotide polymorphisms (SNPs) was done with 754 never smokers (377 matched case-control pairs at Mayo Clinic, Rochester, MN, USA). Second, the top candidate SNPs from the first study were validated in two independent studies among 735 (MD Anderson Cancer Center, Houston, TX, USA) and 253 (Harvard University, Boston, MA, USA) never smokers. Third, further replication of the top SNP was done in 530 never smokers (UCLA, Los Angeles, CA, USA). Fourth, expression quantitative trait loci (eQTL) and gene-expression differences were analysed to further elucidate the causal relation between the validated SNPs and the risk of lung cancer in never smokers.

Findings

44 top candidate SNPs were identified that might alter the risk of lung cancer in never smokers. rs2352028 at chromosome 13q31.3 was subsequently replicated with an additive genetic model in the four independent studies, with a combined odds ratio of 1·46 (95% CI 1·26–1·70, p=5·94×10−6). A cis eQTL analysis showed there was a strong correlation between genotypes of the replicated SNPs and the transcription level of the gene GPC5 in normal lung tissues (p=1·96×10−4), with the high-risk allele linked with lower expression. Additionally, the transcription level of GPC5 in normal lung tissue was twice that detected in matched lung adenocarcinoma tissue (p=6·75×10−11).

Interpretation

Genetic variants at 13q31.3 alter the expression of GPC5, and are associated with susceptibility to lung cancer in never smokers. Downregulation of GPC5 might contribute to the development of lung cancer in never smokers.

Funding

US National Institutes of Health; Mayo Foundation.

Introduction

Tobacco smoking remains the principal cause of lung cancer. However, 15% of men and 53% of women (25% of all cases worldwide) who develop lung cancer do so without any history of having smoked tobacco products (never smokers).1 In Europe and North America, about 10–15% of lung cancers occur in never smokers. By contrast, about 30–40% of lung cancers occur in never smokers in Asian countries.2 Many studies have shown that the aetiology, clinical characteristics, and prognosis of lung cancer in never smokers are substantially different to those in smokers, and lung cancer in never smokers is increasingly recognised as a distinct disease entity.3, 4 Although the causes of lung cancer in never smokers are poorly understood, one of the established risk factors in European and North American countries is exposure to second-hand smoking.5 Other—though inconsistently reported—risk factors include environmental factors, hormones, and viral infections.3, 4 Individual susceptibility to lung cancer has been studied in an attempt to identify and characterise both inherited genetic and acquired somatic changes.6, 7 However, the specific genetic mechanisms that increase the risk of lung cancer remain to be elucidated.

Recently, genome-wide association studies have identified several candidate genes and genomic loci that have a moderate effect on the risk of lung cancer. Current candidates include nicotinic acetylcholine receptor subunit genes, 5p15.33, 15q25.1, and 6p21.33, with estimated odds ratios ranging from 1·14 to 1·32.8, 9, 10, 11 A recent study also indentified RGS17 on 6q23–25 as a gene associated with familial lung cancer.12 To date, no genome-wide association studies have been done with never smokers alone, and the top candidate single nucleotide polymorphisms (SNPs) from previous genome-wide association studies have not been consistently replicated in never smokers.13, 14 To identify genetic loci and candidate genes that increase the risk of lung cancer in never smokers, we did a genome-wide association study in never smokers with lung cancer and matched controls.

Section snippets

Patients

Never smokers were defined as individuals who had smoked less than 100 cigarettes during their lifetime. Written informed consent was obtained from all participants at each of the participating institutions. Research protocols were approved by the institutional review boards of Mayo Clinic (Rochester, MN, USA), MD Anderson Cancer Center (MDACC) and Kelsey-Seybold Clinic (Houston, TX, USA), Harvard School of Public Health and Massachusetts General Hospital (Boston, MA, USA), and University of

Results

We did a four-stage study to systematically investigate common genetic variations associated with the risk of lung cancer in never smokers (figure 1). In the first stage (the Mayo genome-wide association study), we analysed 331 918 SNPs in 377 case-control pairs matched according to age, sex, and ethnic origin (webappendix p 2). The strongest association was detected at two intergenic SNPs on chromosome 12, rs11183940 (p=1·5×10−6) and rs10880785 (p=7·1×10−6; figure 2A). To validate the initial

Discussion

From the first stage of our genome-wide association study searching for common genetic variations responsible for increasing the risk of lung cancer in never smokers, we identified 44 candidate SNPs. Two of these candidate SNPs, rs2352028 and rs2352029, were replicated in stage 2 of our study. These two SNPs are in complete linkage disequilibrium (r2=1) and located at intron 5 of GPC5. rs2352028 was further replicated in stage 3. Subsequent functional analyses, eQTL, and analysis of

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    *

    These authors contributed equally to this work.

    These authors jointly directed the project.

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