The search strategy selected articles from Medline by searches of PubMed. Articles published within the past 10 years were considered for review. The search terms were “never smokers”, “non smokers” “lung cancer”, “NSCLC” cross-referenced with “genomics”, “genetic profile”, “genetic polymorphism”, “molecular biology”, “EGFR”, “erlotinib”, and “gefitinib”. Only papers with abstracts in English were included. Relevant papers cited in articles from the original search results were also
ReviewMolecular genetics of lung cancer in people who have never smoked
Introduction
Lung cancer is a major cause of mortality, having caused 162 460 deaths in the USA in 2006.1 Tobacco smoking alone accounts for 85–90% of all lung-cancer deaths in the USA,2 but about 15 000 people who have never smoked (never smokers) die from lung cancer each year.3 Retrospective epidemiological studies have reported significant variation between lung cancer in never smokers and tobacco-associated lung cancer in terms of presentation and overall survival.4, 5, 6, 7 Most patients with lung cancer who have never smoked are women, and adenocarcinoma is the most common type (figure 1).8, 9 Patients with non-small-cell lung cancer (NSCLC) who have never smoked have a better response to inhibitors of epidermal-growth-factor receptor (EGFR) tyrosine kinase, such as gefitinib and erlotinib, than do those with a history of tobacco smoking.10, 11, 12, 13, 14, 15 Studies have identified differences in chromosomal aberrations, genetic polymorphisms, gene mutations, and methylation status between lung cancer in never smokers and tobacco-associated lung cancer. These clinical and biological differences suggest that the two cancers have overlapping but unique pathways of carcinogenesis.16 We summarise the current knowledge on the unique features of the molecular biology of lung cancer in people who never smoke (figure 2).
Section snippets
Expression profiling
Several microarray studies have been published on global expression profiling and outcomes in patients with NSCLC.17, 18, 19 Tumour genetic expression profiling reliably recapitulates histological classification of NSCLC—adenocarcinoma, squamous cell carcinoma, and large-cell carcinoma.17, 18, 19 In addition, expression studies have identified subclasses within each of these; adenocarcinoma is the most diverse, with two to four subclasses.
In a recent expression profiling analysis of 149
Chromosomal aberrations
Studies have reported significant differences in genome-wide chromosomal aberrations between tobacco-associated lung cancer and lung cancer in never smokers. A matched cohort of 18 never smokers and 27 smokers with adenocarcinoma were examined for chromosomal aberrations using 54 microsatellite markers located on 28 different chromosomal arms.24 The median fractional allelic loss (the number of chromosomal arms showing loss of heterozygosity divided by the total informative chromosomal arms)
P53 mutations
40–60% of NSCLC tumours are associated with mutations of the tumour suppressor gene P53.28 Available evidence indicates that these mutations are more common in tobacco-associated lung cancer than in lung cancer in never smokers. There seems to be a significant dose–response relation between tobacco smoke and P53 mutations in NSCLC.29 In 30 resected samples, the odds of having P53 mutations in patients smoking 20 cigarettes per day for 30 years compared with never smokers with NSCLC was 5·3.
EGFR mutation
Mutations in EGFR tyrosine kinase in NSCLC can cause oncogenic transformation and lead to sensitivity to inhibitors of the enzyme.39, 40, 41
EGFR mutations are much more common in people who have never smoked than in patients who have. In a review of published studies 45% of never smokers had EGFR mutations compared with 7% those with tobacco-associated lung cancer.42 The high incidence of EGFR mutations in never smokers with lung cancer has been a consistent finding across different ethnic and
Methylation
Aberrant methylation causes transcriptional inactivation by methylation of the CpG islands in the promoter sequence. Methylation of several tumour suppressor genes including CDKN2A, DAPK1, RASSF1A, RARβ, APC, CDH13, MGMT, MLH1, MSH2, and GSTP1 leading to epigenetic silencing has been reported in lung cancer.57, 58 Studies have reported that methylation of CDKN2A is less common in lung cancer in people who have never smoked than in comparison to tobacco-associated lung cancer.59, 60, 61, 62, 63
Clinical significance and therapy
Lung cancer in people who have never smoked has gained significant attention with the introduction of the inhibitors of EGFR tyrosine kinase gefitinib and erlotinib in the treatment of NSCLC. Gefitinib was assessed in previously treated patients with advanced NSCLC in the randomised, multi-institutional phase II studies IDEAL 1 and 2 (iressa dose evaluation in advanced lung cancer).66, 67 The response rate was between 9% and 19% and the drug was well tolerated. In the phase III ISEL (iressa
Conclusion
Several epidemiological studies have identified lung cancer in people who have never smoked as a distinct entity from tobacco-associated lung cancer. These findings have been further confirmed by molecular genetics, which has identified unique differences in P53, methylation index, EGFR and KRAS mutations. The EGFR mutation is the most important genetic change in lung cancer in people who have never smoked because it is more common in lung cancer in never smokers than in tobacco-associated lung
Search strategy and selection criteria
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