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

Department of Medicine, Auckland Hospital, Auckland, New Zealand.
PLoS ONE (Impact Factor: 3.23). 02/2011; 6(2):e16476. DOI: 10.1371/journal.pone.0016476
Source: PubMed


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 FEV(1), appears to confer susceptibility to both COPD and lung cancer. The 6p21 locus previously linked to reduced FEV(1) 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.

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Available from: Robert P Young
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    • "Results from recent GWAS suggest a possible overlap in the genetic risk factors predisposing smokers to lung cancer and COPD. Several regions in the genome associated with lung cancer and/or COPD have been identified, including chromosome 1q21, 4q22, 4q24, 4q31, 5p15, 5q32, 6p21, 6q24, 15q25 and19q13 [9,10,41-49]. Several important genes mapping to those regions have also been identified as significant players in the pathogenesis of lung cancer and/or COPD (Table 1), and many of these loci overlap. "
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    • "The frequency of this disease allele was only slightly increased in those with lung cancer alone (but not significant). We have gone on to show something very similar for three other GWA genes recently implicated in COPD that are also relevant to lung cancer (Young et al., 2010b,2011c,d). Interestingly, all of the overlapping genes implicated by the GWA studies encode proteins known to be expressed by lung epithelium and involved in various inflammatory pathways (Young and Hopkins, 2011a). "
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