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Clinical applications of gene-based risk prediction for lung cancer and the central role of chronic obstructive pulmonary disease.

Young RP, Hopkins RJ, Gamble GD - Front Genet (2012)

Bottom Line: It has also been shown that COPD predates lung cancer in 65-70% of cases, conferring a four- to sixfold greater risk of lung cancer compared to smokers with normal lung function.Using this approach, we found that gene-based risk testing helped engage smokers in risk mitigating activities like quitting smoking and undertaking lung cancer screening.We suggest that such an approach could facilitate the targeted selection of smokers for cost-effective life-saving interventions.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medical and Health Sciences, and Biological Sciences, University of Auckland Auckland, New Zealand.

ABSTRACT
Lung cancer is the leading cause of cancer death worldwide and nearly 90% of cases are attributable to smoking. Quitting smoking and early diagnosis of lung cancer, through computed tomographic screening, are the only ways to reduce mortality from lung cancer. Recent epidemiological studies show that risk prediction for lung cancer is optimized by using multivariate risk models that include age, smoking exposure, history of chronic obstructive pulmonary disease (COPD), family history of lung cancer, and body mass index. It has also been shown that COPD predates lung cancer in 65-70% of cases, conferring a four- to sixfold greater risk of lung cancer compared to smokers with normal lung function. Genome-wide association studies of smokers have identified a number of genetic variants associated with COPD or lung cancer. In a case-control study, where smokers with normal lungs were compared to smokers who had spirometry-defined COPD or histology confirmed lung cancer, several of these variants were shown to overlap, conferring the same susceptibility or protective effects on both COPD and lung cancer (independent of COPD status). In this perspective article, we show how combining clinical data with genetic variants can help identify heavy smokers at the greatest risk of lung cancer. Using this approach, we found that gene-based risk testing helped engage smokers in risk mitigating activities like quitting smoking and undertaking lung cancer screening. We suggest that such an approach could facilitate the targeted selection of smokers for cost-effective life-saving interventions.

No MeSH data available.


Related in: MedlinePlus

Trimodal distribution of predicted FEV1 in current and former smokers with heavy smoke exposure defining “susceptible” and “resistant” smokers (modified from Burrows et al., 1977).
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Figure 1: Trimodal distribution of predicted FEV1 in current and former smokers with heavy smoke exposure defining “susceptible” and “resistant” smokers (modified from Burrows et al., 1977).

Mentions: Chronic obstructive pulmonary disease (COPD) is characterized by fixed airflow obstruction, measured by spirometry as a reduced forced expiratory volume in 1 s (FEV1; Mannino et al., 2006). Based on both cross-sectional and prospective studies, it is estimated that 20–30% of smokers develop significant COPD while the remainder maintain near normal lung function (Løkke et al., 2006; Mannino et al., 2006; Kohansal et al., 2009). When smokers are stratified by smoking exposure dose, the distribution of %predicted FEV1 shifts from unimodal in light smokers to a trimodal distribution in heavy smokers (Figure 1; Young et al., 2007). This shift to trimodal distribution, following chronic smoke exposure, defines susceptible smokers with COPD and healthy smokers who are resistant to the effects of smoking. This observation shows that after three to four decades of heavy smoking exposure, a differential response to smoking can be observed that is independent of smoking exposure dose (Young et al., 2007). Such a discordant response to smoking exposure is consistent with a “pharmacogenetic effect” where variation in genetic makeup determines a person’s response to smoking exposure (i.e., drug exposure). These observations argue strongly in favor of a significant gene-by-environment effect whereby COPD occurs in smokers who are genetically susceptible and heavily exposed to decades of smoking (Molfino, 2004; Young and Hopkins, 2011d). Such an observation is unique in common complex diseases by defining two distinct phenotypes – susceptible (responder) phenotype (smokers with COPD) and resistant (non-responder) phenotype (smokers with normal lung function; Young et al., 2007).


Clinical applications of gene-based risk prediction for lung cancer and the central role of chronic obstructive pulmonary disease.

Young RP, Hopkins RJ, Gamble GD - Front Genet (2012)

Trimodal distribution of predicted FEV1 in current and former smokers with heavy smoke exposure defining “susceptible” and “resistant” smokers (modified from Burrows et al., 1977).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472507&req=5

Figure 1: Trimodal distribution of predicted FEV1 in current and former smokers with heavy smoke exposure defining “susceptible” and “resistant” smokers (modified from Burrows et al., 1977).
Mentions: Chronic obstructive pulmonary disease (COPD) is characterized by fixed airflow obstruction, measured by spirometry as a reduced forced expiratory volume in 1 s (FEV1; Mannino et al., 2006). Based on both cross-sectional and prospective studies, it is estimated that 20–30% of smokers develop significant COPD while the remainder maintain near normal lung function (Løkke et al., 2006; Mannino et al., 2006; Kohansal et al., 2009). When smokers are stratified by smoking exposure dose, the distribution of %predicted FEV1 shifts from unimodal in light smokers to a trimodal distribution in heavy smokers (Figure 1; Young et al., 2007). This shift to trimodal distribution, following chronic smoke exposure, defines susceptible smokers with COPD and healthy smokers who are resistant to the effects of smoking. This observation shows that after three to four decades of heavy smoking exposure, a differential response to smoking can be observed that is independent of smoking exposure dose (Young et al., 2007). Such a discordant response to smoking exposure is consistent with a “pharmacogenetic effect” where variation in genetic makeup determines a person’s response to smoking exposure (i.e., drug exposure). These observations argue strongly in favor of a significant gene-by-environment effect whereby COPD occurs in smokers who are genetically susceptible and heavily exposed to decades of smoking (Molfino, 2004; Young and Hopkins, 2011d). Such an observation is unique in common complex diseases by defining two distinct phenotypes – susceptible (responder) phenotype (smokers with COPD) and resistant (non-responder) phenotype (smokers with normal lung function; Young et al., 2007).

Bottom Line: It has also been shown that COPD predates lung cancer in 65-70% of cases, conferring a four- to sixfold greater risk of lung cancer compared to smokers with normal lung function.Using this approach, we found that gene-based risk testing helped engage smokers in risk mitigating activities like quitting smoking and undertaking lung cancer screening.We suggest that such an approach could facilitate the targeted selection of smokers for cost-effective life-saving interventions.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medical and Health Sciences, and Biological Sciences, University of Auckland Auckland, New Zealand.

ABSTRACT
Lung cancer is the leading cause of cancer death worldwide and nearly 90% of cases are attributable to smoking. Quitting smoking and early diagnosis of lung cancer, through computed tomographic screening, are the only ways to reduce mortality from lung cancer. Recent epidemiological studies show that risk prediction for lung cancer is optimized by using multivariate risk models that include age, smoking exposure, history of chronic obstructive pulmonary disease (COPD), family history of lung cancer, and body mass index. It has also been shown that COPD predates lung cancer in 65-70% of cases, conferring a four- to sixfold greater risk of lung cancer compared to smokers with normal lung function. Genome-wide association studies of smokers have identified a number of genetic variants associated with COPD or lung cancer. In a case-control study, where smokers with normal lungs were compared to smokers who had spirometry-defined COPD or histology confirmed lung cancer, several of these variants were shown to overlap, conferring the same susceptibility or protective effects on both COPD and lung cancer (independent of COPD status). In this perspective article, we show how combining clinical data with genetic variants can help identify heavy smokers at the greatest risk of lung cancer. Using this approach, we found that gene-based risk testing helped engage smokers in risk mitigating activities like quitting smoking and undertaking lung cancer screening. We suggest that such an approach could facilitate the targeted selection of smokers for cost-effective life-saving interventions.

No MeSH data available.


Related in: MedlinePlus