Lung Cancer Susceptibility Model Based on Age, Family History and Genetic Variants

Young, Robert P.; Hopkins, Robert E.; Hay, Bryan A.; Epton, Michael; Mills, Graham; Black, Peter; Gardner, H; Sullivan, Richard; Gamble, Gregory D.

doi:10.1371/journal.pone.0005302

Cited by 47 publications

(59 citation statements)

References 47 publications

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“…Genetic variation may confer important effects on the expression of these effector molecules (e.g. CRP, IL-6 and IL-8) that then mediate the downstream effects on COPD [60] and lung cancer [45,61,62]. The heavy oxidant load derived from smoking has effects both locally in lung parenchyma and systemically on muscle function.…”

Section: Copd and Systemic Inflammationmentioning

confidence: 99%

Pharmacological actions of statins: potential utility in COPD

Young

Hopkins²,

Eaton³

2009

European Respiratory Review

122

182

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Chronic obstructive pulmonary disease (COPD) is characterised by minimally reversible airflow limitation and features of systemic inflammation. Current therapies for COPD have been shown to reduce symptoms and infective exacerbations and to improve quality of life. However, these drugs have little effect on the natural history of the disease (progressive decline in lung function and exercise tolerance) and do not improve mortality. The anti-inflammatory effects of statins on both pulmonary and systemic inflammation through inhibition of guanosine triphosphatase and nuclear factor-kB mediated activation of inflammatory and matrix remodelling pathways could have substantial benefits in patients with COPD due to the following. 1) Inhibition of cytokine production (tumour necrosis factor-a, interleukin (IL)-6 and IL-8) and neutrophil infiltration into the lung; 2) inhibition of the fibrotic activity in the lung leading to small airways fibrosis and irreversible airflow limitation; 3) antioxidant and anti-inflammatory (IL-6 mediated) effects on skeletal muscle; 4) reduced inflammatory response to pulmonary infection; and 5) inhibition of the development (or reversal) of epithelial-mesenchymal transition, a precursor event to lung cancer. This review examines the pleiotropic pharmacological action of statins which inhibit key inflammatory and remodelling pathways in COPD and concludes that statins have considerable potential as adjunct therapy in COPD.

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Section: Copd and Systemic Inflammationmentioning

confidence: 99%

Pharmacological actions of statins: potential utility in COPD

Young

Hopkins²,

Eaton³

2009

European Respiratory Review

122

182

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show abstract

“…The heritability of COPD and lung cancer is estimated to be 40-77% and 15-25%, respectively [11,12]. These findings suggest some smokers susceptible to COPD might also be susceptible to lung cancer and that some of the genetic factors conferring this dual susceptibility might overlap [13][14][15]. Recent interest in lung cancer has focused on the role of smoking in epithelial-mesenchymal transition (EMT) [16], a process driven by release of growth factors and matrix metalloproteinases during lung remodelling and repair [17,18].…”

mentioning

confidence: 99%

Chromosome 4q31 locus in COPD is also associated with lung cancer

Young

Whittington²,

Hopkins³

et al. 2010

European Respiratory Journal

108

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Chronic obstructive pulmonary disease (COPD) is the single greatest risk factor for lung cancer in smokers and is found in 50-90% of lung cancer cases. The link between COPD and lung cancer may stem in part from the matrix remodelling and repair processes underlying COPD, and the development of epithelial-mesenchymal transition (EMT) that underlies lung carcinogenesis. The Hedgehog-interacting protein (HHIP), which mediates the epithelial response (EMT) to smoking, has been implicated in COPD and lung cancer. Recent genomewide and candidate gene studies of COPD implicate genetic variants on the chromosomal 4q31 (HHIP/glycophorin A (GYPA)) locus.In a case-control study of smokers with normal lung function, COPD and lung cancer (subphenotyped for COPD), we show the GG genotype of the rs 1489759 HHIP single-nucleotide polymorphism (SNP) and the CC genotype of the rs 2202507 GYPA SNP confers a ''protective'' effect on COPD (OR 0.59, p50.006 for HHIP and OR50.65, p50.006 for GYPA) and lung cancer (OR50.70 (p50.05) for HHIP and OR 0.70 (p50.02) for GYPA).This study suggests that, in smokers, genetic variants of the 4q31 locus conferring a protective effect for COPD are also protective in lung cancer. We conclude that genetic susceptibility to lung cancer includes COPD-related gene variants.

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“…This expansion of risk factors in predictive risk models beyond the traditional epidemiologic data has been elegantly pursued in cardiovascular diseases, wherein biological assay data and some genetic variants had been added into risk score models for prediction of absolute risk of cardiovascular disease (15,16). Similar efforts in cancer studies include addition of mammographic density data to the Gail model for breast cancer (17), inclusion of assay data for DNA repair capacity and mutagen sensitivity into the Spitz lung cancer risk models for former and current smokers (18), and recent combination of a panel of low-risk SNPs with demographic data to form a simple algorithm for lung cancer risk prediction (7).…”

Section: Discussionmentioning

confidence: 99%

“…Within the Liverpool Lung Project (LLP), we have previously developed and validated a predictive model for 5-year absolute risk of developing lung cancer for an individual with a specific combination of epidemiologic risk factors including smoking duration, previous diagnosis of pneumonia, prior diagnosis of malignant tumor, occupational exposure to asbestos, and family history of lung cancer (4). Recent advancement in genetic epidemiology leading to identification of genetic and molecular variants affecting the risk of disease means that genetic markers such as single-nucleotide polymorphisms (SNP) can be added to risk models for improved prediction of future risk of disease (5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Incorporation of a Genetic Factor into an Epidemiologic Model for Prediction of Individual Risk of Lung Cancer: The Liverpool Lung Project

Raji

Agbaje

Duffy

et al. 2010

Cancer Prevention Research

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The Liverpool Lung Project (LLP) has previously developed a risk model for prediction of 5-year absolute risk of lung cancer based on five epidemiologic risk factors. SEZ6L, a Met430IIe polymorphic variant found on 22q12.2 region, has been previously linked with an increased risk of lung cancer in a case-control population. In this article, we quantify the improvement in risk prediction with addition of SEZ6L to the LLP risk model. Data from 388 LLP subjects genotyped for SEZ6L single-nucleotide polymorphism (SNP) were combined with epidemiologic risk factors. Multivariable conditional logistic regression was used to predict 5-year absolute risk of lung cancer with and without this SNP. The improvement in the model associated with the SEZ6L SNP was assessed through pairwise comparison of the area under the receiver operating characteristic curve and the net reclassification improvements (NRI). The extended model showed better calibration compared with the baseline model. There was a statistically significant modest increase in the area under the receiver operating characteristic curve when SEZ6L was added into the baseline model. The NRI also revealed a statistically significant improvement of around 12% for the extended model; this improvement was better for subjects classified into the two intermediate-risk categories by the baseline model (NRI, 27%). Our results suggest that the addition of SEZ6L improved the performance of the LLP risk model, particularly for subjects whose initial absolute risks were unable to discriminate into "low-risk" or "high-risk" group. This work shows an approach to incorporate genetic biomarkers in risk models for predicting an individual's lung cancer risk.

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Lung Cancer Susceptibility Model Based on Age, Family History and Genetic Variants

Cited by 47 publications

References 47 publications

Pharmacological actions of statins: potential utility in COPD

Pharmacological actions of statins: potential utility in COPD

Chromosome 4q31 locus in COPD is also associated with lung cancer

Incorporation of a Genetic Factor into an Epidemiologic Model for Prediction of Individual Risk of Lung Cancer: The Liverpool Lung Project

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