Biobank Study Of Functional Lung Impairment And Lung Cancer Risk

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Globally, cancer of the lung is the most common cause of cancer related mortality. It is also the most commonly diagnosed. Tobacco smoke is a well-known risk factor for the development of lung cancer. Smoking leads to lung impairment and conditions such as chronic obstructive pulmonary disease (COPD), also increase the risk of developing lung cancer.

It was, however, unknown whether lung function impairment itself was an independent risk factor for lung cancer due to confounding factors. A large international study with joint senior authors John S. Witte, PhD, and Rayjean J. Hung, PhD, of the Department of Epidemiology & Biostatistics, University of California San Francisco, and Sinai Health System, Toronto, respectively, investigated this possibility. Their study was published in the journal Nature Communications.

Two cohorts were used the UK Biobank and the International Lung Cancer Consortium OncoArray lung cancer dataset. Laval biobank was also used for eQTL analysis. The UK Biobank data was used to generate genetic signatures of lung impairment and these signatures were applied to the OncoArray dataset using Mendelian randomization to determine the causal relevance of impaired pulmonary function.

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In the UK Biobank study lung function was assessed by spirometry. Hung and colleagues used forced expiratory volume in 1s (FEV1), forced vital capacity (FVC), and the FEV1/FVC ratio to determine the genetic signature of pulmonary function. Lung function associations have been made previously, however the present study discovered an additional 73 independent variants not previously reported.

Using Mendelian randomization, a genetically predicted decrease in FEV1 was significantly associated with an increased risk of lung cancer overall. A genetically predicted 10% decrease in FEV1/FVC was associated with increased risk of lung cancer in some models, but not others. A 10% reduction in FEV1/FVC was associated with a 61% increased risk of lung cancer in those that had never smoked. As expected FEV1/FVC < 0.70 also associated with COPD.

Using Laval Biobank lung tissue gene expression data SECISBP2L, HLA-L, DISP2, MAPT, KANSL1-AS1, LRRC37A4P, and PLEKHM1 lung function genes were associated with lung cancer risk. In those that never smoked FEV1/FVC associated pathways were involved in adaptive immunity and cytokine signaling. Top-ranking pathways included translocation of ZAP-70 to immunological synapse, phosphorylation of CD3 and TCR zeta chains, and PD-1 signaling.

Limitations of the study include low participation in UK Biobank spirometry, only 5.5%, may have resulted in a selection bias, in that those with poor lung function were less inclined to participate. The rate of lung function deterioration may be important for cancer risk, but this was not assessed.

“We hypothesize that the effects of pulmonary obstruction are mediated by chronic inflammation and immune response, which is supported by the over-representation of adaptive immunity and cytokine signaling pathways and pQTL effects among FEV1 and FEV1/FVC instruments,” stated the authors