Nitric Oxide Metabolites and Lung Cancer Incidence: A Matched Case-Control Study Nested in the ESTHER Cohort.

Axel Benner,Yang Xuan,Xīn Gào,Ben Schöttker,Ankita Anusruti,Hermann Brenner

doi:10.1155/2019/6470950

Abstract

Studies suggest that nitric oxide (NO) may have a possible role in lung carcinogenesis. This study is aimed to evaluate the association of the NO metabolites, namely, nitrite and nitrate, with lung cancer incidence. We conducted a matched case-control study (n = 245 incident lung cancer cases and n = 735 controls) based on the German ESTHER cohort (n = 9,940). Controls were matched to cases on age, sex, smoking status (never/former/current smoking), and pack-years of smoking. The sum of nitrite and nitrate was measured in urine samples using a colorimetric assay and was standardized for renal function by urinary creatinine. Conditional logistic regression models, adjusted for lifestyle factors, asthma prevalence, and family history of lung cancer, were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI). Among incident lung cancer cases, high nitrite/nitrate levels were statistically significantly associated with current smoking, a low BMI, and the oxidative stress biomarker 8-isoprostane levels. Nitrite/nitrate levels in the top quintile were statistically significantly associated with lung cancer incidence: the OR (95% CI) was 1.37 (1.04-1.82) for comparison with the bottom quintile. This association was unaltered after additional adjustment for 8-isoprostane levels and C-reactive protein (CRP). In conclusion, this large cohort study suggested that subjects with high urinary nitrite/nitrate concentrations had an increased risk of lung cancer and this association was independent of smoking, CRP, 8-isoprostane levels, and other established lung cancer risk factors. Further studies are needed to validate these findings and to confirm the hypothesis that pathologically high levels of NO are involved in lung cancer development.

Highlights

Lung cancer is one of the most common causes of cancer death worldwide with a poor prognosis [1, 2]
Nitrite/nitrate levels were higher in study participants who were diagnosed with lung cancer during follow-up than among controls, but the median difference was not statistically significant
It shows that the association is not linear and that a statistically significant association is only present at high nitrite/nitrate concentrations. This is in agreement with the findings from the logistic models, in which only an increased lung cancer risk was found in the highest nitrite/nitrate quintile (≥192.8 μmol/mmol creatinine). In this prospective matched case-control study from Germany, we investigated the determinants of urinary nitrite/nitrate levels and the association between nitrite/nitrate levels and lung cancer incidence

Summary

Introduction

Lung cancer is one of the most common causes of cancer death worldwide with a poor prognosis [1, 2]. Oxidative stress is suggested to mediate chronic inflammation-induced lung cancer development [3]. Inflammatory cells are recruited to the site of inflammation leading to respiratory burst, during which the inflammatory cells produce more reactive oxygen species (ROS). The sustained oxidative environment results in the transformation of normal cells to cancer cells [4, 5]. Smokers have a much higher risk of developing lung cancer than nonsmokers [6]. It has been shown that cigarette smoking leads to oxidative stress and inflammation in an acute cigarette smoking model [7]. Oxidative stress and inflammation might partially mediate the effect of smoking on lung cancer development

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