The Ability of Bilirubin in Identifying Smokers with Higher Risk of Lung Cancer: A Large Cohort Study in Conjunction with Global Metabolomic Profiling

Abstract

Purpose We aimed to identify serum metabolites as potential valuable biomarkers for lung cancer and to improve risk stratification in smokers. Experimental Design We performed global metabolomic profiling followed by targeted validation of individual metabolites in a case-control design of 386 lung cancer cases and 193 matched controls. We then validated bilirubin, which consistently showed significant differential levels in cases and controls, as a risk marker for lung cancer incidence and mortality in a large prospective cohort comprised of 425,660 participants. Results Through global metabolomic profiling and following targeted validation, bilirubin levels consistently showed a statistically significant difference among healthy controls and lung cancer cases. In the prospective cohort, the inverse association was only seen in male smokers, regardless of smoking pack-years and intensity. Compared with male smokers in the highest bilirubin group (>1 mg/dL), those in the lowest bilirubin group (<0.75 mg/dL) had 55% and 66% increase in risks of lung cancer incidence and mortality, respectively. For every 0.1 mg/dL decrease of bilirubin, the risks for lung cancer incidence and mortality increased by 5% and 6% in male smokers, respectively (both P < 0.001). There was a significant interaction between low serum bilirubin level and smoking on lung cancer risk (P for interaction = 0.001). Conclusion Low levels of serum bilirubin are associated with higher risks of lung cancer incidence and mortality in male smokers and can be used to identify higher risk smokers for lung cancer.

Elevated serum bilirubin levels are associated with improved survival in patients with curatively resected non-small-cell lung cancer

“…Several studies have shown the inverse association between smoking and bilirubin levels [6,7,17,18]. In our studies, there were more never smokers in the high-TBIL and high-IBIL groups than the low-TBIL and low-IBIL groups, respectively.…”

“…In recent years, the relationship between serum bilirubin and cancer risk has drawn much interest. The inverse association between bilirubin and cancer risk has been suggested in lung cancer [6,7], breast cancer [8] and colorectal cancer [9]. Elevated bilirubin is also associated with longer survival in nonmetastatic breast cancer [10].…”

HO-1/CO system in tumor growth, angiogenesis and metabolism — Targeting HO-1 as an anti-tumor therapy

“…The inverse association between bilirubin and cancer risk has been observed in lung cancer [18], breast cancer [19] In summary, both BV/BR system and iron chelation by ferritin might be responsible for biological effects exerted by HO-1. In addition, liberated CO, through the activation of several down-stream effectors may mimic the antioxidant, anti-inflammatory, anti-apoptotic…”

DHA May Have a Profoundly Protective Impact on the Lungs of Smokers

“…And in COPD patients, serum bilirubin correlated directly with FEV1, and inversely with rate of FEV1 decline [49]. Another recent prospective study found that, in current smokers, lower bilirubin levels predicted a higher risk of developing and dying from lung cancer [50]. In a large Swiss cohort, serum bilirubin correlated positively with parameters of effective lung function [51].…”