Abstract LB-27: Metabolomic profiling identifies bilirubin as a novel serum marker for lung cancer.
Authors: Zhang Fanmao , Wen Chi Pang , Liang Dong , Skinner Heath , Gu Jian , Chow Wong-Ho , Ye Yuanqing , Hildebrandt Michelle A.T. , Pu Xia , Huang Maosheng , Tsai Min Kuang , Tsao Chwen Keng , Wu Xifeng 
Published: August 2014

Abstract
Background. Lung cancer is the leading cause of cancer death in the United States. Cost-effective screening and early detection is essential for reducing lung cancer mortality. Serum metabolites are emerging as promising biomarkers for improving risk prediction and early detection of lung cancer.
Methods. In the discovery phase, we performed global, unbiased metabolomic profiling in serum samples from 20 healthy controls, 20 early stage, and 20 late stage lung cancer patients who were matched on age and gender. We then selected three differentially expressed metabolites for validation in two additional case control populations, followed by final validation of one metabolite in a large Taiwanese prospective cohort of 435,985 individuals.
Results. A total of 403 named metabolites were identified by metabolomic profiling in the discovery phase, with 306 metabolites remaining after initial quality assurance. Of these, 29 metabolites exhibited a significant trend when comparing normal controls, early stage and late stage lung cancer cases. Three of the top differentially expressed metabolites, gamma-glutamylalanine, bilirubin and allantoin, were selected and validated in two additional sets of subjects, one set comprised of 50 controls, 50 early stage and 50 late stage lung cancer cases, and the second comprised of 123 controls, 123 early stage and 123 late stage lung cancer cases. The most promising metabolite, bilirubin was further validated in a large prospective cohort. In this cohort, the incidence rate of lung cancer per 10,000 person-years in men was 3.73 (95% confidence interval [CI], 3.13-4.43) in the highest quartile of bilirubin level compared to 7.02 (95% CI, 6.16-7.99) in the lowest quartile, which translates into a 38% increase in lung cancer incidence for the low bilirubin group (P=0.003). The corresponding lung cancer specific mortality rate in men was 2.46 (95% CI, 2.02-3.00) in the highest quartile compared to 4.84 (95% CI, 4.19-5.60) in the lowest quartile, a 53% increase in lung cancer specific mortality for the low bilirubin group (P&lt;0.001). Finally, we found that the inverse relationship between serum bilirubin and lung cancer was only significant in ever-smokers but not never-smokers and there was a significant joint effect between bilirubin level and smoking status on both lung cancer incidence and mortality, indicating the importance of bilirubin in ever-smokers independent of smoking.
Conclusions. Smokers with low bilirubin levels had significantly increased risks for both lung cancer incidence and mortality. Serum bilirubin is a valuable biomarker for lung cancer risk prediction in ever-smokers.
Citation Format: Fanmao Zhang, Chi Pang Wen, Dong Liang, Heath Skinner, Jian Gu, Wong-Ho Chow, Yuanqing Ye, Michelle A.T. Hildebrandt, Xia Pu, Maosheng Huang, Min Kuang Tsai, Chwen Keng Tsao, Xifeng Wu. Metabolomic profiling identifies bilirubin as a novel serum marker for lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-27. doi:10.1158/1538-7445.AM2013-LB-27