High resolution metabolomics to discriminate compounds in serum of male lung cancer patients in South Korea

Aryo D. Pamungkas, Changyoung Park, Sungyong Lee, Sun Ha Jee, Youngja H. Park

The cancer death rate escalated during 20th century. In South Korea, lung cancer is expected to contribute 12,736 deaths in men, the highest amount among all cancers. Several risk factors may increase the chance to acquiring lung cancer, with mostly related to exogenous compounds found in cigarette smoke and synthetic manufacturing materials. As the mortality rate of lung cancer increases, deeper understanding is necessary to explore risk factors that may lead to this malignancy. In this regard, this study aims to apply high resolution metabolomics (HRM) using LC-MS to detect significant compounds that might contribute in inducing lung cancer and find the correlation of these compounds to the subjects' smoking habit. The comparison was made between healthy control and lung cancer groups for metabolic differences. Further analyses to determine if these differences are related to tobacco-induced lung cancer (past-smoker control vs. past-smoker lung cancer patients (LCPs) and non-smoker control vs. current-smoker LCPs) were selected. The univariate analysis was performed, including a false discovery rate (FDR) of q = 0.05, to determine the significant metabolites between the analyses. Hierarchical clustering analysis (HCA) was done to discriminate metabolites between the control and case subjects. Selected compounds based on significant m/z features of human serum then experienced MS/MS examination, showing that for many m/z, the patterns of ion dissociation matched with standards. Then, the significant metabolites were identified using Metlin database and features were mapped on the human metabolic pathway mapping tool of the Kyoto Encyclopedia of Genes and Genomes (KEGG). Using metabolomics-wide association studies, metabolic changes were observed among control group and lung cancer patients. Bisphenol A (211.11, [M + H-H2O](+)), retinol (287.23, [M + H](+)) and L-proline (116.07, [M + H](+)) were among the significant compounds found to have contributed in the discrimination between these groups, suggesting that these compounds might be related in the development of lung cancer. Retinol has been seen to have a correlation with smoking while both bisphenol A and L-proline were found to be unrelated. Two potential biomarkers, retinol and L-proline, were identified and these findings may create opportunities for the development of new lung cancer diagnostic tools.