Association between Metabolites and the Risk of Lung Cancer: A Systematic Literature Review and Meta-Analysis of Observational Studies

Abstract

Globally, lung cancer is the most prevalent cancer type. However, screening and early detection is challenging. Previous studies have identified metabolites as promising lung cancer biomarkers. This systematic literature review and meta-analysis aimed to identify metabolites associated with lung cancer risk in observational studies. The literature search was performed in PubMed and EMBASE databases, up to 31 December 2019, for observational studies on the association between metabolites and lung cancer risk. Heterogeneity was assessed using the I2 statistic and Cochran’s Q test. Meta-analyses were performed using either a fixed-effects or random-effects model, depending on study heterogeneity. Fifty-three studies with 297 metabolites were included. Most identified metabolites (252 metabolites) were reported in individual studies. Meta-analyses were conducted on 45 metabolites. Five metabolites (cotinine, creatinine riboside, N-acetylneuraminic acid, proline and r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene) and five metabolite groups (total 3-hydroxycotinine, total cotinine, total nicotine, total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (sum of concentrations of the metabolite and its glucuronides), and total nicotine equivalent (sum of total 3-hydroxycotinine, total cotinine and total nicotine)) were associated with higher lung cancer risk, while three others (folate, methionine and tryptophan) were associated with lower lung cancer risk. Significant heterogeneity was detected across most studies. These significant metabolites should be further evaluated as potential biomarkers for lung cancer.

Metabolomic Profiling in Lung Cancer: A Systematic Review

“…It is well known this metabolite is involved in various important activities in cancer cells, such as nucleotide biosynthesis via the one-carbon metabolism pathway and protein synthesis. Relating specifically to lung cancer, several published studies suggested that plasma methionine concentration is decreased [ 45 ].…”

“…NANA is involved in the formation of glycans, which plays several important roles in cells, namely in proteins synthesis, cell signaling and adhesion. Increased NANA levels may be a result of increased turnover and shedding of tumor cells, which in turn results in the release of glycans into the serum [ 45 ].…”

Amanida: an R package for meta-analysis of metabolomics non-integral data

“…To evaluate the package, we selected a metabolomics meta-analysis with data disclosed ( Lee et al , 2020 ) which describes the association of metabolites with lung cancer risk. We could only use the information of amino acids concentration disclosed in six studies to compare both methodologies, as it was the only fully available ( Supplementary Table S2 ).…”

“…Typical protocols for meta-analysis only consider one metric to conduct the analysis, whether statistical significance or relative change. They require raw data [Metaboanalyst’ ( Chong et al , 2018 )] or statistics parameters like standard error, standard deviation or variance [R package ‘meta’ ( Balduzzi et al , 2019 )], rarely disclosed in metabolomics studies ( Lee et al , 2020 ; Tofte et al , 2020 ). This causes that in some cases about half of the studies on systematic reviews are not suitable to be included in the meta-analysis ( Guasch-Ferré et al , 2016 ; Pang et al , 2021 ).…”

Serum Exosomes and Their miRNA Load—A Potential Biomarker of Lung Cancer

“…Another candidate for the biomarker of lung cancer is circulating free DNA (cfDNA) [ 14 ] and circulating tumor cells (CTC) [ 15 ]. More recently, serum metabolites and lipids have emerged as another class of potential biomarkers in lung cancer [ 16 , 17 ]. Several other review papers could be suggested that cover this well-researched field [ 11 , 12 , 13 , 18 , 19 , 20 , 21 ].…”