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

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.


Contents
Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

Protocol and registration 5
Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
-Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

Section 2.2
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. Section 2.1 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).
a Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.

Study selection 17
Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.  For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. Table 1 Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). Table 2 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).

Summary of evidence 24
Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

Limitations 25
Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

Conclusions 26
Provide a general interpretation of the results in the context of other evidence, and implications for future research.

Funding 27
Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.
a Total NNAL is defined as the total concentration of NNAL and its glucuronides b Total 3-HC is defined as the total concentration of 3-HC and its glucuronides c Total cotinine is defined as the total concentration of cotinine and its glucuronides d Total nicotine is defined as the total concentration of nicotine and its glucuronides e TNE is defined as the sum of the concentration of nicotine, cotinine, 3-HC and their respective glucuronides f Total nicotine metabolite is defined as the total concentration of nicotine, cotinine and all their other pyridylcontaining metabolites g Total OH-Phe is defined as the total concentration of 1-, 2-, 3-and 4-hydroxyphenanthrene
The metabolites are (a) serum/plasma cotinine, (b) serum/plasma folate, (c) urinary creatine riboside, (d) urinary NANA, (e) urinary PheT, (f) urinary total 3-HC, (g) urinary total cotinine, (h) urinary total nicotine, (i) urinary total NNAL and (j) urinary TNE. Refer to Supplementary material List 1 for the name of abbreviated metabolites.   Figure S5. Weighted mean difference (WMD) and 95% confidence interval (CI) of the metabolite concentration between lung cancer patients and healthy controls for metabolites that did not achieve statistical significance.
Data are presented as μmol/L.