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. 2024 Aug 15;30(16):3592-3602.
doi: 10.1158/1078-0432.CCR-24-0637.

Urinary Metabolite Diagnostic and Prognostic Liquid Biopsy Biomarkers of Lung Cancer in Nonsmokers and Tobacco Smokers

Bhavik Dalal #  1 , Takeshi Tada #  1 , Daxesh P Patel  1 , Sharon R Pine  2 , Mohammed Khan  1 , Takahiro Oike  1 , Yasuyuki Kanke  1 , Amelia L Parker  1 , Majda Haznadar  1 , Leila Toulabi  1 , Kristopher W Krausz  3 , Ana I Robles  4 , Elise D Bowman  1 , Frank J Gonzalez  3 , Curtis C Harris  1
Affiliations

Urinary Metabolite Diagnostic and Prognostic Liquid Biopsy Biomarkers of Lung Cancer in Nonsmokers and Tobacco Smokers

Bhavik Dalal et al. Clin Cancer Res. .

Abstract

Purpose: Nonsmokers account for 10% to 13% of all lung cancer cases in the United States. Etiology is attributed to multiple risk factors including exposure to secondhand smoking, asbestos, environmental pollution, and radon, but these exposures are not within the current eligibility criteria for early lung cancer screening by low-dose CT (LDCT).

Experimental design: Urine samples were collected from two independent cohorts comprising 846 participants (exploratory cohort) and 505 participants (validation cohort). The cancer urinary biomarkers, creatine riboside (CR) and N-acetylneuraminic acid (NANA), were analyzed and quantified using liquid chromatography-mass spectrometry to determine if nonsmoker cases can be distinguished from sex and age-matched controls in comparison with tobacco smoker cases and controls, potentially leading to more precise eligibility criteria for LDCT screening.

Results: Urinary levels of CR and NANA were significantly higher and comparable in nonsmokers and tobacco smoker cases than population controls in both cohorts. Receiver operating characteristic analysis for combined CR and NANA levels in nonsmokers of the exploratory cohort resulted in better predictive performance with the AUC of 0.94, whereas the validation cohort nonsmokers had an AUC of 0.80. Kaplan-Meier survival curves showed that high levels of CR and NANA were associated with increased cancer-specific death in nonsmokers as well as tobacco smoker cases in both cohorts.

Conclusions: Measuring CR and NANA in urine liquid biopsies could identify nonsmokers at high risk for lung cancer as candidates for LDCT screening and warrant prospective studies of these biomarkers.

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Conflict of interest statement

No disclosures were reported.

Figures

Figure 1.
Figure 1.
Box plots showing the distribution of CR and NANA urinary metabolite levels in the (A) exploratory cohort and (B) validation cohort were quantitatively measured by UPLC–MS/MS in the study participants. Kruskal–Wallis ANOVA; posthoc multiple comparisons, ****P < 0.0001; **P < 0.01. LCC, lung cancer cases; x͂ = median.
Figure 2.
Figure 2.
Distribution of CR and NANA metabolite levels in former and current smoker cases. Violin plots were used to depict the summary statistics and the density of each variable in different groups within the (A) exploratory cohort and (B) validation cohort. ****P < 0.0001; ***P < 0.001; **P < 0.01; ns, not significant; x͂ = median.
Figure 3.
Figure 3.
K–M plots of the overall survival of lung cancer cases stratified by the median cutoff value of CR and NANA for nonsmokers in the (A) exploratory cohort and (B) validation cohort.
Figure 4.
Figure 4.
ROC curves represent the accuracy of metabolite CR, NANA, and the combination with AUC for smoking status in both cohorts: (A) nonsmokers and (B) smokers. PC, population controls.
See this image and copyright information in PMC

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