Urinary Metabolite Risk Biomarkers of Lung Cancer: A Prospective Cohort Study

Abstract

Background: Lung cancer is a major health burden causing 160,000 and 1.6 million deaths annually in the United States and worldwide, respectively.

Methods: While seeking to identify stable and reproducible biomarkers in noninvasively collected biofluids, we assessed whether previously identified metabolite urinary lung cancer biomarkers, creatine riboside (CR), N-acetylneuraminic acid (NANA), cortisol sulfate, and indeterminate metabolite 561+, were elevated in the urines of subjects prior to lung cancer diagnosis in a well-characterized prospective Southern Community Cohort Study (SCCS). Urine was examined from 178 patients and 351 nondiseased controls, confirming that one of four metabolites was associated with lung cancer risk in the overall case-control set, whereas two metabolites were associated with lung cancer risk in European-Americans.

Results: OR of lung cancer associated with elevated CR levels, and adjusted for smoking and other potential confounders, was 2.0 [95% confidence interval (CI), 1.2-3.4; P= 0.01]. In European-Americans, both CR and NANA were significantly associated with lung cancer risk (OR = 5.3; 95% CI, 1.6-17.6; P= 0.006 and OR=3.5; 95% CI, 1.5-8.4; P= 0.004, respectively). However, race itself did not significantly modify the associations. ROC analysis showed that adding CR and NANA to a model containing previously established lung cancer risk factors led to a significantly improved classifier (P= 0.01). Increasing urinary levels of CR and NANA displayed a positive association with increasing tumor size, strengthening a previously established link to altered tumor metabolism.

Conclusion and impact: These replicated results provide evidence that identified urinary metabolite biomarkers have a potential utility as noninvasive, clinical screening tools for early diagnosis of lung cancer. Cancer Epidemiol Biomarkers Prev; 25(6); 978-86. ©2016 AACR.

Figure 1

Receiver Operating Characteristic (ROC) analysis of selected demographic, smoking and behavioral characteristics associated with lung cancer risk, CR, NANA, and combinations thereof in A) all subjects, and B) European Americans. CR: creatine riboside; NANA: N-acetylneuraminic acid; PPV: Positive Predictive Value; NPV: Negative Predictive Value; risk factors model comprises: age (age at enrollment), education (achieved level of education), income (household income), smoking (smoking status (current-, former-, never-smoker)), pack-years (amount smoked indicated by pack-years), BMI (body mass index), COPD (history of chronic obstructive pulmonary disease), family history of lung cancer.

Figure 2

Mean levels of A) creatine riboside and B) NANA in SCCS lung cancer cases across tumor size strata.