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Published on: November 27, 2016
Urinary 27-nor-5β-cholestane-3α,7α,12α,24R,25S-pentol glucuronide as a biomarker of non-small cell lung cancer in
Seyon Chung1, Huaitian Liu2, Mohammed Khan1
1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Background:
Lung cancer in never-smokers is excluded from low-dose computed tomography screening because eligibility is defined by smoking history, and no non-invasive marker is available to select never-smokers for imaging. We evaluated urinary 27-nor-5β-cholestane3α,7α,12α,24R,25S-pentol glucuronide (CPG), a structurally authenticated bile alcohol glucuronide, as a marker of non-small cell lung cancer (NSCLC) in never-smokers.
Methods:
CPG was quantified by ultra-performance liquid chromatography-tandem mass spectrometry against a synthetic standard in urine from two independent case-control studies (661 cases, 690 controls). The primary analyses compared never-smoker cases directly with never-smoker controls (NCI-Maryland, 114 cases and 203 controls; Colorado, 80 cases and 108 controls) by logistic regression adjusted for age, sex and race, for all stages and by stage, pooled across studies. Survival among never-smoker cases was analyzed by Kaplan-Meier and Cox regression. Analyses of all participants and of tumor transcriptomes were secondary.
Results:
CPG was higher in never-smoker cases than in never-smoker controls in both studies (both P < 0.001). Adjusted odds ratios (OR) per standard deviation were near-identical across studies (1.83, 95% CI 1.32-2.54, and 1.81, 1.24-2.65; heterogeneity P = 0.96; pooled 1.82, 1.43-2.31). Elevation was present in stage I-II disease (pooled OR 1.38, 1.04-1.82) and greater in stage III-IV disease (2.27, 1.66-3.12). Single-marker discrimination was modest (area under the curve 0.63 and 0.70). High CPG was associated with shorter overall survival among never-smoker cases in NCI-Maryland independently of stage (hazard ratio 2.56, 1.58-4.14), and in the same direction in Colorado (1.63, 0.72-3.69). Among all participants, CPG was also higher in cases (pooled OR 1.61, 1.42-1.82), without effect modification by smoking, and remained associated after mutual adjustment for creatine riboside and N-acetylneuraminic acid. Tumors from patients with high urinary CPG showed enrichment of xenobiotic-metabolism, aryl hydrocarbon receptor/cytochrome P450 and Nrf2 programs.
Conclusions:
Urinary CPG is reproducibly elevated in never-smokers with NSCLC compared with never-smoker controls, including in early-stage disease, in two independent studies. These phase 2 data support evaluation of CPG within multimarker panels in pre-diagnostic urine from never-smokers, a population with no current screening pathway.
