{
  "abstract": "BackgroundLung 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-5{beta}-cholestane-3,7,12,24R,25S-pentol glucuronide (CPG), a structurally authenticated bile alcohol glucuronide, as a marker of non-small cell lung cancer (NSCLC) in never-smokers.\n\nMethodsCPG 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.\n\nResultsCPG 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.\n\nConclusionsUrinary 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.",
  "abstract_shown": true,
  "affiliations": [
    "National Cancer Institute"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "name": "S. Chung"
    },
    {
      "name": "H. Liu"
    },
    {
      "name": "M. Khan"
    },
    {
      "affs": [
        0
      ],
      "name": "T. S. Patel"
    },
    {
      "name": "B. Blackman"
    },
    {
      "name": "R. E. Swenson"
    },
    {
      "name": "S. R. Pine"
    },
    {
      "name": "F. J. Gonzalez"
    },
    {
      "name": "C. C. Harris"
    },
    {
      "affs": [
        0
      ],
      "name": "D. P. Patel"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/94ka2esv1r80d.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.07.27.26359037",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.07.27.26359037v2.full",
  "id": "94ka2esv1r80d",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.07.27.26359037v2",
  "language": null,
  "licence": "CC0-1.0",
  "licence_label": "CC0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/publicdomain/zero/1.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "oncology"
    ],
    [
      "openalex",
      "2730|Lung Cancer Research Studies"
    ]
  ],
  "openalex": "W7171924651",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.07.27.26359037v2.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-07-27",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/94ka2esv1r80d.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:49Z",
      "native_id": "10.64898/2026.07.27.26359037",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.07.27.26359037v2"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:oncology",
      "subfield": "oncology"
    }
  ],
  "title": "Urinary 27-nor-5β-cholestane-3α,7α,12α,24R,25S-pentol glucuronide as a biomarker of non-small cell lung cancer in never-smokers: two independent case-control studies",
  "title_text": "Urinary 27-nor-5β-cholestane-3α,7α,12α,24R,25S-pentol glucuronide as a biomarker of non-small cell lung cancer in never-smokers: two independent case-control studies",
  "type": "preprint",
  "updated_at": "2026-10-30T12:20:49Z",
  "url": "https://research.draconitic.com/paper/94ka2esv1r80d",
  "venue": "medRxiv",
  "versions": []
}