{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:53Z","timestamp":1792790393847,"version":"4.5.0"},"posted":{"date-parts":[[2026,7,31]]},"group-title":"Oncology","reference-count":25,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH","award":["ZIA BC 011492"],"award-info":[{"award-number":["ZIA BC 011492"]}],"id":[{"id":"https:\/\/ror.org\/05bjen692","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institutes of Health","award":["R01CA239093"],"award-info":[{"award-number":["R01CA239093"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    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-5\u03b2-cholestane-3\u03b1,7\u03b1,12\u03b1,24\n                    <jats:italic>R<\/jats:italic>\n                    ,25\n                    <jats:italic>S<\/jats:italic>\n                    -pentol glucuronide (CPG), a structurally authenticated bile alcohol glucuronide, as a marker of non-small cell lung cancer (NSCLC) in never-smokers.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>CPG was quantified by ultra-performance liquid chromatography\u2013tandem mass spectrometry against a synthetic standard in urine from two independent case\u2013control 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\u2013Meier and Cox regression. Analyses of all participants and of tumor transcriptomes were secondary.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    CPG was higher in never-smoker cases than in never-smoker controls in both studies (both P &lt; 0.001). Adjusted odds ratios (OR) per standard deviation were near-identical across studies (1.83, 95% CI 1.32\u20132.54, and 1.81, 1.24\u20132.65; heterogeneity P = 0.96; pooled 1.82, 1.43\u20132.31). Elevation was present in stage I\u2013II disease (pooled OR 1.38, 1.04\u20131.82) and greater in stage III\u2013IV disease (2.27, 1.66\u20133.12). 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\u20134.14), and in the same direction in Colorado (1.63, 0.72\u20133.69). Among all participants, CPG was also higher in cases (pooled OR 1.61, 1.42\u20131.82), without effect modification by smoking, and remained associated after mutual adjustment for creatine riboside and\n                    <jats:italic>N<\/jats:italic>\n                    -acetylneuraminic acid. Tumors from patients with high urinary CPG showed enrichment of xenobiotic-metabolism, aryl hydrocarbon receptor\/cytochrome P450 and Nrf2 programs.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.27.26359037","type":"posted-content","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T15:35:12Z","timestamp":1785512112000},"source":"Crossref","is-referenced-by-count":1,"title":["Urinary 27-nor-5\u03b2-cholestane-3\u03b1,7\u03b1,12\u03b1,24R,25S-pentol glucuronide as a biomarker of non-small cell lung cancer in never-smokers: two independent case\u2013control studies"],"prefix":"10.64898","author":[{"given":"Seyon","family":"Chung","sequence":"first","affiliation":[{"name":"Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaitian","family":"Liu","sequence":"additional","affiliation":[{"name":"CCR Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Khan","sequence":"additional","affiliation":[{"name":"Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanvi S.","family":"Patel","sequence":"additional","affiliation":[{"name":"Bowie State University, Bowie, MD 20715, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Burchelle","family":"Blackman","sequence":"additional","affiliation":[{"name":"Chemistry and Chemical Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf E.","family":"Swenson","sequence":"additional","affiliation":[{"name":"Chemistry and Chemical Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon R.","family":"Pine","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank J.","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Curtis C.","family":"Harris","sequence":"additional","affiliation":[{"name":"Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daxesh P.","family":"Patel","sequence":"additional","affiliation":[{"name":"Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026101619201483000_2026.07.27.26359037v2.1","doi-asserted-by":"publisher","DOI":"10.3322\/CAAC.21834"},{"key":"2026101619201483000_2026.07.27.26359037v2.2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21820"},{"key":"2026101619201483000_2026.07.27.26359037v2.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-023-00844-0"},{"key":"2026101619201483000_2026.07.27.26359037v2.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00920-0"},{"key":"2026101619201483000_2026.07.27.26359037v2.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05874-3"},{"key":"2026101619201483000_2026.07.27.26359037v2.6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1102873"},{"key":"2026101619201483000_2026.07.27.26359037v2.7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1911793"},{"key":"2026101619201483000_2026.07.27.26359037v2.8","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.1117"},{"key":"2026101619201483000_2026.07.27.26359037v2.9","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.jtho.2021.07.031","article-title":"Screening for lung cancer in individuals who never smoked: an International Association for the Study of Lung Cancer Early Detection and Screening Committee report","volume":"17","year":"2022","journal-title":"J Thorac Oncol"},{"key":"2026101619201483000_2026.07.27.26359037v2.10","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/S2213-2600(23)00338-7","article-title":"Low-dose CT screening among never-smokers with or without a family history of lung cancer in Taiwan: a prospective cohort study","volume":"12","year":"2024","journal-title":"Lancet Respir Med"},{"key":"2026101619201483000_2026.07.27.26359037v2.11","doi-asserted-by":"crossref","first-page":"3592","DOI":"10.1158\/1078-0432.CCR-24-0637","article-title":"Urinary metabolite diagnostic and prognostic liquid biopsy biomarkers of lung cancer in nonsmokers and tobacco smokers","volume":"30","year":"2024","journal-title":"Clin Cancer Res"},{"key":"2026101619201483000_2026.07.27.26359037v2.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopen.2018.05.001"},{"key":"2026101619201483000_2026.07.27.26359037v2.13","doi-asserted-by":"publisher","DOI":"10.5604\/01.3001.0010.5493"},{"key":"2026101619201483000_2026.07.27.26359037v2.14","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-0109"},{"key":"2026101619201483000_2026.07.27.26359037v2.15","doi-asserted-by":"crossref","first-page":"2781","DOI":"10.3390\/molecules29122781","article-title":"Isolation and identification of a urinary biomarker for lung cancer: 27-nor-5\u03b2-cholestane-3\u03b1,7\u03b1,12\u03b1,24R,25S pentol glucuronide and its deuterated analog","volume":"29","year":"2024","journal-title":"Molecules"},{"key":"2026101619201483000_2026.07.27.26359037v2.16","doi-asserted-by":"publisher","DOI":"10.1172\/JCI108366"},{"key":"2026101619201483000_2026.07.27.26359037v2.17","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.00939"},{"key":"2026101619201483000_2026.07.27.26359037v2.18","doi-asserted-by":"crossref","first-page":"113596","DOI":"10.1016\/j.jpba.2020.113596","article-title":"Improved detection and precise relative quantification of the urinary cancer metabolite biomarkers - creatine riboside, creatinine riboside, creatine and creatinine by UPLC-ESI-MS\/MS: application to the NCI-Maryland cohort population controls and lung cancer cases","volume":"191","year":"2020","journal-title":"J Pharm Biomed Anal"},{"key":"2026101619201483000_2026.07.27.26359037v2.19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"2026101619201483000_2026.07.27.26359037v2.20","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","year":"2015","journal-title":"Cell Syst"},{"key":"2026101619201483000_2026.07.27.26359037v2.21","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6602678"},{"key":"2026101619201483000_2026.07.27.26359037v2.22","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)61602-X"},{"key":"2026101619201483000_2026.07.27.26359037v2.23","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/93.14.1054"},{"key":"2026101619201483000_2026.07.27.26359037v2.24","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1093\/jnci\/djad227","article-title":"Revisiting the standard blueprint for biomarker development to address emerging cancer early detection technologies","volume":"116","year":"2024","journal-title":"J Natl Cancer Inst"},{"key":"2026101619201483000_2026.07.27.26359037v2.25","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-1415"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.07.27.26359037","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T02:20:29Z","timestamp":1792203629000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.07.27.26359037"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,31]]},"references-count":25,"URL":"https:\/\/doi.org\/10.64898\/2026.07.27.26359037","relation":{},"subject":[],"published":{"date-parts":[[2026,7,31]]},"subtype":"preprint"}}