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Even though the screening programs have decreased the incidence rates, the prognosis for CRC varies depending on the stage at diagnosis. Thus, early diagnosis is still a big challenge due to screening methods, and subsequent diagnosis is not very sensitive. Methods: In this work, LC-MS-based metabolomics, a powerful and sensitive tool to study complex dynamic changes, was used to analyze 211 human fecal samples from control individuals (CTRL), adenoma (AA), and CRC patients. Results: Multivariate and univariate statistical analysis highlighted cholesteryl esters (CEs) and fecal haemoglobin, quantified by fecal immunochemical test (FIT), as relevant biomarkers that clearly differentiate CRC from AA and CTRL. Predictive models based on random forest and the area under the curve (AUC) of the receiver operating characteristic curve (ROC) demonstrate that CEs, together with FIT measurement, improved the CRC and CTRL classification, but not AA. This study revealed that the AA group is a transitional stage with high heterogeneity. The increased tendency observed in CEs from CTRL to CRC might be related to the imbalance of cholesterol homeostasis due to cancer cells requiring a high cholesterol level for cell development and proliferation. The free cholesterol is probably obtained from CEs, as it is the most cost\/effective way to obtain the needed cholesterol. Conclusions: The accumulation of CEs is produced by two possible approaches: (1) dysfunction of cholesterol absorption in the small intestine and\/or (2) transported inside exosomes from cell to cell to promote proliferation.<\/jats:p>","DOI":"10.3390\/cancers17142339","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T08:04:41Z","timestamp":1752566681000},"page":"2339","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic Signature in Combination with Fecal Immunochemical Test as a Non-Invasive Tool for Advanced Colorectal Neoplasia Diagnosis"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3663-6794","authenticated-orcid":false,"given":"Oihane E.","family":"Alb\u00f3niga","sequence":"first","affiliation":[{"name":"Metabolomics Platform, CICbioGUNE-BRTA, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd), Bizkaia Technology Park, 48160 Derio, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9994-4831","authenticated-orcid":false,"given":"Joaqu\u00edn","family":"Cubiella","sequence":"additional","affiliation":[{"name":"Grupo de Investigaci\u00f3n de Oncolog\u00eda Digestiva-Ourense, Department of Gastroenterology, Hospital Universitario de Ourense, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CI-BERehd), Complexo Hospitalario Universidad de Ourense, 32005 Ourense, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis","family":"Bujanda","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Donosti Hospital, Universidad del Pa\u00eds Vasco (UPV\/EHU), 20014 San Sebasti\u00e1n, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd), Biodonostia Health Research Institute, 20014 San Sebasti\u00e1n, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Aspichueta","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd), Biodonostia Health Research Institute, 20014 San Sebasti\u00e1n, Spain"},{"name":"Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV\/EHU, 48940 Leioa, Spain"},{"name":"Biobizkaia Health Research Institute, 48903 Barakaldo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4032-8003","authenticated-orcid":false,"given":"Mar\u00eda Encarnaci\u00f3n","family":"Blanco","sequence":"additional","affiliation":[{"name":"OWL Metabolomics (Rubi\u00f3 Metabolomics S.L.U.), Bizkaia Technology Park, 48160 Derio, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Borja","family":"Lanza","sequence":"additional","affiliation":[{"name":"OWL Metabolomics (Rubi\u00f3 Metabolomics S.L.U.), Bizkaia Technology Park, 48160 Derio, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2019-678X","authenticated-orcid":false,"given":"Cristina","family":"Alonso","sequence":"additional","affiliation":[{"name":"OWL Metabolomics (Rubi\u00f3 Metabolomics S.L.U.), Bizkaia Technology Park, 48160 Derio, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3133-0670","authenticated-orcid":false,"given":"Juan Manuel","family":"Falc\u00f3n-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Metabolomics Platform, CICbioGUNE-BRTA, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd), Bizkaia Technology Park, 48160 Derio, Spain"},{"name":"Exosomes Laboratory, CIC bioGUNE-BRTA, CIBERehd Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd), Bizkaia Technology Park, 48160 Derio, Spain"},{"name":"IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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