{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:32:23Z","timestamp":1789086743928,"version":"build-2803163510"},"reference-count":82,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:00:00Z","timestamp":1745798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ASPIRE Precision Medicine Research Institute Abu Dhabi (ASPIREPMRIAD)","award":["VRI-20-10"],"award-info":[{"award-number":["VRI-20-10"]}]},{"name":"ASPIRE Precision Medicine Research Institute Abu Dhabi (ASPIREPMRIAD)","award":["23010902146"],"award-info":[{"award-number":["23010902146"]}]},{"name":"University of Sharjah","award":["VRI-20-10"],"award-info":[{"award-number":["VRI-20-10"]}]},{"name":"University of Sharjah","award":["23010902146"],"award-info":[{"award-number":["23010902146"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Colorectal cancer (CRC) progression occurs through three stages: adenoma (pre-cancerous lesion), carcinoma in situ (CIS) and adenocarcinoma, with tumor stage playing a pivotal role in the prognosis and treatment outcomes. Despite therapeutic advancements, the lack of stage-specific biomarkers hinders the development of accurate diagnostic tools and effective therapeutic strategies. This study aims to identify stage-specific gene expression profiles and key molecular mechanisms in CRC providing insights into molecular alterations across disease progression. Our methodological approach integrates the use of absolute gene set enrichment analysis (absGSEA) on formalin-fixed paraffin-embedded (FFPE)-derived transcriptomic data, combined with large-scale clinical validation and experimental confirmation. A comparative whole transcriptomic analysis (RNA-seq) was performed on FFPE samples including adenoma (n = 10), carcinoma in situ (CIS) (n = 8) and adenocarcinoma (n = 11) samples. Using absGSEA, we identified significant cellular pathways and putative molecular biomarkers associated with each stage of CRC progression. Key findings were then validated in a large independent CRC patient cohort (n = 1926), with survival analysis conducted from 1336 patients to assess the prognostic relevance of the candidate biomarkers. The key differentially expressed genes were experimentally validated using real-time PCR (RT-qPCR). Pathway analysis revealed that in CIS, apoptotic processes and Wnt signaling pathways were more prominent than in adenoma samples, while in adenocarcinoma, transcriptional co-regulatory mechanisms and protein kinase activity, which are critical for tumor growth and metastasis, were significantly enriched compared to adenoma. Additionally, extracellular matrix organization pathways were significantly enriched in adenocarcinoma compared to CIS. Distinct gene signatures were identified across CRC stages that differentiate between adenoma, CIS and adenocarcinoma. In adenoma, ARRB1, CTBP1 and CTBP2 were overexpressed, suggesting their involvement in early tumorigenesis, whereas in CIS, RPS3A and COL4A5 were overexpressed, suggesting their involvement in the transition from benign to malignant stage. In adenocarcinoma, COL1A2, CEBPZ, MED10 and PAWR were overexpressed, suggesting their involvement in advanced disease progression. Functional analysis confirmed that ARRB1 and CTBP1\/2 were associated with early tumor development, while COL1A2 and CEBPZ were involved in extracellular matrix remodeling and transcriptional regulation, respectively. Experimental validation with RT-qPCR confirmed the differential expression of the candidate biomarkers (ARRB1, RPS3A, COL4A5, COL1A2 and MED10) across the three CRC stages reinforcing their potential as stage-specific biomarkers in CRC progression. These findings provide a foundation to distinguish between the CRC stages and for the development of accurate stage-specific diagnostic and prognostic biomarkers, which helps in the development of more effective therapeutic strategies for CRC.<\/jats:p>","DOI":"10.3390\/ijms26094194","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T07:49:36Z","timestamp":1745912976000},"page":"4194","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Transcriptome-Wide Analysis and Experimental Validation from FFPE Tissue Identifies Stage-Specific Gene Expression Profiles Differentiating Adenoma, Carcinoma In-Situ and Adenocarcinoma in Colorectal Cancer Progression"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3553-7217","authenticated-orcid":false,"given":"Faisal","family":"Alhosani","sequence":"first","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Medical Systems Biology Group, L\u00fcbeck Institute of Experimental Dermatology, University of L\u00fcbeck, Ratzeburger Allee 160, 23538 L\u00fcbeck, Germany"},{"name":"Forensic Laboratory Department, Sharjah Police Headquarters, Sharjah P.O. Box 1965, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2893-2872","authenticated-orcid":false,"given":"Reem Sami","family":"Alhamidi","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2068-1089","authenticated-orcid":false,"given":"Burcu Yener","family":"Ilce","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaa Muayad","family":"Altaie","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nival","family":"Ali","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaa Mohamed","family":"Hamad","sequence":"additional","affiliation":[{"name":"College of Health Sciences, Abu Dhabi University, Abu Dhabi P.O. Box 59911, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0692-2105","authenticated-orcid":false,"given":"Axel","family":"K\u00fcnstner","sequence":"additional","affiliation":[{"name":"Medical Systems Biology Group, L\u00fcbeck Institute of Experimental Dermatology, University of L\u00fcbeck, Ratzeburger Allee 160, 23538 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4655-6269","authenticated-orcid":false,"given":"Cyrus","family":"Khandanpour","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University Cancer Center Schleswig-Holstein, University Hospital Schleswig-Holstein, University of L\u00fcbeck, 23562 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4763-4521","authenticated-orcid":false,"given":"Hauke","family":"Busch","sequence":"additional","affiliation":[{"name":"Medical Systems Biology Group, L\u00fcbeck Institute of Experimental Dermatology, University of L\u00fcbeck, Ratzeburger Allee 160, 23538 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1657-1938","authenticated-orcid":false,"given":"Basel","family":"Al-Ramadi","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates"},{"name":"Zayed Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates"},{"name":"ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6672-2944","authenticated-orcid":false,"given":"Rania","family":"Harati","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kadria","family":"Sayed","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, American Hospital Dubai, Dubai P.O. Box 3050, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"AlFazari","sequence":"additional","affiliation":[{"name":"Mediclinic Welcare Hospital, Dubai P.O. Box 31500, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riyad","family":"Bendardaf","sequence":"additional","affiliation":[{"name":"Oncology Unit, University Hospital Sharjah, Sharjah P.O. Box 72772, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1402-0868","authenticated-orcid":false,"given":"Rifat","family":"Hamoudi","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Center of Excellence for Precision Medicine, Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"BIMAI-Lab, Biomedically Informed Artificial Intelligence Laboratory, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"ASPIRE Precision Medicine Research Institute Abu Dhabi, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Division of Surgery and Interventional Science, University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,28]]},"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 A Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.semcdb.2019.05.018","article-title":"Metabolic pathways regulating colorectal cancer initiation and progression","volume":"98","year":"2020","journal-title":"Semin. Cell Dev. 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