{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T14:37:35Z","timestamp":1790519855304,"version":"4.1.0"},"reference-count":62,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,8,3]],"date-time":"2020-08-03T00:00:00Z","timestamp":1596412800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["ID 23573 project\u2014P.I. Loris De Cecco"],"award-info":[{"award-number":["ID 23573 project\u2014P.I. Loris De Cecco"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["ID 21740 project\u2014P.I. Paolo Bossi"],"award-info":[{"award-number":["ID 21740 project\u2014P.I. Paolo Bossi"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Oral premalignant lesions (OPLs) represent the most common oral precancerous conditions. One of the major challenges in this field is the identification of OPLs at higher risk for oral squamous cell cancer (OSCC) development, by discovering molecular pathways deregulated in the early steps of malignant transformation. Analysis of deregulated levels of single genes and pathways has been successfully applied to head and neck squamous cell cancers (HNSCC) and OSCC with prognostic\/predictive implications. Exploiting the availability of gene expression profile and clinical follow-up information of a well-characterized cohort of OPL patients, we aim to dissect tissue OPL gene expression to identify molecular clusters\/signatures associated with oral cancer free survival (OCFS). Materials and methods: The gene expression data of 86 OPL patients were challenged with: an HNSCC specific 6 molecular subtypes model (Immune related: HPV related, Defense Response and Immunoreactive; Mesenchymal, Hypoxia and Classical); one OSCC-specific signature (13 genes); two metabolism-related signatures (3 genes and signatures raised from 6 metabolic pathways associated with prognosis in HNSCC and OSCC, respectively); a hypoxia gene signature. The molecular stratification and high versus low expression of the signatures were correlated with OCFS by Kaplan\u2013Meier analyses. The association of gene expression profiles among the tested biological models and clinical covariates was tested through variance partition analysis. Results: Patients with Mesenchymal, Hypoxia and Classical clusters showed an higher risk of malignant transformation in comparison with immune-related ones (log-rank test, p = 0.0052) and they expressed four enriched hallmarks: \u201cTGF beta signaling\u201d \u201cangiogenesis\u201d, \u201cunfolded protein response\u201d, \u201capical junction\u201d. Overall, 54 cases entered in the immune related clusters, while the remaining 32 cases belonged to the other clusters. No other signatures showed association with OCFS. Our variance partition analysis proved that clinical and molecular features are able to explain only 21% of gene expression data variability, while the remaining 79% refers to residuals independent of known parameters. Conclusions: Applying the existing signatures derived from HNSCC to OPL, we identified only a protective effect for immune-related signatures. Other gene expression profiles derived from overt cancers were not able to identify the risk of malignant transformation, possibly because they are linked to later stages of cancer progression. The availability of a new well-characterized set of OPL patients and further research is needed to improve the identification of adequate prognosticators in OPLs.<\/jats:p>","DOI":"10.3390\/cells9081828","type":"journal-article","created":{"date-parts":[[2020,8,3]],"date-time":"2020-08-03T09:02:48Z","timestamp":1596445368000},"page":"1828","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Gene Expression Clustering and Selected Head and Neck Cancer Gene Signatures Highlight Risk Probability Differences in Oral Premalignant Lesions"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6804-9984","authenticated-orcid":false,"given":"Andrea","family":"Carenzo","sequence":"first","affiliation":[{"name":"Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara S.","family":"Serafini","sequence":"additional","affiliation":[{"name":"Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Roca","sequence":"additional","affiliation":[{"name":"Department of Medical &amp; Surgical Specialties, Radiological Sciences &amp; Public Health, University of Brescia, ASST Spedali Civili, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1621-2142","authenticated-orcid":false,"given":"Alberto","family":"Paderno","sequence":"additional","affiliation":[{"name":"Unit of Otorhinolaryngology-Head and Neck Surgery, Azienda Socio Sanitaria Territoriale (ASST), Spedali Civili di Brescia, Department of Medical and Surgical Specialties, Radiologic Sciences, and Public Health, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7023-6746","authenticated-orcid":false,"given":"Davide","family":"Mattavelli","sequence":"additional","affiliation":[{"name":"Unit of Otorhinolaryngology-Head and Neck Surgery, Azienda Socio Sanitaria Territoriale (ASST), Spedali Civili di Brescia, Department of Medical and Surgical Specialties, Radiologic Sciences, and Public Health, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Romani","sequence":"additional","affiliation":[{"name":"Angelo Nocivelli Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Saintigny","sequence":"additional","affiliation":[{"name":"Centre L\u00e9on B\u00e9rard, Centre de Recherche en Canc\u00e9rologie de Lyon, University Lyon, Universit\u00e9 Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, 69100 Lyon, France"},{"name":"France &amp; Department of Medical Oncology, Centre L\u00e9on B\u00e9rard, 69100 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Senada","family":"Koljenovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus University Medical Center, University Medical Center Rotterdam, 3000 Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Licitra","sequence":"additional","affiliation":[{"name":"Head and Neck Cancer Medical Oncology 3 Department, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), 20122 Milan, Italy"},{"name":"Department of Hematology and Oncology, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7066-473X","authenticated-orcid":false,"given":"Loris","family":"De Cecco","sequence":"additional","affiliation":[{"name":"Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0135-0224","authenticated-orcid":false,"given":"Paolo","family":"Bossi","sequence":"additional","affiliation":[{"name":"Department of Medical &amp; 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