{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T15:25:28Z","timestamp":1780500328682,"version":"3.54.1"},"reference-count":28,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Epigenetic alterations, particularly DNA methylation, play a crucial role in the progression of oral squamous cell carcinoma (OSCC) from oral leukoplakia (OL). However, the molecular mechanisms driving this transition remain poorly understood. Using interpretable machine learning (IML) on genome-wide methylation data from 118 samples (22 OL, 74 OSCC, and 22 controls), we identified 20 key CpG sites among 820\u2009193 loci through SHAP (SHapley Additive exPlanations) analysis. Notably, cg19853638, cg25393842, cg01743793, and cg10784570 mapped to pivotal genes such as TNFRSF19, ALOX5, and SH3PXD2A, which regulate cell morphology, inflammatory pathways, and immune responses\u2014 critical processes influencing OSCC malignancy and progression. To assess generalizability and confirm the robustness of classifier, the predictive model was validated on an independent Taiwanese cohort (GSE38532) profiled on a different array platform, achieving 98.8% accuracy and ROC\u2013AUC of 0.999 demonstrating robust cross-population performance. Furthermore, cross-omics integration with an independent transcriptomic dataset (GSE31056) identified eight genes, including ALOX5, FOXP1, and VTI1A, showing consistent methylation and expression patterns, underscoring their biological relevance. Our findings highlight the functional relevance of SH3PXD2A, TNFRSF19, and ALOX5 in OSCC pathophysiology: SH3PXD2A mediates cell migration and invasion, TNFRSF19 is involved in survival signaling, and ALOX5 regulates inflammatory responses. These multi-layered analyses provide novel insights into epigenetic mechanisms underlying OL to OSCC progression and highlight candidate biomarkers with strong translational potential. By combining IML based methylation modeling with external and cross-omics validation, this study advances the development of reliable, interpretable biomarkers for precision oral cancer diagnostics and management.<\/jats:p>","DOI":"10.1093\/intbio\/zyag003","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T12:39:03Z","timestamp":1770295143000},"source":"Crossref","is-referenced-by-count":0,"title":["Application of interpretable machine learning to analyze DNA methylation sites in the progression from oral Leukoplakia to oral squamous cell carcinoma"],"prefix":"10.1093","volume":"18","author":[{"given":"Khushi","family":"Yadav","sequence":"first","affiliation":[{"name":"Department of Biotechnology, Delhi Technological University (DTU) , Shahbad Daulatpur, Main Bawana Road, Delhi, Delhi 110042 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0116-0711","authenticated-orcid":false,"given":"Yasha","family":"Hasija","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Delhi Technological University (DTU) , Shahbad Daulatpur, Main Bawana Road, Delhi, Delhi 110042 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"key":"2026060310434837200_ref1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-023-48572-w","article-title":"Correlation of PD-1 and PD-L1 expression in oral leukoplakia and oral squamous cell carcinoma: an immunohistochemical study","volume":"13","author":"Greeshma","year":"2023","journal-title":"Sci Rep"},{"key":"2026060310434837200_ref2","doi-asserted-by":"publisher","first-page":"ZC09","DOI":"10.7860\/JCDR\/2014\/9251.4949","article-title":"Promoter hypermethylation profile of tumour suppressor genes in oral Leukoplakia and oral squamous cell carcinoma","volume":"8","author":"Asokan","year":"2014","journal-title":"J Clin Diagn Res"},{"key":"2026060310434837200_ref3","doi-asserted-by":"publisher","volume-title":"Archives of Oral Biology","author":"","DOI":"10.1016\/j.archoralbio.2010.08.009"},{"key":"2026060310434837200_ref4","doi-asserted-by":"publisher","first-page":"5808","DOI":"10.3390\/CANCERS14235808\/S1","article-title":"Screening for biomarkers for progression from oral Leukoplakia to oral squamous cell carcinoma and evaluation of diagnostic efficacy by multiple machine learning algorithms","volume":"14","author":"Jing","year":"2022","journal-title":"Cancers (Basel)"},{"key":"2026060310434837200_ref5","doi-asserted-by":"publisher","first-page":"4935","DOI":"10.3390\/CANCERS14194935\/S1","article-title":"Machine learning-based genome-wide salivary DNA methylation analysis for identification of noninvasive biomarkers in oral cancer diagnosis","volume":"14","author":"Adeoye","year":"2022","journal-title":"Cancers (Basel)"},{"key":"2026060310434837200_ref6","doi-asserted-by":"publisher","first-page":"1544","DOI":"10.3390\/DIAGNOSTICS12071544","article-title":"Improving the diagnostic performance by adding methylation marker to conventional visual examination in identifying oral cancer","volume":"12","author":"Yang","year":"2022","journal-title":"Diagnostics"},{"key":"2026060310434837200_ref7","doi-asserted-by":"publisher","DOI":"10.1186\/S13148-023-01510-Z","article-title":"Genome-wide DNA methylation profiling of HPV-negative leukoplakia and gingivobuccal complex cancers. 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