Promoter DNA methylation patterns in oral, laryngeal and oropharyngeal anatomical regions are associated with tumor differentiation, nodal involvement and survival

Rivera-Peña,Bianca; Rivera-Peña,Bianca; Folawiyo,Oluwasina; Folawiyo,Oluwasina; Turaga,Nitesh; Turaga,Nitesh; Rodríguez-Benítez,Rosa J.; Rodríguez-Benítez,Rosa J.; Felici,Marcos E.; Felici,Marcos E.; Aponte-Ortiz,Jaime A.; Aponte-Ortiz,Jaime A.; Pirini,Francesca; Pirini,Francesca; Rodríguez-Torres,Sebastián; Rodríguez-Torres,Sebastián; Vázquez,Roger; Vázquez,Roger; López,Ricardo; López,Ricardo; Sidransky,David; Sidransky,David; Guerrero-Preston,Rafael; Guerrero-Preston,Rafael; Báez,Adriana; Báez,Adriana

doi:10.3892/ol.2024.14223

Promoter DNA methylation patterns in oral, laryngeal and oropharyngeal anatomical regions are associated with tumor differentiation, nodal involvement and survival

Authors:
- Bianca Rivera-Peña
- Oluwasina Folawiyo
- Nitesh Turaga
- Rosa J. Rodríguez-Benítez
- Marcos E. Felici
- Jaime A. Aponte-Ortiz
- Francesca Pirini
- Sebastián Rodríguez-Torres
- Roger Vázquez
- Ricardo López
- David Sidransky
- Rafael Guerrero-Preston
- Adriana Báez
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Affiliations: Department of Biology, University of Puerto Rico, San Juan 00925, Puerto Rico, Department of Otolaryngology‑Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA, Department of General Social Sciences, Faculty of Social Sciences, University of Puerto Rico, San Juan 00925, Puerto Rico, Oral Health Division, Puerto Rico Department of Health, San Juan 00927, Puerto Rico, Department of General Surgery, University of Puerto Rico School of Medicine, San Juan 00936, Puerto Rico, Biosciences Laboratory, IRCCS Instituto Romagnolo per lo Studio dei Tumori ‘Dino Amadori’, Meldola I-47014, Italy, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA, Department of Pharmacology, University of Puerto Rico School of Medicine, San Juan 00936, Puerto Rico
Published online on: January 8, 2024 https://doi.org/10.3892/ol.2024.14223
Article Number: 89
Copyright: © Rivera-Peña et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Differentially methylated regions (DMRs) can be used as head and neck squamous cell carcinoma (HNSCC) diagnostic, prognostic and therapeutic targets in precision medicine workflows. DNA from 21 HNSCC and 10 healthy oral tissue samples was hybridized to a genome‑wide tiling array to identify DMRs in a discovery cohort. Downstream analyses identified differences in promoter DNA methylation patterns in oral, laryngeal and oropharyngeal anatomical regions associated with tumor differentiation, nodal involvement and survival. Genome‑wide DMR analysis showed 2,565 DMRs common to the three subsites. A total of 738 DMRs were unique to laryngeal cancer (n=7), 889 DMRs were unique to oral cavity cancer (n=10) and 363 DMRs were unique to pharyngeal cancer (n=6). Based on the genome‑wide analysis and a Gene Ontology analysis, 10 candidate genes were selected to test for prognostic value and association with clinicopathological features. TIMP3 was associated with tumor differentiation in oral cavity cancer (P=0.039), DAPK1 was associated with nodal involvement in pharyngeal cancer (P=0.017) and PAX1 was associated with tumor differentiation in laryngeal cancer (P=0.040). A total of five candidate genes were selected, DAPK1, CDH1, PAX1, CALCA and TIMP3, for a prevalence study in a larger validation cohort: Oral cavity cancer samples (n=42), pharyngeal cancer tissues (n=25) and laryngeal cancer samples (n=52). PAX1 hypermethylation differed across HNSCC anatomic subsites (P=0.029), and was predominantly detected in laryngeal cancer. Kaplan‑Meier survival analysis (P=0.043) and Cox regression analysis of overall survival (P=0.001) showed that DAPK1 methylation is associated with better prognosis in HNSCC. The findings of the present study showed that the HNSCC subsites oral cavity, pharynx and larynx display substantial differences in aberrant DNA methylation patterns, which may serve as prognostic biomarkers and therapeutic targets.

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