{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T03:46:43Z","timestamp":1792900003136,"version":"4.5.0"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T00:00:00Z","timestamp":1749600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81802271 81801734"],"award-info":[{"award-number":["81802271 81801734"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p>Currently, adjuvant concurrent radio-chemotherapy (ACRT) is the standard of care for head-and-neck squamous cell carcinoma (HNSC) with microscopically involved surgical margins (MISM) and\/or extra-nodal extension (ENE), whereas the toxicity of cisplatin-based chemotherapy is non-negligible.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In the current study, we identified a novel biomarker, referred to as RPMB (Repair Gene Promoter Methylation Burden), with the aim of identifying the subset of HNSC patients who are likely to respond favorably to ACRT. RPMB is defined as the proportion of methylated DNA repair genes (DRGs) relative to the total number of DRGs. We obtained the methylation profiles and clinical data for 528 HNSC patients from the Cancer Genome Atlas (TCGA) database.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Analysis revealed that the DRGs in HNSC were significantly hypomethylated compared to the other genes across the entire methylation profile (all <jats:italic>p<\/jats:italic>-values &amp;lt;0.001). HNSCs with higher RPMB tended to be \u226570\u00a0years old, female, and with primary anatomic location of oral cavity. High RPMB was found significantly related to a poor DFS in HNSCs in subgroup analysis (HR = 1.475, <jats:italic>p<\/jats:italic> = 0.024, 95% CI: 1.053\u20132.065). Moreover, Kaplan-Meier analysis showed that high RPMB was significantly associated with a poor DFS in these patients who received ACRT due to MISM or ENE (HR = 2.721, 95% Cl: 1.094\u20136.767, <jats:italic>p<\/jats:italic> = 0.025). The median DFS for patients with lower RPMB was 2.33\u00a0years (95% CI: 1.07 to +\u221e years) and median DFS for those with higher RPMB was 0.64\u00a0years (95% CI: 0.62 to +\u221e years).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Low RPMB might serve as a promising indicator for identifying suitable HNSC patients who might be medically fit for ACRT.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fgene.2025.1585970","type":"journal-article","created":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T05:15:04Z","timestamp":1749618904000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["RPMB predicts the disease-free survival of head-and-neck squamous carcinoma after adjuvant concurrent radio-chemotherapy"],"prefix":"10.3389","volume":"16","author":[{"given":"Ning","family":"An","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongchun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haijun","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1007\/s12013-013-9555-2","article-title":"DNA methylation and cancer development: molecular mechanism","volume":"67","author":"Akhavan-Niaki","year":"2013","journal-title":"Cell Biochem. Biophys."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e11783","DOI":"10.1016\/j.heliyon.2022.e11783","article-title":"High RPMB predicts poor disease-free survival of male N1 papillary thyroid cancer after adjuvant radioiodine therapy","volume":"8","author":"An","year":"2022","journal-title":"Heliyon"},{"key":"B3","doi-asserted-by":"publisher","first-page":"e18266","DOI":"10.1016\/j.heliyon.2023.e18266","article-title":"Prediction of disease-free survival of N1\/2 non-small cell lung cancer after adjuvant chemotherapy by the biomarker RPMB","volume":"9","author":"An","year":"2023","journal-title":"Heliyon"},{"key":"B4","doi-asserted-by":"publisher","first-page":"18616","DOI":"10.1038\/srep18616","article-title":"Developmental genes significantly afflicted by aberrant promoter methylation and somatic mutation predict overall survival of late-stage colorectal cancer","volume":"5","author":"An","year":"2015","journal-title":"Sci. Rep."},{"key":"B5","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.omto.2020.06.006","article-title":"Promoter methylation of DNA repair genes predicts disease-free survival of gastric adenocarcinoma after adjuvant radiotherapy","volume":"18","author":"An","year":"2020","journal-title":"Mol. Ther. Oncolytics"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1948","DOI":"10.1126\/science.277.5334.1948","article-title":"Tying it all together: epigenetics, genetics, cell cycle, and cancer","volume":"277","author":"Baylin","year":"1997","journal-title":"Science"},{"key":"B7","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1002\/hed.20279","article-title":"Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501)","volume":"27","author":"Bernier","year":"2005","journal-title":"Head. Neck"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1945","DOI":"10.1056\/NEJMoa032641","article-title":"Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer","volume":"350","author":"Bernier","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.2165\/00003495-200363150-00004","article-title":"Long-term complications of chemotherapy for germ cell tumours","volume":"63","author":"Chaudhary","year":"2003","journal-title":"Drugs"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1937","DOI":"10.1056\/NEJMoa032646","article-title":"Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck","volume":"350","author":"Cooper","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1198","DOI":"10.1016\/j.ijrobp.2012.05.008","article-title":"Long-term follow-up of the RTOG 9501\/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck","volume":"84","author":"Cooper","year":"2012","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"B13","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1136\/jmg.38.5.285","article-title":"Methylation matters","volume":"38","author":"Costello","year":"2001","journal-title":"J. Med. Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/j.ymeth.2010.06.017","article-title":"DNA methylation profiling using bisulfite-based epityping of pooled genomic DNA","volume":"52","author":"Docherty","year":"2010","journal-title":"Methods"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1350","DOI":"10.1056\/NEJM200011093431901","article-title":"Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents","volume":"343","author":"Esteller","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/0360-3016(82)90380-7","article-title":"Analysis of the parameters relating to failures above the clavicles in patients treated by postoperative irradiation for squamous cell carcinomas of the oral cavity or oropharynx","volume":"8","author":"Feldman","year":"1982","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1871","DOI":"10.1158\/1078-0432.ccr-03-0384","article-title":"Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide","volume":"10","author":"Hegi","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1056\/NEJMoa043331","article-title":"MGMT gene silencing and benefit from temozolomide in glioblastoma","volume":"352","author":"Hegi","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1016\/0360-3016(92)90664-4","article-title":"Adjuvant chemotherapy for resectable squamous cell carcinoma of the head and neck. Report on Intergroup Study 0034","volume":"23","author":"Hong","year":"1992","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"B20","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1038\/nrc1045","article-title":"The power and the promise of DNA methylation markers","volume":"3","author":"Laird","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"B21","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/nrg2719","article-title":"Establishing, maintaining and modifying DNA methylation patterns in plants and animals","volume":"11","author":"Law","year":"2010","journal-title":"Nat. Rev. Genet."},{"key":"B22","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.ebiom.2018.12.018","article-title":"DNA methylation changes and somatic mutations as tumorigenic events in Lynch syndrome-associated adenomas retaining mismatch repair protein expression","volume":"39","author":"Maki-Nevala","year":"2019","journal-title":"EBioMedicine"},{"key":"B23","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s13148-018-0447-6","article-title":"Promoter methylation of DNA damage repair (DDR) genes in human tumor entities: RBBP8\/CtIP is almost exclusively methylated in bladder cancer","volume":"10","author":"Mijnes","year":"2018","journal-title":"Clin. Epigenetics"},{"key":"B24","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/0360-3016(85)90180-4","article-title":"Combined surgery and postoperative radiation therapy for advanced laryngeal and hypopharyngeal carcinomas","volume":"11","author":"Mirimanoff","year":"1985","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.1200\/JCO.2017.74.9457","article-title":"Once-a-Week versus once-every-3-weeks cisplatin chemoradiation for locally advanced head and neck cancer: a phase III randomized noninferiority trial","volume":"36","author":"Noronha","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1200\/JCO.1992.10.4.574","article-title":"Long-term effects of chemotherapy in patients with testicular cancer","volume":"10","author":"Osanto","year":"1992","journal-title":"J. Clin. Oncol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/0360-3016(93)90167-t","article-title":"Evaluation of the dose for postoperative radiation therapy of head and neck cancer: first report of a prospective randomized trial","volume":"26","author":"Peters","year":"1993","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"B28","doi-asserted-by":"publisher","first-page":"17","DOI":"10.3322\/caac.21763","article-title":"Cancer statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J. Clin."},{"key":"B29","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1056\/NEJMoa043330","article-title":"Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma","volume":"352","author":"Stupp","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"8961","DOI":"10.1158\/0008-5472.CAN-05-1187","article-title":"CpG island methylation of DNA damage response genes in advanced ovarian cancer","volume":"65","author":"Teodoridis","year":"2005","journal-title":"Cancer Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"A68","DOI":"10.5114\/wo.2014.47136","article-title":"The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge","volume":"19","author":"Tomczak","year":"2015","journal-title":"Contemp. Oncol. Pozn."},{"key":"B32","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1186\/s13148-019-0666-5","article-title":"DNA methylation at an enhancer of the three prime repair exonuclease 2 gene (TREX2) is linked to gene expression and survival in laryngeal cancer","volume":"11","author":"Weigel","year":"2019","journal-title":"Clin. Epigenetics"},{"key":"B33","doi-asserted-by":"publisher","first-page":"e1004996","DOI":"10.1371\/journal.pgen.1004996","article-title":"An integrative multi-scale analysis of the dynamic DNA methylation landscape in aging","volume":"11","author":"Yuan","year":"2015","journal-title":"PLoS Genet."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1585970\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T05:15:04Z","timestamp":1749618904000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1585970\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,11]]},"references-count":32,"alternative-id":["10.3389\/fgene.2025.1585970"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2025.1585970","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,11]]},"article-number":"1585970"}}