PMID- 33005105 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220417 IS - 1475-2867 (Print) IS - 1475-2867 (Electronic) IS - 1475-2867 (Linking) VI - 20 DP - 2020 TI - Identification and validation of methylation-driven genes prognostic signature for recurrence of laryngeal squamous cell carcinoma by integrated bioinformatics analysis. PG - 472 LID - 10.1186/s12935-020-01567-3 [doi] LID - 472 AB - BACKGROUND: Recurrence remains a major obstacle to long-term survival of laryngeal squamous cell carcinoma (LSCC). We conducted a genome-wide integrated analysis of methylation and the transcriptome to establish methylation-driven genes prognostic signature (MDGPS) to precisely predict recurrence probability and optimize therapeutic strategies for LSCC. METHODS: LSCC DNA methylation datasets and RNA sequencing (RNA-seq) dataset were acquired from the Cancer Genome Atlas (TCGA). MethylMix was applied to detect DNA methylation-driven genes (MDGs). By univariate and multivariate Cox regression analyses, five genes of DNA MDGs was developed a recurrence-free survival (RFS)-related MDGPS. The predictive accuracy and clinical value of the MDGPS were evaluated by receiver operating characteristic (ROC) and decision curve analysis (DCA), and compared with TNM stage system. Additionally, prognostic value of MDGPS was validated by external Gene Expression Omnibus (GEO) database. According to 5 MDGs, the candidate small molecules for LSCC were screen out by the CMap database. To strengthen the bioinformatics analysis results, 30 pairs of clinical samples were evaluated by digoxigenin-labeled chromogenic in situ hybridization (CISH). RESULTS: A total of 88 DNA MDGs were identified, and five RFS-related MDGs (LINC01354, CCDC8, PHYHD1, MAGEB2 and ZNF732) were chosen to construct a MDGPS. The MDGPS can effectively divide patients into high-risk and low-risk group, with the area under curve (AUC) of 0.738 (5-year RFS) and AUC of 0.74 (3-year RFS). Stratification analysis affirmed that the MDGPS was still a significant statistical prognostic model in subsets of patients with different clinical variables. Multivariate Cox regression analysis indicated the efficacy of MDGPS appears independent of other clinicopathological characteristics. In terms of predictive capacity and clinical usefulness, the MDGPS was superior to traditional TNM stage. Additionally, the MDGPS was confirmed in external LSCC cohorts from GEO. CMap matched the 9 most significant small molecules as promising therapeutic drugs to reverse the LSCC gene expression. Finally, CISH analysis in 30 LSCC tissues and paired adjacent normal tissues revealed that MAGEB2 has significantly higher expression of LSCC compared to adjacent non-neoplastic tissues; LINC01354, CCDC8, PHYHD1, and ZNF732 have significantly lower expression of LSCC compared to adjacent non-neoplastic tissues, which were in line with bioinformatics analysis results. CONCLUSION: A MDGPS, with five DNA MDGs, was identified and validated in LSCC patients by combining transcriptome and methylation datasets analysis. Compared TNM stage alone, it generates more accurate estimations of the recurrence prediction and maybe offer novel research directions and prospects for individualized treatment of patients with LSCC. CI - (c) The Author(s) 2020. FAU - Cui, Jie AU - Cui J AD - Department of Head and Neck Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095 Guangdong P. R. China. GRID: grid.410737.6. ISNI: 0000 0000 8653 1072 FAU - Wang, Liping AU - Wang L AD - Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Hainan Medical University, Haikou, 570102 Hainan P. R. China. GRID: grid.443397.e. ISNI: 0000 0004 0368 7493 FAU - Zhong, Waisheng AU - Zhong W AD - Department of Head Neck Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000 Hunan P. R. China. GRID: grid.216417.7. ISNI: 0000 0001 0379 7164 FAU - Chen, Zhen AU - Chen Z AD - Department of Intensive Care Unit, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, 528308, Guangdong P. R. China. GRID: grid.284723.8. ISNI: 0000 0000 8877 7471 FAU - Chen, Jie AU - Chen J AD - Department of Head Neck Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000 Hunan P. R. China. GRID: grid.216417.7. ISNI: 0000 0001 0379 7164 FAU - Yang, Hong AU - Yang H AD - Department of Head and Neck Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095 Guangdong P. R. China. GRID: grid.410737.6. ISNI: 0000 0000 8653 1072 FAU - Liu, Genglong AU - Liu G AUID- ORCID: 0000-0002-9163-4396 AD - Department of Pathology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095 Guangdong P. R. China. GRID: grid.410737.6. ISNI: 0000 0000 8653 1072 LA - eng PT - Journal Article DEP - 20200929 PL - England TA - Cancer Cell Int JT - Cancer cell international JID - 101139795 PMC - PMC7526132 OTO - NOTNLM OT - DNA methylation-driven genes OT - Epigenetics OT - Laryngeal squamous cell carcinoma OT - Prediction OT - Recurrence-free survival COIS- Competing interestsThe authors declare that they have no competing interests. EDAT- 2020/10/03 06:00 MHDA- 2020/10/03 06:01 PMCR- 2020/09/29 CRDT- 2020/10/02 05:43 PHST- 2020/04/24 00:00 [received] PHST- 2020/09/23 00:00 [accepted] PHST- 2020/10/02 05:43 [entrez] PHST- 2020/10/03 06:00 [pubmed] PHST- 2020/10/03 06:01 [medline] PHST- 2020/09/29 00:00 [pmc-release] AID - 1567 [pii] AID - 10.1186/s12935-020-01567-3 [doi] PST - epublish SO - Cancer Cell Int. 2020 Sep 29;20:472. doi: 10.1186/s12935-020-01567-3. eCollection 2020.