Epigenome-wide gene-age interaction study reveals reversed effects of MORN1 DNA methylation on survival between young and elderly oral squamous cell carcinoma patients

Ziang Xu; Yan Gu; Jiajin Chen; Xinlei Chen; Yunjie Song; Juanjuan Fan; Xinyu Ji; Yanyan Li; Wei Zhang; Ruyang Zhang

doi:10.3389/fonc.2022.941731

Epigenome-wide gene-age interaction study reveals reversed effects of MORN1 DNA methylation on survival between young and elderly oral squamous cell carcinoma patients

Front Oncol. 2022 Jul 28:12:941731. doi: 10.3389/fonc.2022.941731. eCollection 2022.

Authors

Ziang Xu^{1

2}, Yan Gu^{1

3

4}, Jiajin Chen⁵, Xinlei Chen^{1

2}, Yunjie Song⁵, Juanjuan Fan⁵, Xinyu Ji⁵, Yanyan Li^{1

2}, Wei Zhang^{1

2}, Ruyang Zhang^{5

6}

Affiliations

¹ Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.
² Department of Oral Special Consultation, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.
³ Department of Orthodontics, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.
⁴ Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China.
⁵ Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
⁶ China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China.

Abstract

DNA methylation serves as a reversible and prognostic biomarker for oral squamous cell carcinoma (OSCC) patients. It is unclear whether the effect of DNA methylation on OSCC overall survival varies with age. As a result, we performed a two-phase gene-age interaction study of OSCC prognosis on an epigenome-wide scale using the Cox proportional hazards model. We identified one CpG probe, cg11676291 _MORN1 , whose effect was significantly modified by age (HR_discovery = 1.018, p = 4.07 × 10^-07, FDR-q = 3.67 × 10^-02; HR_validation = 1.058, p = 8.09 × 10^-03; HR _combined = 1.019, p = 7.36 × 10^-10). Moreover, there was an antagonistic interaction between hypomethylation of cg11676291 _MORN1 and age (HR_interaction = 0.284; 95% CI, 0.135-0.597; p = 9.04 × 10^-04). The prognosis of OSCC patients was well discriminated by the prognostic score incorporating cg11676291 _MORN1 -age interaction (HR _{high vs. low} = 3.66, 95% CI: 2.40-5.60, p = 1.93 × 10^-09). By adding 24 significant gene-age interactions using a looser criterion, we significantly improved the area under the receiver operating characteristic curve (AUC) of the model at 3- and 5-year prognostic prediction (AUC_3-year = 0.80, AUC_5-year = 0.79, C-index = 0.75). Our study identified a significant interaction between cg11676291 _MORN1 and age on OSCC survival, providing a potential therapeutic target for OSCC patients.

Keywords: DNA methylation; OSCC; age; gene–age interaction analysis; overall survival.