Long interspersed nuclear element 1 hypomethylation has novel prognostic value and potential utility in liquid biopsy for oral cavity cancer

• Published in: Biomarker Research
• Main Authors: Misawa, Kiyoshi, Yamada, Satoshi, Mima, Masato, Nakagawa, Takuya, Kurokawa, Tomoya, Imai, Atsushi, Mochizuki, Daiki, Shinmura, Daichi, Yamada, Taiki, Kita, Junya, Ishikawa, Ryuji, Yamaguchi, Yuki, Misawa, Yuki, Kanazawa, Takeharu, Kawasaki, Hideya, Mineta, Hiroyuki
• Format: Web Resource
• Language: English
• Published: Durham Research Square 07.10.2020
• Subjects: Biomarkers; Medical prognosis
• DOI: 10.21203/rs.3.rs-55509/v2

Background: New biomarkers are urgently needed to improve personalized treatment approaches for head and neck squamous cell carcinoma (HNSCC). Global DNA hypomethylation has wide-ranging functions in multistep carcinogenesis, and the hypomethylation of long interspersed nucleotide element-1 (LINE-1) has been generally considered to be related with increased retrotransposon activity and induced genome instability. However, little information is available regarding LINE-1 hypomethylation and its prognostic implications in HNSCC. Methods: In this study, we analyzed LINE-1 hypomethylation levels in a well-characterized dataset of 317 matched pairs of HNSCC tissues and oral cavity cancer (OCC) circulating tumor DNA (ctDNA) using quantitative real-time methylation and unmethylation PCR. This analysis was performed according to various clinical characteristics and prognostic implications. Results: Our results demonstrated that LINE-1 hypomethylation levels were significantly higher in HNSCC tissues than in corresponding normal tissues from the same individuals (P < 0.001). Univariate analysis revealed that high levels of LINE-1 hypomethylation were correlated with poor disease-free survival (DFS; log-rank test, P = 0.038), whereas multivariate analysis demonstrated that it is a significant independent prognostic factor for DFS (hazard ratio: 2.10, 95% confidence interval: 1.02–4.36; P = 0.045). Moreover, patients with high LINE-1 hypomethylation levels exhibited the greatest decrease in 5-hydroxymethylcytosine (5-hmC) levels and increase in tumor-suppressor gene methylation index (P = 0.006 and P < 0.001, respectively). Further ctDNA studies also showed that LINE-1 hypomethylation had high predictive ability for OCC. Conclusions: LINE-1 hypomethylation is associated with a higher risk of early OCC relapse, and is hence, a potential predictive biomarker for OCC. Furthermore, 5-hmC levels also exhibited predictive potential in OCC, based on its inverse correlation with LINE-1 hypomethylation levels. LINE-1 hypomethylation analysis, therefore, has applications in determining patient prognosis and real-time surveillance for disease recurrence, and could serve as an alternative method for OCC screening.