LINE-1 hypomethylation is associated with poor outcomes in locoregionally advanced oropharyngeal cancer
Journal Title
Clinical Epigenetics
Publication Type
Research article
Abstract
BACKGROUND AND PURPOSE: Currently, human papillomavirus (HPV) positivity represents a strong prognostic factor for both reduced risk of relapse and improved survival in patients with oropharyngeal squamous cell carcinoma (OPSCC). However, a subset of HPV-positive OPSCC patients still experience poor outcomes. Furthermore, HPV-negative OPSCC patients, who have an even higher risk of relapse, are still lacking suitable prognostic biomarkers for clinical outcome. Here, we evaluated the prognostic value of LINE-1 methylation level in OPSCC patients and further addressed the relationship between LINE-1 methylation status and p53 protein expression as well as genome-wide/gene-specific DNA methylation. RESULTS: In this study, DNA was extracted from 163 formalin-fixed paraffin-embedded tissue samples retrospectively collected from stage III-IVB OPSCC patients managed with curative intent with up-front treatment. Quantitative methylation-specific PCR revealed that LINE-1 hypomethylation was directly associated with poor prognosis (5-year overall survival-OS: 28.1% for LINE-1 methylation < 35% vs. 69.1% for >/= 55%; p < 0.0001). When LINE-1 methylation was dichotomized as < 55% versus >/= 55%, interaction with HPV16 emerged: compared with hypermethylated HPV16-positive patients, subjects with hypomethylated HPV16-negative OPSCC reported an adjusted higher risk of death (HR 4.83, 95% CI 2.24-10.38) and progression (HR 4.54, 95% CI 2.18-9.48). Tumor protein p53 (TP53) gene is often mutated and overexpressed in HPV-negative OPSCC. Since p53 has been reported to repress LINE-1 promoter, we then analyzed the association between p53 protein expression and LINE-1 methylation levels. Following p53 immunohistochemistry, results indicated that among HPV16-negative patients with p53 >/= 50%, LINE-1 methylation levels declined and remained stable at approximately 43%; any HPV16-positive patient reported p53 >/= 50%. Finally, DNA methylation analysis demonstrated that genome-wide average methylation level at cytosine-phosphate-guanine sites was significantly lower in HPV16-negative OPSCC patients who relapsed within two years. The subsequent integrative analysis of gene expression and DNA methylation identified 20 up-regulated/hypomethylated genes in relapsed patients, and most of them contained LINE-1 elements in their promoter sequences. CONCLUSIONS: Evaluation of the methylation level of LINE-1 may help in identifying the subset of OPSCC patients with bad prognosis regardless of their HPV status. Aberrant LINE-1 hypomethylation might occur along with TP53 mutations and lead to altered gene expression in OPSCC.
Keywords
Humans; Tumor Suppressor Protein p53/genetics/metabolism; *Papillomavirus Infections/complications; Long Interspersed Nucleotide Elements; DNA Methylation; Retrospective Studies; Neoplasm Recurrence, Local/genetics; *Oropharyngeal Neoplasms; *Carcinoma, Squamous Cell/metabolism; Squamous Cell Carcinoma of Head and Neck/genetics; Prognosis; *Head and Neck Neoplasms/genetics; Hpv; Line-1; Oropharyngeal squamous cell carcinoma; p53
Department(s)
Laboratory Research
PubMed ID
36503584
Open Access at Publisher's Site
https://doi.org/10.1186/s13148-022-01386-5
Terms of Use/Rights Notice
Refer to copyright notice on published article.


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