Abstract
Abstract Background: Cancer cells are characterized by alterations of DNA methylation patterns involving global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Global DNA hypomethylation is thought to play a role in genetic instability and tumor aggressiveness. Long interspersed nucleotide element-1 (L1/LINE-1) repetitive elements represent 40% of the genome and their methylation is a good indicator of the global DNA methylation level. Although LINE-1 methylation has been previously shown to be associated with prognosis of patients with cancer, the value of LINE-1 methylation in predicting recurrence of patients with localized clear-cell renal cell carcinomas remains unknown. Material and Methods: We quantified the LINE-1 methylation using bisulfite pyrosequencing in cohort of 200 patients with resected clear-cell renal cell carcinomas (AJCC stage I-III). LINE-1 methylation of adjacent normal kidney was also assessed in 128 cases. Threshold of tumor LINE-1 hypomethylation was defined as LINE-1 methylation in normal samples minus three standard deviation. Results: Median methylation of tumor samples was 59.01% versus 61.61% for normal adjacent kidney samples (p<10-5). LINE-1 methylation level of normal adjacent kidney was associated with tumor size (Spearman R=0.21, P=0.02) but not with age (p=0.24) or Leibovitch score (p=0.05). Tumor LINE-1 hypomethylation was observed in 20 samples (n=10%). Strikingly, those were enriched for tumors occurring in female (60% versus 27.7%) (p=0.005); of note, no association was found between LINE-1 tumor hypomethylation and tumor grade (p=0.31), stage (p=1), age (p=0.24) and Leibovitch score (p=0.82). In multivariate analysis, only Leibovitch score and LINE-1 hypomethylation were independently associated with poor recurrence-free survival. Conclusion: LINE-1 hypomethylation is associated with shorter recurrence-free survival in patients with resected clear-cell renal cell carcinomas, suggesting the possibility of using it as predictive biomarker of recurrence. Citation Format: Gabriel G. Malouf, Roger Mouawad, Frederick Allanic, Eva Compérat, Morgan Roupret, David Khayat, Jean-Philippe Spano. LINE-1 tumor hypomethylation is associated with shorter recurrence-free survival in localized clear-cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2389. doi:10.1158/1538-7445.AM2017-2389
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