Methylome sequencing for fibrolamellar hepatocellular carcinoma depicts distinctive features

Gabriel G. Malouf, Tomomitsu Tahara, Valerie Paradis, Monique Fabre, Catherine Guettier, Jumpei Yamazaki, Hi Long, Yue Lu, Noel J.M. Raynal, Jaroslav Jelinek, Roger Mouawad, David Khayat, Laurence Brugieres, Eric Raymond, Jean Pierre J. Issa

研究成果: Article査読

14 被引用数 (Scopus)

抄録

With the goal of studying epigenetic alterations in fibrolamellar hepatocellular carcinoma (FLC) and establish an associated DNA methylation signature, we analyzed LINE-1 methylation in a cohort of FLC and performed next- generation sequencing of DNA methylation in a training set of pure-FLCs and non-cirrhotic hepatocellular carcinomas (nc-HCC). DNA methylation was correlated with gene expression. Furthermore, we established and validated an epigenetic signature differentiating pure-FLC from other HCCs. LINE-1 methylation correlated with shorter recurrence- free survival and overall survival in resected pure-FLC patients. Unsupervised clustering using CG sites located in islands distinguished pure-FLC from nc-HCC. Major DNA methylation changes occurred outside promoters, mainly in gene bodies and intergenic regions located in the vicinity of liver developmental genes (i.e., SMARCA4 and RXRA). Partially methylated domains were more prone to DNA methylation changes. Furthermore, we identified several putative tumor suppressor genes (e.g., DLEU7) and oncogenes (e.g., DUSP4). While ̴70% of identified gene promoters gaining methylation were marked by bivalent histone marks (H3K4me3/H3K27me3) in embryonic stem cells, ̴70% of those losing methylation were marked by H3K4me3. Finally, we established a pure FLC DNA methylation signature and validated it in an independent dataset. Our analysis reveals a distinct epigenetic signature of pure FLC as compared to nc-HCC, with DNA methylation changes occurring in the vicinity of liver developmental genes. These data suggest new options for targeting FLC based on cancer epigenome aberrations.

本文言語English
ページ(範囲)872-881
ページ数10
ジャーナルEpigenetics
10
9
DOI
出版ステータスPublished - 2015
外部発表はい

All Science Journal Classification (ASJC) codes

  • 分子生物学
  • 癌研究

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