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

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)872-881
Number of pages10
JournalEpigenetics
Volume10
Issue number9
DOIs
Publication statusPublished - 01-01-2015

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DNA Methylation
Methylation
Epigenomics
Developmental Genes
Hepatocellular Carcinoma
Histone Code
Body Regions
Intergenic DNA
Survival
Fibrolamellar hepatocellular carcinoma
Liver
Embryonic Stem Cells
Tumor Suppressor Genes
Oncogenes
Islands
Genes
Cluster Analysis
Gene Expression
Recurrence
Neoplasms

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

Cite this

Malouf, G. G., Tahara, T., Paradis, V., Fabre, M., Guettier, C., Yamazaki, J., ... Issa, J. P. J. (2015). Methylome sequencing for fibrolamellar hepatocellular carcinoma depicts distinctive features. Epigenetics, 10(9), 872-881. https://doi.org/10.1080/15592294.2015.1076955
Malouf, Gabriel G. ; Tahara, Tomomitsu ; Paradis, Valerie ; Fabre, Monique ; Guettier, Catherine ; Yamazaki, Jumpei ; Long, Hi ; Lu, Yue ; Raynal, Noel J.M. ; Jelinek, Jaroslav ; Mouawad, Roger ; Khayat, David ; Brugieres, Laurence ; Raymond, Eric ; Issa, Jean Pierre J. / Methylome sequencing for fibrolamellar hepatocellular carcinoma depicts distinctive features. In: Epigenetics. 2015 ; Vol. 10, No. 9. pp. 872-881.
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Malouf, GG, Tahara, T, Paradis, V, Fabre, M, Guettier, C, Yamazaki, J, Long, H, Lu, Y, Raynal, NJM, Jelinek, J, Mouawad, R, Khayat, D, Brugieres, L, Raymond, E & Issa, JPJ 2015, 'Methylome sequencing for fibrolamellar hepatocellular carcinoma depicts distinctive features', Epigenetics, vol. 10, no. 9, pp. 872-881. https://doi.org/10.1080/15592294.2015.1076955

Methylome sequencing for fibrolamellar hepatocellular carcinoma depicts distinctive features. / Malouf, Gabriel G.; Tahara, Tomomitsu; Paradis, Valerie; Fabre, Monique; Guettier, Catherine; Yamazaki, Jumpei; Long, Hi; Lu, Yue; Raynal, Noel J.M.; Jelinek, Jaroslav; Mouawad, Roger; Khayat, David; Brugieres, Laurence; Raymond, Eric; Issa, Jean Pierre J.

In: Epigenetics, Vol. 10, No. 9, 01.01.2015, p. 872-881.

Research output: Contribution to journalArticle

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T1 - Methylome sequencing for fibrolamellar hepatocellular carcinoma depicts distinctive features

AU - Malouf, Gabriel G.

AU - Tahara, Tomomitsu

AU - Paradis, Valerie

AU - Fabre, Monique

AU - Guettier, Catherine

AU - Yamazaki, Jumpei

AU - Long, Hi

AU - Lu, Yue

AU - Raynal, Noel J.M.

AU - Jelinek, Jaroslav

AU - Mouawad, Roger

AU - Khayat, David

AU - Brugieres, Laurence

AU - Raymond, Eric

AU - Issa, Jean Pierre J.

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