TY - JOUR
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.
N1 - Publisher Copyright:
© 2015 Taylor & Francis Group, LLC.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - DNA methylation
KW - Fibrolamellar carcinoma
KW - LINE-1
KW - Next-generation sequencing
KW - Oncogenes
KW - Partially methylated domains
KW - Tumor suppressor genes
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U2 - 10.1080/15592294.2015.1076955
DO - 10.1080/15592294.2015.1076955
M3 - Article
C2 - 26224146
AN - SCOPUS:84954561784
SN - 1559-2294
VL - 10
SP - 872
EP - 881
JO - Epigenetics
JF - Epigenetics
IS - 9
ER -