title: Methylome sequencing for fibrolamellar hepatocellular carcinoma depicts distinctive features.
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.
authors.affiliation: a Department of Leukemia ; the University of Texas MD Anderson Cancer Center ; Houston , TX USA.
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Malouf
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Tahara
authors.forename: Valérie
authors.initials: V
authors.lastname: Paradis
authors.forename: Monique
authors.initials: M
authors.lastname: Fabre
authors.forename: Catherine
authors.initials: C
authors.lastname: Guettier
authors.forename: Jumpei
authors.initials: J
authors.lastname: Yamazaki
authors.forename: Hi
authors.initials: H
authors.lastname: Long
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.forename: Noël J-M
authors.initials: NJ
authors.lastname: Raynal
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Jelinek
authors.forename: Roger
authors.initials: R
authors.lastname: Mouawad
authors.forename: David
authors.initials: D
authors.lastname: Khayat
authors.forename: Laurence
authors.initials: L
authors.lastname: Brugières
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
mesh_terms: D000293:Adolescent; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002648:Child; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA / Q000379:methods*; D016019:Survival Analysis; D055815:Young Adult
keywords: DNA methylation; LINE-1; fibrolamellar carcinoma; next-generation sequencing; oncogenes; partially methylated domains; tumor suppressor genes