Epigenetic priming in chronic liver disease impacts the transcriptional and genetic landscapes of hepatocellular carcinoma.
Epigenetic priming in chronic liver disease impacts the transcriptional and genetic landscapes of hepatocellular carcinoma.
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DOI：
10.1002/1878-0261.13154
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发表时间：
2022-03
影响因子：
6.6
通讯作者：
Piscuoglio S
中科院分区：
文献类型：
--
作者：
Gallon J;Coto-Llerena M;Ercan C;Bianco G;Paradiso V;Nuciforo S;Taha-Melitz S;Meier MA;Boldanova T;Pérez-Del-Pulgar S;Rodríguez-Tajes S;von Flüe M;Soysal SD;Kollmar O;Llovet JM;Villanueva A;Terracciano LM;Heim MH;Ng CKY;Piscuoglio S
肝细胞癌(HC)通常由慢性肝病(CLD)引起。在慢性炎症环境中的癌前细胞可能是表观遗传启动的，使它们对致癌转化敏感。我们调查了CLD中的表观遗传启动是否可能通过影响肝细胞癌的基因组和转录格局来影响肝细胞癌的预后。对10对CLD-肝癌DNA甲基化阵列的分析发现，与健康肝脏相比，有339个共同的CpG异常位点和18个共同的差异甲基化区域。这些区域与泛素D(UBD)、细胞色素P450家族2亚家族C成员19(CYP2C19)和O-6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)等相关基因的异常表达有关。甲基化改变在9对CLD-肝细胞癌的独立队列中被概括。在两个独立的肝癌队列中，CLD甲基化评分高，定义为CLD和肝癌中124个异常的CPG，与较差的存活率、增加的体细胞遗传改变和TP53突变有关。致癌基因转录和甲基化异常在CLD中很明显，在肝细胞癌中是复合的。CLD中的表观遗传启动塑造了肝细胞癌的转录格局，并创造了有利于获得基因改变的环境，这表明CLD中表观启动的程度可能会影响疾病的结局。慢性疾病肝脏(CLD)中的癌前细胞可能是表观遗传启动的，使它们对致癌转化敏感。我们调查了CLD中的表观遗传启动是否也影响肝细胞癌(HCC)的预后。我们发现，这雕刻了肝细胞癌转录组，创造了一个有利于获得基因改变的环境。我们基于DNA甲基化的评分显示了表观遗传启动在CLD中发生的程度，并影响了肝细胞癌的预后。
Hepatocellular carcinomas (HCCs) usually arise from chronic liver disease (CLD). Precancerous cells in chronically inflamed environments may be ‘epigenetically primed’, sensitising them to oncogenic transformation. We investigated whether epigenetic priming in CLD may affect HCC outcomes by influencing the genomic and transcriptomic landscapes of HCC. Analysis of DNA methylation arrays from 10 paired CLD‐HCC identified 339 shared dysregulated CpG sites and 18 shared differentially methylated regions compared with healthy livers. These regions were associated with dysregulated expression of genes with relevance in HCC, including ubiquitin D (UBD), cytochrome P450 family 2 subfamily C member 19 (CYP2C19) and O‐6‐methylguanine‐DNA methyltransferase (MGMT). Methylation changes were recapitulated in an independent cohort of nine paired CLD‐HCC. High CLD methylation score, defined using the 124 dysregulated CpGs in CLD and HCC in both cohorts, was associated with poor survival, increased somatic genetic alterations and TP53 mutations in two independent HCC cohorts. Oncogenic transcriptional and methylation dysregulation is evident in CLD and compounded in HCC. Epigenetic priming in CLD sculpts the transcriptional landscape of HCC and creates an environment favouring the acquisition of genetic alterations, suggesting that the extent of epigenetic priming in CLD could influence disease outcome. Precancerous cells in chronically diseased livers (CLD) may be ‘epigenetically primed’, sensitising them to oncogenic transformation. We investigated whether epigenetic priming in CLD also affects hepatocellular carcinoma (HCC) outcome. We found this sculpts the HCC transcriptome, creating an environment favouring the acquisition of genetic alterations. Our DNA methylation‐based score shows the extent to which epigenetic priming occurs in CLD and influences HCC outcome.
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影响因子：
25.7
作者：
Fujiwara N;Friedman SL;Goossens N;Hoshida Y
通讯作者：
Hoshida Y
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
乙型肝炎相关肝病肝祖细胞组织发生中的上皮-间质转化标志物分析。
影响因子：
2.6
作者：
Xu W;Wang NR;Wang HF;Feng Q;Deng J;Gong ZQ;Sun J;Lou XL;Yu XF;Zhou L;Hu JP;Huang XF;Qi XQ;Deng YJ;Gong R;Guo Y;Wang MM;Xiao JC;Deng H
通讯作者：
Deng H
影响因子：
28.2
作者：
Chang MT;Bhattarai TS;Schram AM;Bielski CM;Donoghue MTA;Jonsson P;Chakravarty D;Phillips S;Kandoth C;Penson A;Gorelick A;Shamu T;Patel S;Harris C;Gao J;Sumer SO;Kundra R;Razavi P;Li BT;Reales DN;Socci ND;Jayakumaran G;Zehir A;Benayed R;Arcila ME;Chandarlapaty S;Ladanyi M;Schultz N;Baselga J;Berger MF;Rosen N;Solit DB;Hyman DM;Taylor BS
通讯作者：
Taylor BS
影响因子：
3.7
作者：
Hlady, Ryan A.;Zhou, Dan;Robertson, Keith D.
通讯作者：
Robertson, Keith D.