Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress
Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress
复制标题
DOI：
10.1038/s41467-018-07552-9
复制
发表时间：
2018-12-07
影响因子：
16.6
通讯作者：
Letouze, Eric
中科院分区：
文献类型：
--
作者：
Bayard, Quentin;Meunier, Lea;Letouze, Eric
细胞周期蛋白A2和EL通过促进S期的进入和进展来调节细胞周期。在这里，我们确定了一个肝细胞癌亚群，通过不同的机制表现出周期蛋白的激活，包括乙肝病毒(乙肝病毒)和腺相关病毒2型(AAV2)的插入，增强子劫持和复发的CcNA2融合。Cyclin A2或E1的改变定义了侵袭性肝癌的同质性实体，主要发生在非肝硬变患者中，其特征是E2F和ATR通路的转录激活，以及RB1和PTEN的高频率失活。细胞周期蛋白驱动的肝细胞癌表现出独特的结构重排特征，有数百个串联重复和模板插入，经常激活TERT启动子。这些重排强烈地富含在早期复制的活性染色质区域，与断裂诱导的复制机制一致。泛癌分析显示，BRCA1突变的乳腺癌和卵巢癌也有类似的特征。总之，这项分析揭示了一个新的预后不良的肝细胞癌实体和一个与复制应激相关的重排特征。
Cyclins A2 and El regulate the cell cycle by promoting S phase entry and progression. Here, we identify a hepatocellular carcinoma (HCC) subgroup exhibiting cyclin activation through various mechanisms including hepatitis B virus (HBV) and adeno-associated virus type 2 (AAV2) insertions, enhancer hijacking and recurrent CCNA2 fusions. Cyclin A2 or E1 alterations define a homogenous entity of aggressive HCC, mostly developed in non-cirrhotic patients, characterized by a transcriptional activation of E2F and ATR pathways and a high frequency of RB1 and PTEN inactivation. Cyclin-driven HCC display a unique signature of structural rearrangements with hundreds of tandem duplications and templated insertions frequently activating TERT promoter. These rearrangements, strongly enriched in early-replicated active chromatin regions, are consistent with a break-induced replication mechanism. Pan-cancer analysis reveals a similar signature in BRCA1-mutated breast and ovarian cancers. Together, this analysis reveals a new poor prognosis HCC entity and a rearrangement signature related to replication stress.