Nature:慢性肝病患者细胞存在频繁的趋同进化

2021-10-14 haibei MedSci原创

最近,研究人员分析了34个肝脏样本中1,590个基因组的体细胞突变,包括健康对照组、酒精相关肝病和非酒精性脂肪肝。

慢性肝病最常见的原因是长期饮酒、非酒精性脂肪肝(NAFLD)和病毒性肝炎。非酒精性脂肪肝和酒精相关肝病(ARLD)有一个重叠的病理谱,肝细胞中的脂肪堆积(脂肪肝)在两者中都很突出。长期饮酒和热量过剩破坏了肝脏中的脂质处理,脂肪酸氧化减少,脂肪生成增加,甘油三酯输出受损,导致肝细胞中储存物质和有毒的脂质种类积累。

慢性肝病向肝细胞癌的发展是由影响20-30个癌基因的体细胞突变引起的。与正常肝脏相比,慢性肝病的体细胞突变负担更重,克隆扩展更大,这使得正选择能够塑造基因组景观。

最近,研究人员分析了34个肝脏样本中1,590个基因组的体细胞突变,包括健康对照组、酒精相关肝病和非酒精性脂肪肝。29名肝病患者中有7人在FOXO1中发生了突变,FOXO1是胰岛素信号传导的主要转录因子。这些突变影响了该基因内的一个热点,损害了胰岛素介导的FOXO1的出核

慢性肝病中汇聚的FOXO1基因突变。

值得注意的是,七名具有FOXO1S22W热点突变的患者中,有六名表现出趋同的进化,每个患者有多达九个不同的肝细胞克隆独立获得变体。

此外,调节肝细胞脂滴代谢的CIDEB,和从游离脂肪酸产生储存三酰甘油的GPAM,也有明显的突变过剩。研究人员再次观察到频繁的趋同进化:每个病人有CIDEB突变的独立克隆多达14个,每个病人有GPAM突变的独立克隆多达7个。

代谢基因的突变分布在肝脏的多个解剖区段,增加了克隆的大小,在酒精相关肝病和非酒精性脂肪肝中都能看到,但在肝细胞癌中很少见。

因此,该研究表明,代谢途径的主调控者是酒精相关和非酒精性脂肪肝中细胞趋同突变的频繁目标

 

原始出处:

Stanley W. K. Ng et al. Convergent somatic mutations in metabolism genes in chronic liver disease. Nature (2021). 

 

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    2021-12-18 liye789132251
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    2021-10-15 ms2000000182667314

    学到了

    0

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    2021-10-15 法荣

    受益

    0

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    2021-10-14 ms6000000133404500

    学习了,受益,谢谢!

    0

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