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“良性”疾病的体细胞突变
Somatic Mutations in “Benign” Disease


Satu Mustjoki ... 其他 • 2021.05.27

1866年,威廉·古尔爵士(Sir William Gull)描述了一名烟囱清洁工患“间歇性血红素尿”(一种血管内溶血综合征)。1882年,保罗·史卓宾(Paul Strübing)博士将这种疾病命名为阵发性睡眠性血红蛋白尿(PNH)1。科学家使用简单的红细胞凝胶,强力分离极少量的粒细胞,并最终鉴定出基因PIGA突变(PIGA基因产物是呈递糖基磷脂酰肌醇(GPI)锚定的细胞表面蛋白所必需的),这些使我们认识到PNH是由造血干细胞的获得性突变引起的2,3。2020年,“基因组学优先”(genomics first)方法帮助我们发现了同样起源于造血干细胞的蛋白质降解基因UBA1突变,并发现了与其相关的重度炎症综合征4。体细胞突变被描述为“隐藏于众目睽睽之下”5,但数十年来,我们已认识到体细胞突变是成人罕见病和婴儿组织镶嵌现象(这些婴儿的遗传综合征是固有的,但不是因胚胎起源而遗传的)的原因6-10

突变在传统上被分成生殖细胞系突变或在生命中获得的体细胞突变。有害的生殖细胞系突变通常会导致儿童期发病,常累及多个器官,并有家族史。体细胞突变被认为是癌症(老年人的主要疾病)的起源,且会导致癌细胞表型。我们在本文中综述了体细胞突变的一个不太为人们熟悉,也比较少探讨的方面,即作为“良性”疾病的病因。这里的“良性”一词表示“非恶性”,但许多“良性”综合征也会导致严重疾病和死亡。深度核苷酸测序和单细胞分析已确定体细胞突变是人类多种疾病的原因(见补充附录表S1,补充附录与本文全文可在NEJM.org获取)。随着这些先进方法在整个医学领域的应用,这类疾病的清单将会扩大。测序表明,所有组织中的健康细胞都承受着沉重的突变负担11,12,突变并非例外,而是常态。健康器官中癌基因突变的存在模糊了癌症和健康组织之间的基因组界限,以及固有疾病和获得性疾病之间的界限。此外,一些“良性”疾病会发生恶性转化。





作者信息

Satu Mustjoki, M.D., and Neal S. Young, M.D.
From the Translational Immunology Research Program and the Department of Clinical Chemistry and Hematology, University of Helsinki, the Hematology Research Unit, Helsinki University Hospital Comprehensive Cancer Center, and the iCAN Digital Precision Cancer Medicine Flagship — all in Helsinki (S.M.); and the Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD (N.S.Y.). Address reprint requests to Dr. Mustjoki at the Translational Immunology Research Program, Faculty of Medicine, P.O. Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Helsinki, Finland, or at satu.mustjoki@helsinki.fi; or to Dr. Young at the National Heart, Lung, and Blood Institute, Bldg. 10-CRC, Rm. 3E-5140, 10 Center Dr., Bethesda, MD 20892-1202, or at youngns@mail.nih.gov.

 

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