携带 AML 相关突变的克隆性造血在健康成年人中普遍存在。

Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults.

机构信息

Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, Saint Louis, Missouri 63108, USA.

Center for Genome Sciences and Systems Biology, Washington University School of Medicine, Saint Louis, Missouri 63108, USA.

出版信息

Nat Commun. 2016 Aug 22;7:12484. doi: 10.1038/ncomms12484.

Abstract

Clonal haematopoiesis is thought to be a rare condition that increases in frequency with age and predisposes individuals to haematological malignancy. Recent studies, utilizing next-generation sequencing (NGS), observed haematopoietic clones in 10% of 70-year olds and rarely in younger individuals. However, these studies could only detect common haematopoietic clones->0.02 variant allele fraction (VAF)-due to the error rate of NGS. To identify and characterize clonal mutations below this threshold, here we develop methods for targeted error-corrected sequencing, which enable the accurate detection of clonal mutations as rare as 0.0003 VAF. We apply these methods to study serially banked peripheral blood samples from healthy 50-60-year-old participants in the Nurses' Health Study. We observe clonal haematopoiesis, frequently harbouring mutations in DNMT3A and TET2, in 95% of individuals studied. These clonal mutations are often stable longitudinally and present in multiple haematopoietic compartments, suggesting a long-lived haematopoietic stem and progenitor cell of origin.

摘要

克隆性造血被认为是一种罕见的情况,随着年龄的增长而增加频率,并使个体易患血液恶性肿瘤。最近的研究利用下一代测序(NGS)在 10%的 70 岁老年人中观察到造血克隆,但在年轻个体中很少见。然而,由于 NGS 的错误率,这些研究只能检测到常见的造血克隆(<0.02 变异等位基因分数(VAF)。为了在这个阈值以下识别和表征克隆突变,我们在这里开发了针对靶向纠错测序的方法,这些方法能够准确检测到罕见的克隆突变,低至 0.0003 VAF。我们将这些方法应用于研究来自健康 50-60 岁护士健康研究参与者的定期保存的外周血样本。我们观察到克隆性造血,在 95%的研究个体中经常存在 DNMT3A 和 TET2 突变。这些克隆突变通常在纵向稳定存在,并存在于多个造血区室中,提示存在起源于长寿造血干细胞和祖细胞的克隆突变。

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