DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions
DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions
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DOI：
10.1182/blood-2017-04-777029
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发表时间：
2017-08-10
期刊：
影响因子：
20.3
通讯作者：
Busque, Lambert
中科院分区：
文献类型：
--
作者：
Buscarlet, Manuel;Provost, Sylvie;Busque, Lambert
由髓系癌相关基因获得性突变引起的年龄相关克隆造血在正常人群中非常普遍。其病因、对造血的生物学影响和致癌风险目前尚未明确。为了深入了解这一现象，我们分析了2530名相关和非相关血液学正常个体（年龄55至101岁）的队列。我们使用了一种敏感的基因靶向深度测序方法来精确地获得驱动突变的确切患病率和受影响基因的比例。突变状态与生物学参数相关。我们报告了更高的驱动突变总体患病率（13.7%），其中大部分（93%）发生在DNMT3A或TET2中，并且与年龄高度相关。这两个基因的突变对末端有不同的影响。TET2突变更具年龄依赖性，与中度中性粒细胞减少效应相关（9%，P= 0.012），表现出家族聚集性，并与慢性阻塞性肺疾病相关。DNMT3A突变对血液计数或指标没有影响。这两个基因的突变负担与x失活偏态相关，但与年龄调整的端粒长度减少没有显著关联。这两个基因突变的高流行率与它们有限的生物学影响之间的不一致提出了表观遗传修饰因子失调在正常衰老造血中的潜在作用的问题，这可能包括支持造血失败。
Age-associated clonal hematopoiesis caused by acquired mutations in myeloid cancer-associated genes is highly prevalent in the normal population. Its etiology, biological impact on hematopoiesis, and oncogenic risk is poorly defined at this time. To gain insight into this phenomenon, we analyzed a cohort of 2530 related and unrelated hematologically normal individuals (ages 55 to 101 years). We used a sensitive gene-targeted deep sequencing approach to gain precision on the exact prevalence of driver mutations and the proportions of affected genes. Mutational status was correlated with biological parameters. We report a higher overall prevalence of driver mutations (13.7%), which occurred mostly (93%) in DNMT3A or TET2 and were highly age-correlated. Mutation in these 2 genes had some distinctive effects on end points. TET2 mutations were more age-dependent, associated with a modest neutropenic effect (9%, P=.012), demonstrated familial aggregation, and associated with chronic obstructive pulmonary disease. Mutations in DNMT3A had no impact on blood counts or indices. Mutational burden of both genes correlated with X-inactivation skewing but no significant association with age-adjusted telomere length reduction was documented. The discordance between the high prevalence of mutations in these 2 genes and their limited biological impact raise the question of the potential role of dysregulated epigenetic modifiers in normal aging hematopoiesis, which may include support to failing hematopoiesis.