Age-related mutations and chronic myelomonocytic leukemia.
Age-related mutations and chronic myelomonocytic leukemia.
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慢性粒单核细胞白血病（CMML）是一种血液恶性肿瘤，几乎局限于老年人。以前的研究，以确定CMML的体细胞突变的发病率和预后意义依赖于候选基因测序，虽然没有进行无偏的突变搜索。由于CMML中常见突变的许多基因最近与年龄相关的克隆性造血（ARCH）相关，并且老年造血的特征是骨髓单核细胞分化偏好，因此我们假设CMML和老年造血可能密切相关。我们首先通过全外显子组测序和基因靶向验证建立了CMML的体细胞突变图谱。在大约10%的患者中突变的基因是SRSF2、TET2、ASXL1、RUNX1、SETBP1、KRAS、EZH2、CBL和NRAS，以及新的CMML基因FAT4、ARIH1、DNAH2和CSMD 1。大多数CMML患者（71%）存在102个ARCH基因突变，52%的患者总体上存在107个突变。较高的突变负荷与较短的生存期相关。经统计学校正的人群发病率和报告的CMML突变率与一个模型一致，在该模型中，当积累了足够数量的随机获得的年龄相关突变时，临床CMML增强，这表明CMML代表了骨髓单核细胞谱系偏向的老年造血系统的白血病转化。
Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy nearly confined to the elderly. Previous studies to determine incidence and prognostic significance of somatic mutations in CMML have relied on candidate gene sequencing, although an unbiased mutational search has not been conducted. As many of the genes commonly mutated in CMML were recently associated with age-related clonal hematopoiesis (ARCH) and aged hematopoiesis is characterized by a myelomonocytic differentiation bias, we hypothesized that CMML and aged hematopoiesis may be closely related. We initially established the somatic mutation landscape of CMML by whole exome sequencing followed by gene-targeted validation. Genes mutated in ⩾ 10% of patients were SRSF2, TET2, ASXL1, RUNX1, SETBP1, KRAS, EZH2, CBL and NRAS, as well as the novel CMML genes FAT4, ARIH1, DNAH2 and CSMD1. Most CMML patients (71%) had mutations in ⩾ 2 ARCH genes and 52% had ⩾ 7 mutations overall. Higher mutation burden was associated with shorter survival. Age-adjusted population incidence and reported ARCH mutation rates are consistent with a model in which clinical CMML ensues when a sufficient number of stochastically acquired age-related mutations has accumulated, suggesting that CMML represents the leukemic conversion of the myelomonocytic-lineage-biased aged hematopoietic system.
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DOI：
10.1038/gim.2011.68
发表时间：
2012-04
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
通讯作者：
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宇宙（癌症中的体细胞突变目录）数据库和网站。
影响因子：
8.8
作者：
Bamford, S;Dawson, E;Forbes, S;Clements, J;Pettett, R;Dogan, A;Flanagan, A;Teague, J;Futreal, PA;Stratton, MR;Wooster, R
通讯作者：
Wooster, R
影响因子：
8.8
作者：
McKerrell T;Park N;Moreno T;Grove CS;Ponstingl H;Stephens J;Understanding Society Scientific Group;Crawley C;Craig J;Scott MA;Hodkinson C;Baxter J;Rad R;Forsyth DR;Quail MA;Zeggini E;Ouwehand W;Varela I;Vassiliou GS
通讯作者：
Vassiliou GS
DOI：
10.1038/nri3062
发表时间：
2011-09-09
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA