Prediction of acute myeloid leukaemia risk in healthy individuals.
Prediction of acute myeloid leukaemia risk in healthy individuals.
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在健康个体中预测急性髓样白血病的风险。
DOI：
10.1038/s41586-018-0317-6
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发表时间：
2018-07
期刊：
影响因子：
64.8
通讯作者：
Shlush LI
中科院分区：
文献类型：
--
作者：
Abelson S;Collord G;Ng SWK;Weissbrod O;Mendelson Cohen N;Niemeyer E;Barda N;Zuzarte PC;Heisler L;Sundaravadanam Y;Luben R;Hayat S;Wang TT;Zhao Z;Cirlan I;Pugh TJ;Soave D;Ng K;Latimer C;Hardy C;Raine K;Jones D;Hoult D;Britten A;McPherson JD;Johansson M;Mbabaali F;Eagles J;Miller JK;Pasternack D;Timms L;Krzyzanowski P;Awadalla P;Costa R;Segal E;Bratman SV;Beer P;Behjati S;Martincorena I;Wang JCY;Bowles KM;Quirós JR;Karakatsani A;La Vecchia C;Trichopoulou A;Salamanca-Fernández E;Huerta JM;Barricarte A;Travis RC;Tumino R;Masala G;Boeing H;Panico S;Kaaks R;Krämer A;Sieri S;Riboli E;Vineis P;Foll M;McKay J;Polidoro S;Sala N;Khaw KT;Vermeulen R;Campbell PJ;Papaemmanuil E;Minden MD;Tanay A;Balicer RD;Wareham NJ;Gerstung M;Dick JE;Brennan P;Vassiliou GS;Shlush LI
急性髓性白血病（AML）的发病率随着年龄的增长而增加，65岁以后确诊时死亡率超过90%。大多数病例没有可检测到的前驱症状，并出现骨髓衰竭的急性并发症。这种新发AML病例的发作通常在经历克隆扩增的前白血病造血干细胞和祖细胞（HSPC）中体细胞突变的积累之前。然而，复发性AML突变也会在未发生AML的健康个体的衰老过程中在HSPC中积累，这种现象称为年龄相关性克隆造血（AML）。为了区分患有AML的高风险个体与患有良性AML的个体，我们对AML诊断前平均6.3年采样的95名个体（AML前组）的外周血细胞中AML复发突变的基因进行了深度测序，以及414名年龄和性别匹配的个体（对照组）。前AML病例与对照不同，每个样本具有更多的突变，更高的变异等位基因频率（VAF）反映了更大的克隆扩增，以及特定基因突变的富集。使用遗传参数推导出准确预测无AML生存期的模型;该模型在29例前AML和262例对照的独立队列中进行了验证。由于AML很罕见，我们还使用大型电子健康记录数据库开发了一个AML预测模型，该数据库可以识别出风险更高的个体。总的来说，我们的研究结果提供了一个概念验证，即在恶性转化之前许多年就可以将AML与前AML区分开来。这可能在未来实现更早的检测，监测和潜在的知情干预。
The incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without a detectable prodrome and present with the acute complications of bone marrow failure. The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in pre-leukaemic haematopoietic stem and progenitor cells (HSPC) that undergo clonal expansion. However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis (ARCH),. To distinguish individuals at high risk of developing AML from those with benign ARCH, we undertook deep sequencing of genes recurrently mutated in AML in the peripheral blood cells of 95 individuals sampled on average 6.3 years before AML diagnosis (pre-AML group), together with 414 unselected age- and gender-matched individuals (control group). Pre-AML cases were distinct from controls with more mutations per sample, higher variant allele frequencies (VAF) reflective of greater clonal expansion, and enrichment for mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival; this model was validated in an independent cohort of 29 pre-AMLs and 262 controls. Since AML is rare, we also developed an AML predictive model using a large electronic health record database that identified individuals at greater risk. Collectively our findings provide a proof-of-concept that it is possible to discriminate ARCH from pre-AML many years prior to malignant transformation. This could in the future enable earlier detection, monitoring and potentially inform intervention.
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影响因子：
12.3
作者：
Buels R;Yao E;Diesh CM;Hayes RD;Munoz-Torres M;Helt G;Goodstein DM;Elsik CG;Lewis SE;Stein L;Holmes IH
通讯作者：
Holmes IH
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
影响因子：
9.8
作者：
Acuna-Hidalgo, Rocio;Sengul, Hilal;Hoischen, Alexander
通讯作者：
Hoischen, Alexander
影响因子：
--
作者：
Hu L;Li M;Ding Y;Pu L;Liu J;Xie J;Cabanero M;Li J;Xiang R;Xiong S
通讯作者：
Xiong S
DOI：
10.1056/nejmoa1701719
发表时间：
2017-07-13
期刊：
The New England journal of medicine
影响因子：
--
作者：
Jaiswal S;Natarajan P;Silver AJ;Gibson CJ;Bick AG;Shvartz E;McConkey M;Gupta N;Gabriel S;Ardissino D;Baber U;Mehran R;Fuster V;Danesh J;Frossard P;Saleheen D;Melander O;Sukhova GK;Neuberg D;Libby P;Kathiresan S;Ebert BL
通讯作者：
Ebert BL