Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.
Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.
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DOI：
10.1056/nejmoa1409405
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发表时间：
2014-12-25
期刊：
影响因子：
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通讯作者：
McCarroll SA
中科院分区：
文献类型：
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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
癌症是由多个获得性突变引起的，这些突变可能发生多年。癌症发展的早期阶段可能在癌症变得临床明显之前几年就存在。我们分析了来自12，380人外周血细胞DNA全外显子组测序的数据，这些人被诊断为癌症或血液学表型。我们根据不寻常的等位基因片段鉴定了体细胞突变。我们使用瑞典国家患者登记处的数据，在DNA采样后跟踪2至7年的健康结果。在10%的65岁以上的人中观察到具有体细胞突变的克隆性造血，但在50岁以下的人中仅观察到1%。可检测的克隆扩增最常涉及三个基因（DNMT 3A、ASXL 1和TET 2）的体细胞突变，这些基因先前与血液学癌症有关。克隆性造血是随后发生血液系统癌症的一个强风险因素（风险比，12.9; 95%置信区间，5.8 - 28.7）。该队列中约42%的血液学癌症发生在首次诊断癌症前6个月进行DNA采样时具有克隆性的人中。对两名确诊为急性髓细胞白血病的患者的骨髓活检标本进行分析，发现他们的癌症来自早期克隆。具有体细胞突变的克隆造血很容易通过DNA测序检测到，随着人们年龄的增长越来越常见，并且与血液癌症和死亡的风险增加有关。在骨髓癌患者中突变的基因子集在表面健康的人中经常突变;这些突变可能代表血液癌发展中的特征性早期事件。（由国家人类基因组研究所和其他机构资助。
Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent. We analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes. We identified somatic mutations on the basis of unusual allelic fractions. We used data from Swedish national patient registers to follow health outcomes for 2 to 7 years after DNA sampling. Clonal hematopoiesis with somatic mutations was observed in 10% of persons older than 65 years of age but in only 1% of those younger than 50 years of age. Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (hazard ratio, 12.9; 95% confidence interval, 5.8 to 28.7). Approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling, more than 6 months before a first diagnosis of cancer. Analysis of bone marrow–biopsy specimens obtained from two patients at the time of diagnosis of acute myeloid leukemia revealed that their cancers arose from the earlier clones. Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers. (Funded by the National Human Genome Research Institute and others.)