Xie Mingchao, Lu Charles, Wang Jiayin, McLellan Michael D, Johnson Kimberly J, Wendl Michael C, McMichael Joshua F, Schmidt Heather K, Yellapantula Venkata, Miller Christopher A, Ozenberger Bradley A, Welch John S, Link Daniel C, Walter Matthew J, Mardis Elaine R, Dipersio John F, Chen Feng, Wilson Richard K, Ley Timothy J, Ding Li
1] The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.
Nat Med. 2014 Dec;20(12):1472-8. doi: 10.1038/nm.3733. Epub 2014 Oct 19.
Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. The Cancer Genome Atlas (TCGA) provides a unique resource for comprehensive discovery of mutations and genes in blood that may contribute to the clonal expansion of hematopoietic stem/progenitor cells. Here, we analyzed blood-derived sequence data from 2,728 individuals from TCGA and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia and/or lymphoma-associated genes, and nine were recurrently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5-6% of people older than 70 years) contain mutations that may represent premalignant events that cause clonal hematopoietic expansion.
在没有明显血液系统恶性肿瘤的个体血液中，已检测到几种白血病和淋巴瘤特有的基因改变。癌症基因组图谱（TCGA）为全面发现血液中可能导致造血干/祖细胞克隆性扩增的突变和基因提供了独特资源。在此，我们分析了来自TCGA的2728名个体的血液来源序列数据，在癌症相关基因中发现了77个血液特异性突变，其中大多数与高龄有关。值得注意的是，这些突变中有83%来自19个白血病和/或淋巴瘤相关基因，9个基因发生了反复突变（DNMT3A、TET2、JAK2、ASXL1、TP53、GNAS、PPM1D、BCORL1和SF3B1）。我们在极少数血细胞中又鉴定出14个突变，可能代表造血干细胞克隆性扩增的最早阶段。将这些发现与血液系统恶性肿瘤中的突变进行比较，确定了几个可能是疾病起始因素的反复突变基因。我们的分析表明，超过2%的个体（70岁以上人群的5 - 6%）的血细胞含有可能代表导致克隆性造血扩增的癌前事件的突变。
