Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis
Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis
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DOI：
10.1182/blood-2011-12-397620
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发表时间：
2012-06-21
期刊：
影响因子：
20.3
通讯作者：
Maciejewski, Jaroslaw P.
中科院分区：
文献类型：
--
作者：
Jerez, Andres;Sugimoto, Yuka;Maciejewski, Jaroslaw P.
影响染色体7 q的杂合性丢失在急性髓细胞白血病和骨髓增生异常综合征中很常见，指出该区域在疾病表型和克隆进化中的重要作用。最近开发的基因组平台提供的更高分辨率可用于建立更精确的临床相关性并识别特定的靶基因。我们使用最新的基因组技术分析了一系列骨髓疾病患者（1458例通过单核苷酸多态性阵列[SNP-A]，226例通过下一代测序，183例通过表达微阵列）。使用SNP-A，我们在1458例患者中的161例（11%）中确定了染色体7 q杂合性片段缺失; 26%的慢性粒单核细胞白血病患者具有7 q单亲二体性，其中41%具有纯合EZH 2突变。此外，我们描述了一个SNP-A-孤立的缺失7低细胞骨髓增生异常综合征子集，具有高的进展率。使用直接和平行测序，我们发现在典型的大缺失7 q和单体7患者中没有复发突变。相比之下，我们检测到我们的SNP-A定义的最小缺失区域中包含的基因的表达显著降低。虽然在大多数7 q单亲二体性和骨髓增生性表型患者中存在2-命中模型，但7 q特定区域的单倍缺陷表达可能是缺失和主要发育异常特征患者发病机制的基础。（血。2012;119（25）：6109-6117）
Loss of heterozygosity affecting chromosome 7q is common in acute myeloid leukemia and myelodysplastic syndromes, pointing toward the essential role of this region in disease phenotype and clonal evolution. The higher resolution offered by recently developed genomic platforms may be used to establish more precise clinical correlations and identify specific target genes. We analyzed a series of patients with myeloid disorders using recent genomic technologies (1458 by single-nucleotide polymorphism arrays [SNP-A], 226 by next-generation sequencing, and 183 by expression microarrays). Using SNP-A, we identified chromosome 7q loss of heterozygosity segments in 161 of 1458 patients (11%); 26% of chronic myelomonocytic leukemia patients harbored 7q uniparental disomy, of which 41% had a homozygous EZH2 mutation. In addition, we describe an SNP-A-isolated deletion 7 hypocellular myelodysplastic syndrome subset, with a high rate of progression. Using direct and parallel sequencing, we found no recurrent mutations in typically large deletion 7q and monosomy 7 patients. In contrast, we detected a markedly decreased expression of genes included in our SNP-A defined minimally deleted regions. Although a 2-hit model is present in most patients with 7q uniparental disomy and a myeloproliferative phenotype, haplodeficient expression of defined regions of 7q may underlie pathogenesis in patients with deletions and predominant dysplastic features. (Blood. 2012;119(25):6109-6117)