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背景导致急性髓细胞样白血病(AML)的诸多基因突变尚未明确。突变模式与表观遗传学表型的关系尚不清楚。方法研究者对200例临床解释为新型AML的成人患者的基因组进行了分析,采用全基因组测序(50例)或全外显子测序(150例),并且采用RNA、小分子RNA测序和DNA甲基化分析。结果 AML基因组突变数量较其他成人癌症突变数量少,平均仅13个基因发生突变。在这些基因中平均有5个基因发生多次突变,有23个基因发生显著突变,另有237个基因在≥2个标本中发生突变。几乎所有标本至少有一处非同义突变发生在几乎确认和癌症发生相关的九大类基因中的一类,包括转录因子融合(18%)、基因编码核磷蛋白(NPM1)(27%)、肿瘤抑制基因(16%)、DNA甲基化相关基因(44%)、信号通路基因(59%)、染色体-修饰基因(30%)、髓细胞转录因子基因(22%)、粘连蛋白复合物基因(13%)及剪接体复合物基因(14%)。相互协同及排斥模式表明几种基因和类别间有较强的生物学联系。结论研究者在几乎所有AML样本中识别出至少1个具有潜在驱动作用的突变,并且发现复杂的遗传事件相互作用与个别AML患者发病有关。本研究数据可广泛用于今后对AML发病机制、分级和危险分层的进一步调查中。
Background Many mutations in genes that cause acute myeloid leukemia (AML) have not yet been clarified. The relationship between the mutation pattern and the epigenetic phenotype is unclear. METHODS: The researchers analyzed the genomes of 200 adult patients clinically interpreted as novel AML using whole genome sequencing (50 cases) or whole exon sequencing (150 cases) and using RNA, small RNA sequencing, and DNA. Baseline analysis. Results The number of AML genome mutations was smaller than that of other adult cancer mutations. On average, only 13 genes were mutated. In these genes, an average of 5 genes were mutated multiple times, 23 genes were significantly mutated, and 237 genes were mutated in ≥ 2 samples. Nearly all non-synonymous mutations in almost all specimens occurred in one of the nine major genes identified to be associated with cancer development, including transcription factor fusion (18%), gene-encoded nuclear phosphoprotein (NPM1) (27%), Tumor suppressor genes (16%), DNA methylation-related genes (44%), signaling pathway genes (59%), chromosome-modified genes (30%), myeloid transcription factor genes (22%), fibronectin complexes Gene (13%) and spliceosome complex genes (14%). The mutual cooperation and exclusion model indicates that there are strong biological relationships between several genes and categories. CONCLUSIONS: The researchers identified at least one potentially-driven mutation in almost all AML samples and found that complex genetic events interact with the onset of individual AML patients. The data from this study can be widely used in future investigations of the pathogenesis, grading, and risk stratification of AML.