Institute of Medical Data Processing, Biometrics and Epidemiology (IBE), Faculty of Medicine, LMU Munich, Munich, Germany.
Data Integration for Future Medicine (DiFuture, www.difuture.de), LMU Munich, Munich, Germany.
Sci Rep. 2019 Aug 13;9(1):11796. doi: 10.1038/s41598-019-48167-4.
The patho-mechanism of somatic driver mutations in cancer usually involves transcription, but the proportion of mutations and wild-type alleles transcribed from DNA to RNA is largely unknown. We systematically compared the variant allele frequencies of recurrently mutated genes in DNA and RNA sequencing data of 246 acute myeloid leukaemia (AML) patients. We observed that 95% of all detected variants were transcribed while the rest were not detectable in RNA sequencing with a minimum read-depth cut-off (10x). Our analysis focusing on 11 genes harbouring recurring mutations demonstrated allelic imbalance (AI) in most patients. GATA2, RUNX1, TET2, SRSF2, IDH2, PTPN11, WT1, NPM1 and CEBPA showed significant AIs. While the effect size was small in general, GATA2 exhibited the largest allelic imbalance. By pooling heterogeneous data from three independent AML cohorts with paired DNA and RNA sequencing (N = 253), we could validate the preferential transcription of GATA2-mutated alleles. Differential expression analysis of the genes with significant AI showed no significant differential gene and isoform expression for the mutated genes, between mutated and wild-type patients. In conclusion, our analyses identified AI in nine out of eleven recurrently mutated genes. AI might be a common phenomenon in AML which potentially contributes to leukaemogenesis.
体细胞驱动基因突变的病理机制通常涉及转录，但从 DNA 转录到 RNA 的突变和野生型等位基因的比例在很大程度上是未知的。我们系统比较了 246 例急性髓系白血病（AML）患者的 DNA 和 RNA 测序数据中反复突变基因的变异等位基因频率。我们观察到，所有检测到的变异中有 95%在转录，而其余的在 RNA 测序中用最小读深度截止值（10x）是不可检测的。我们对 11 个含有反复突变的基因的分析表明，大多数患者存在等位基因失衡（AI）。GATA2、RUNX1、TET2、SRSF2、IDH2、PTPN11、WT1、NPM1 和 CEBPA 显示出显著的 AI。虽然一般来说效应大小较小，但 GATA2 表现出最大的等位基因失衡。通过汇集来自三个具有配对 DNA 和 RNA 测序的独立 AML 队列的异质数据（N = 253），我们可以验证 GATA2 突变等位基因的优先转录。对具有显著 AI 的基因进行差异表达分析显示，突变和野生型患者之间，突变基因的基因和异构体表达没有显著差异。总之，我们的分析确定了十一个反复突变基因中的九个存在 AI。AI 可能是 AML 中的一种常见现象，可能有助于白血病的发生。
