Department of Frontier Surgery, Graduated School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, Japan.
Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan.
Esophagus. 2022 Apr;19(2):294-302. doi: 10.1007/s10388-021-00900-7. Epub 2022 Jan 11.
Recent progress of large-scale international studies has provided comprehensive catalogs of somatic mutations in cancers. Additionally, it has become evident that allelic imbalance in the abundance of somatic mutations between DNA and RNA were pervasive in various types of cancer. However, the allelic imbalance of the abundance of somatic mutations in esophageal squamous cell carcinoma (ESCC) has not been fully analyzed.
We performed exome sequencing for 25 Japanese patients with ESCC to detect a comprehensive catalog of somatic mutations in ESCC. Additionally, we performed mRNA sequencing to evaluate the allelic imbalance of the identified somatic mutations at the transcriptional level by comparing the mutant allele frequencies between RNA and DNA.
The exome sequencing showed that TP53 and ZNF750 were significantly mutated genes. The expression levels of TP53 and ZNF750 were different depending on the mutation status. In almost all the tumors with missense mutations in TP53 and ZNF750, the mutant allele frequencies were higher in the RNA sequencing than those in the exome sequencing, indicating that the mutant alleles were preferentially expressed. By examining the allelic imbalances for all the identified missense mutations, we demonstrated that genes showing preferential expressions of the mutant alleles were involved in the pathways including cell cycle, cell death, and chromatin modification.
The results of this study suggest that the allelic imbalance of the abundance of somatic mutations plays important roles in the initiation and progression of ESCC by modulating cancer-related biological pathways.
最近大规模国际研究的进展提供了癌症中体细胞突变的综合目录。此外，显然在各种类型的癌症中，DNA 和 RNA 之间体细胞突变丰度的等位基因不平衡是普遍存在的。然而，食管鳞状细胞癌（ESCC）中体细胞突变丰度的等位基因不平衡尚未得到充分分析。
我们对 25 名日本 ESCC 患者进行了外显子组测序，以检测 ESCC 中体细胞突变的综合目录。此外，我们进行了 mRNA 测序，通过比较 RNA 和 DNA 之间的突变等位基因频率，评估鉴定出的体细胞突变在转录水平上的等位基因不平衡。
外显子组测序显示 TP53 和 ZNF750 是显著突变的基因。TP53 和 ZNF750 的表达水平因突变状态而异。在 TP53 和 ZNF750 错义突变的几乎所有肿瘤中，RNA 测序中的突变等位基因频率均高于外显子组测序中的突变等位基因频率，表明突变等位基因优先表达。通过检查所有鉴定出的错义突变的等位基因不平衡，我们证明了优先表达突变等位基因的基因参与了包括细胞周期、细胞死亡和染色质修饰在内的途径。
这项研究的结果表明，通过调节与癌症相关的生物学途径，体细胞突变丰度的等位基因不平衡在 ESCC 的发生和发展中起着重要作用。
