Zhang Yun, Weh Katherine M, Howard Connor L, Riethoven Jean-Jack, Clarke Jennifer L, Lagisetty Kiran H, Lin Jules, Reddy Rishindra M, Chang Andrew C, Beer David G, Kresty Laura A
Department of Surgery, Thoracic Surgery Section, University of Michigan, Ann Arbor, MI 48109, USA.
Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Mol Ther Nucleic Acids. 2022 Aug 17;29:749-768. doi: 10.1016/j.omtn.2022.08.018. eCollection 2022 Sep 13.
Isoform switching events with predicted functional consequences are common in many cancers, but characterization of switching events in esophageal adenocarcinoma (EAC) is lacking. Next-generation sequencing was used to detect levels of RNA transcripts and identify specific isoforms in treatment-naïve esophageal tissues ranging from premalignant Barrett's esophagus (BE), BE with low- or high-grade dysplasia (BE.LGD, BE.HGD), and EAC. Samples were stratified by histopathology and mutation status, identifying significant isoform switching events with predicted functional consequences. Comparing BE.LGD with BE.HGD, a histopathology linked to cancer progression, isoform switching events were identified in 75 genes including , and . Stratification based on status increased the number of significant isoform switches to 135, suggesting switching events affect cellular functions based on mutation and tissue histopathology. Analysis of isoforms agnostic, exclusive, and shared with mutant revealed unique signatures including demethylation, lipid and retinoic acid metabolism, and glucuronidation, respectively. Nearly half of isoform switching events were identified without significant gene-level expression changes. Importantly, two -interacting isoforms, and , were significantly linked to patient survival. Thus, analysis of isoform switching events may provide new insight for the identification of prognostic markers and inform new potential therapeutic targets for EAC.
具有预测功能后果的异构体转换事件在许多癌症中很常见，但食管腺癌（EAC）中转换事件的特征尚缺乏。使用下一代测序来检测RNA转录本水平，并在未经治疗的食管组织中鉴定特定异构体，这些组织包括癌前巴雷特食管（BE）、低级别或高级别发育异常的BE（BE.LGD、BE.HGD）以及EAC。样本按组织病理学和突变状态分层，确定具有预测功能后果的显著异构体转换事件。将与癌症进展相关的组织病理学BE.LGD与BE.HGD进行比较，在75个基因中鉴定出异构体转换事件，包括 、 和 。基于 状态的分层将显著异构体转换的数量增加到135个，表明转换事件根据 突变和组织病理学影响细胞功能。对与突变 无关、排他和共享的异构体分析分别揭示了独特的特征，包括去甲基化、脂质和视黄酸代谢以及葡萄糖醛酸化。近一半的异构体转换事件在无显著基因水平表达变化的情况下被鉴定出来。重要的是，两种与 相互作用的异构体 和 与患者生存显著相关。因此，异构体转换事件的分析可能为鉴定预后标志物提供新的见解，并为EAC提供新的潜在治疗靶点。
