Kim So Yeon, Yin Jun, Bohlman Stephen, Walker Phillip, Dacic Sanja, Kim Chul, Khan Hina, Liu Stephen V, Ma Patrick C, Nagasaka Misako, Reckamp Karen L, Abraham Jim, Uprety Dipesh, Wang Feng, Xiu Joanne, Zhang Jian, Cheng Haiying, Halmos Balazs
Department of Medical Oncology, Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, New York.
Yale School of Medicine, New Haven, Connecticut.
JTO Clin Res Rep. 2022 Jul 22;3(9):100381. doi: 10.1016/j.jtocrr.2022.100381. eCollection 2022 Sep.
Genomic alterations in the juxtamembrane exon 14 splice sites in NSCLC lead to increased MET stability and oncogenesis. We present the largest cohort study of Exon 14 (ex14) using whole transcriptome sequencing.
A total of 21,582 NSCLC tumor samples underwent complete genomic profiling with next-generation sequencing of DNA (592 Gene Panel, NextSeq, whole exome sequencing, NovaSeq) and RNA (NovaSeq, whole transcriptome sequencing). Clinicopathologic information including programmed death-ligand 1 and tumor mutational burden were collected and RNA expression for mutation subtypes and amplification were quantified. Immunogenic signatures and potential pathways of invasion were characterized using single-sample gene set enrichment analysis and mRNA gene signatures.
A total of 533tumors (2.47%) with ex14 were identified. The most common alterations were point mutations (49.5%) at donor splice sites. Most alterations translated to increased expression, with co-amplification resulting in synergistic increase in expression (q < 0.05). Common coalterations were amplifications of (19.0% versus 1.8% wild-type [WT]), (13.2% versus 0.98% WT), and (10.0% versus 1.5% WT) (q < 0.05). High programmed death-ligand 1 > 50% (52.5% versus 27.3% WT, q < 0.0001) and lower proportion of high tumor mutational burden (>10 mutations per megabase, 8.3% versus 36.7% WT, < 0.0001) were associated with ex14, which were also enriched in both immunogenic signatures and immunosuppressive checkpoints. Pathways associated with ex14 included angiogenesis and apical junction pathways (q < 0.05).
ex14 splicing alterations and co-amplification translated to higher and synergistic expression at the transcriptomic level. High frequencies of and co-amplifications and association with multiple immunosuppressive checkpoints and angiogenic pathways provide insight into potential actionable targets for combination strategies in ex14 NSCLC.
非小细胞肺癌（NSCLC）中近膜外显子14剪接位点的基因组改变会导致MET稳定性增加和肿瘤发生。我们采用全转录组测序对最大队列的外显子14（ex14）进行了研究。
共有21582例NSCLC肿瘤样本通过DNA的新一代测序（592基因检测板、NextSeq、全外显子测序、NovaSeq）和RNA（NovaSeq、全转录组测序）进行了完整的基因组分析。收集了包括程序性死亡配体1和肿瘤突变负荷在内的临床病理信息，并对突变亚型和扩增的RNA表达进行了定量分析。使用单样本基因集富集分析和mRNA基因特征对免疫原性特征和潜在的侵袭途径进行了表征。
共鉴定出533例（2.47%）存在ex14改变的肿瘤。最常见的改变是供体剪接位点的点突变（49.5%）。大多数改变导致表达增加，共扩增导致表达协同增加（q<0.05）。常见的共改变包括（19.0%对野生型[WT]1.8%）、（13.2%对WT 0.98%）和（10.0%对WT 1.5%）的扩增（q<0.05）。高程序性死亡配体1>50%（52.5%对WT 27.3%，q<0.0001）和高肿瘤突变负荷比例较低（每兆碱基>10个突变，8.3%对WT 36.7%，<0.0001）与ex14相关，且在免疫原性特征和免疫抑制检查点中均有富集。与ex14相关的途径包括血管生成和顶端连接途径（q<0.05）。
ex14剪接改变和共扩增在转录组水平上导致更高的协同MET表达。高频率的和共扩增以及与多种免疫抑制检查点和血管生成途径的关联为ex14 NSCLC联合治疗策略的潜在可操作靶点提供了见解。
