Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
Caris Life Sciences, 4610 S 44th Pl, Phoenix, AZ 85040 USA.
Lung Cancer. 2024 Oct;196:107935. doi: 10.1016/j.lungcan.2024.107935. Epub 2024 Sep 2.
MET exon 14 skipping alterations (METex14+) represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) with distinct biological and genomic features. We characterized this heterogeneity in a large cohort, integrating genomic and transcriptomic profiling with clinical outcomes, to elucidate the histologic and molecular traits and survival patterns of METex14+ NSCLC.
NSCLC tissue samples (n = 28,739) underwent DNA-based next-generation sequencing (592 genes, NextSeq) or whole-exome sequencing (NovaSeq), RNA-sequencing including whole transcriptome sequencing (WTS, NovaSeq), and PD-L1 IHC (Dako 22C3) at Caris Life Sciences. Immune cell fractions were estimated from bulk RNA sequencing (quanTIseq). Real-world survival data (mOS) was calculated from insurance claims. Statistical analyses employed Chi-square, Fisher's exact, or Mann-Whitney U and log-rank tests and were corrected for hypothesis testing where applicable.
A total of 711 METex14+ cases were detected. Of 575 cases of defined histology, 77 (13.6 %) were squamous (Sq), 474 (82.3 %) were nSq (non-squamous), and 24 (4.1 %) were adenosquamous. Mutations in POT1 and BRCA2 were enriched, and amplifications in MDM2, HMGA2, CDK4, and MET were common in METex14+ tumors. TMB-high and TP53 mutated tumors were reduced in METex14+ independent of histology. KEAP1 (2.1 vs 14.7 %) and STK11 mutations (0.8 vs 17.1 %) were reduced only in METex14+ nSq (vs METex14+ Sq, q < 0.05). While the prevalence of PD-L1 high tumors was enriched in METex14+ independent of histology, T-cell inflamed tumors were enriched only in nSq METex14+. B-cells and CD8+ T-cells (1.07-1.43-fold) were enriched in nSq METex14+, and dendritic cells (0.32 fold) were reduced only in METex14+ Sq. METex14+ tumors had a modest improvement in mOS compared to METex14- tumors (mOS = 22.9 m vs 18.6 m, HR = 0.914, p = 0.04). Moreover, METex14+ tumors who received immunotherapy (IO) had a modest improvement in survival (mOS = 27.5 m vs 21.8 m; HR = 0.803, p = 0.03) compared to those who did not receive IO. METex14+ nSq tumors were associated with improved mOS compared to METex14+ Sq tumors (mOS = 27.7 vs 8.9 m, HR = 0.493, p < 0.0001).
METex14+ alterations are a heterogeneous subgroup of NSCLC. Our analysis reveals that METex14+ nSq exhibit improved survival compared to METex14+ Sq. The distinct genomic and transcriptomic variations across histologies warrant clinical consideration.
MET 外显子 14 跳跃改变（METex14+）是非小细胞肺癌（NSCLC）的一个具有独特生物学和基因组特征的异质亚组。我们通过整合基因组和转录组分析与临床结果，对这一异质性进行了特征描述，以阐明 METex14+ NSCLC 的组织学和分子特征以及生存模式。
在 Caris Life Sciences 公司，对 28739 例 NSCLC 组织样本进行了基于 DNA 的下一代测序（592 个基因，NextSeq）或全外显子测序（NovaSeq）、包括全转录组测序（WTS，NovaSeq）的 RNA 测序以及 PD-L1 IHC（Dako 22C3）检测。从批量 RNA 测序（quanTIseq）中估计免疫细胞分数。从保险索赔中计算真实世界的生存数据（mOS）。统计分析采用卡方检验、Fisher 确切检验或曼-惠特尼 U 检验和对数秩检验，并在适用时对假设检验进行了校正。
共检测到 711 例 METex14+病例。在 575 例明确组织学的病例中，77 例（13.6%）为鳞状（Sq），474 例（82.3%）为非鳞状（nSq），24 例（4.1%）为腺鳞。POT1 和 BRCA2 突变丰富，METex14+肿瘤中 MDM2、HMGA2、CDK4 和 MET 的扩增常见。TMB 高和 TP53 突变的肿瘤在 METex14+中独立于组织学减少。KEAP1（2.1%比 14.7%）和 STK11 突变（0.8%比 17.1%）仅在 METex14+ nSq 中减少（与 METex14+ Sq 相比，q<0.05）。虽然 METex14+独立于组织学的 PD-L1 高肿瘤的患病率增加，但 T 细胞炎症肿瘤仅在 nSq METex14+中增加。nSq METex14+中 B 细胞和 CD8+T 细胞（1.07-1.43 倍）增加，树突状细胞（0.32 倍）减少，仅在 METex14+ Sq 中。与 METex14-肿瘤相比，METex14+肿瘤的 mOS 略有改善（mOS=22.9 个月比 18.6 个月，HR=0.914，p=0.04）。此外，与未接受免疫治疗（IO）的患者相比，接受 IO 的 METex14+肿瘤的生存改善（mOS=27.5 个月比 21.8 个月；HR=0.803，p=0.03）。与 METex14+ Sq 肿瘤相比，METex14+ nSq 肿瘤的 mOS 更好（mOS=27.7 个月比 8.9 个月，HR=0.493，p<0.0001）。
METex14+改变是非小细胞肺癌的一个异质性亚组。我们的分析表明，METex14+ nSq 与 METex14+ Sq 相比，生存改善。不同组织学之间的独特基因组和转录组变化值得临床关注。
