Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
Clin Lung Cancer. 2024 Sep;25(6):567-576.e1. doi: 10.1016/j.cllc.2024.05.001. Epub 2024 May 10.
Mutation or amplification of the mesenchymal-epithelial transition (MET) tyrosine kinase receptor causes dysregulation of receptor function and stimulates tumor growth in non-small cell lung cancer (NSCLC) with the most common mutation being MET exon 14 (METex14). We sought to compare the genomic and immune landscape of MET-altered NSCLC with MET wild-type NSCLC.
18,047 NSCLC tumors were sequenced with Tempus xT assay. Tumors were categorized based on MET exon 14 (METex14) mutations; low MET amplification defined as a copy number gain (CNG) 6-9, high MET amplification defined as CNG ≥ 10, and MET other type mutations. Immuno-oncology (IO) biomarkers and the frequency of other somatic gene alterations were compared across MET-altered and MET wild-type groups.
276 (1.53%) METex14, 138 (0.76%) high METamp, 63 (0.35%) low METamp, 27 (0.15%) MET other, and 17,543 (97%) MET wild-type were identified. Patients with any MET mutation including METex14 were older, while patients with METex14 were more frequently female and nonsmokers. MET gene expression was highest in METamp tumors. PD-L1 positivity rates were higher in MET-altered groups than MET wild-type. METex14 exhibited the lowest tumor mutational burden (TMB) and lowest neoantigen tumor burden (NTB). METamp exhibited the lowest proportion of CD4 T cells and the highest proportion of NK cells. There were significant differences in co-alterations between METamp and METex14.
METex14 tumors exhibited differences in IO biomarkers and the somatic landscape compared to non-METex14 NSCLC tumors. Variations in immune profiles can affect immunotherapy selection in MET-altered NSCLC and require further exploration.
间质-上皮转化（MET）酪氨酸激酶受体的突变或扩增导致受体功能失调，并刺激非小细胞肺癌（NSCLC）的肿瘤生长，最常见的突变是 MET 外显子 14（METex14）。我们试图比较 MET 改变的 NSCLC 与 MET 野生型 NSCLC 的基因组和免疫景观。
使用 Tempus xT 检测对 18047 例 NSCLC 肿瘤进行测序。根据 MET 外显子 14（METex14）突变对肿瘤进行分类；低 MET 扩增定义为拷贝数增益（CNG）6-9，高 MET 扩增定义为 CNG≥10，以及 MET 其他类型的突变。比较免疫肿瘤学（IO）生物标志物和其他体细胞基因改变的频率在 MET 改变和 MET 野生型组之间。
鉴定出 276 例（1.53%）METex14、138 例（0.76%）高 METamp、63 例（0.35%）低 METamp、27 例（0.15%）MET 其他类型和 17543 例（97%）MET 野生型。任何 MET 突变（包括 METex14）的患者年龄较大，而 METex14 患者更常为女性和非吸烟者。MET 基因表达在 METamp 肿瘤中最高。MET 改变组的 PD-L1 阳性率高于 MET 野生型组。METex14 表现出最低的肿瘤突变负担（TMB）和最低的新抗原肿瘤负担（NTB）。METamp 表现出最低比例的 CD4 T 细胞和最高比例的 NK 细胞。METamp 和 METex14 之间存在明显的共同改变。
与非 METex14 NSCLC 肿瘤相比，METex14 肿瘤在 IO 生物标志物和体细胞景观方面存在差异。免疫谱的变化可能会影响 MET 改变的 NSCLC 的免疫治疗选择，需要进一步探索。
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