Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：间充质上皮转化（MET）酪氨酸激酶受体的突变或扩增会导致非小细胞肺癌（NSCLC）中受体功能失调并刺激肿瘤生长，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的基因组和免疫前景。
方法：用TempusxT法对18,047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加（CNG）6-9，高MET扩增定义为CNG≥10，以及MET其他类型的突变。在MET改变的和MET野生型组中比较了免疫肿瘤学(IO)生物标志物和其他体细胞基因改变的频率。
结果：276（1.53％）METex14，138（0.76％）高METamp，63（0.35％）低METamp，27（0.15%）其他MET，并鉴定出17,543（97％）MET野生型。包括METex14在内的任何MET突变的患者年龄较大，而METex14患者更常见的是女性和非吸烟者。MET基因在METamp肿瘤中表达最高。MET改变组的PD-L1阳性率高于MET野生型。METex14表现出最低的肿瘤突变负荷(TMB)和最低的新抗原肿瘤负荷(NTB)。METamp的CD4T细胞比例最低，NK细胞比例最高。METex14和METex14之间的共同改变存在显着差异。
结论：与非METex14NSCLC肿瘤相比，METex14肿瘤在IO生物标志物和躯体景观方面表现出差异。免疫谱的变化可以影响MET改变的NSCLC中的免疫治疗选择，需要进一步探索。
方法：用TempusxT法对18,047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加（CNG）6-9，高MET扩增定义为CNG≥10，以及MET其他类型的突变。在MET改变的和MET野生型组中比较了免疫肿瘤学(IO)生物标志物和其他体细胞基因改变的频率。
结果：276（1.53％）METex14，138（0.76％）高METamp，63（0.35％）低METamp，27（0.15%）其他MET，并鉴定出17,543（97％）MET野生型。包括METex14在内的任何MET突变的患者年龄较大，而METex14患者更常见的是女性和非吸烟者。MET基因在METamp肿瘤中表达最高。MET改变组的PD-L1阳性率高于MET野生型。METex14表现出最低的肿瘤突变负荷(TMB)和最低的新抗原肿瘤负荷(NTB)。METamp的CD4T细胞比例最低，NK细胞比例最高。METex14和METex14之间的共同改变存在显着差异。
结论：与非METex14NSCLC肿瘤相比，METex14肿瘤在IO生物标志物和躯体景观方面表现出差异。免疫谱的变化可以影响MET改变的NSCLC中的免疫治疗选择，需要进一步探索。
