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Published on: August 14, 2018
Genomic and Immune Landscape Comparison of MET Exon 14 Skipping and MET-Amplified Non-small Cell Lung Cancer
Rachel L Minne1, Natalie Y Luo1, Anne M Traynor2
1Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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.
Insights
MET exon 14 mutations and MET amplification in non-small cell lung cancer (NSCLC) alter the tumor immune microenvironment. These genomic alterations impact immunotherapy selection and require further investigation for personalized treatment strategies.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- Dysregulation of the MET tyrosine kinase receptor, through mutation or amplification, drives tumor growth in non-small cell lung cancer (NSCLC).
- MET exon 14 (METex14) skipping mutations are the most frequent MET alteration in NSCLC.
- Understanding the genomic and immune landscape of MET-altered NSCLC is crucial for targeted therapies.
Purpose of the Study:
- To compare the genomic and immune profiles of MET-altered NSCLC with MET wild-type NSCLC.
- To investigate differences in immuno-oncology (IO) biomarkers and somatic gene alterations across various MET alteration subtypes.
- To explore the potential impact of MET alterations on immunotherapy response.
Main Methods:
- Genomic sequencing of 18,047 NSCLC tumors using the Tempus xT assay.
- Categorization of tumors based on MET exon 14 (METex14) mutations, low MET amplification (CNG 6-9), high MET amplification (CNG ≥ 10), and other MET mutations.
- Comparative analysis of IO biomarkers and somatic gene alterations between MET-altered and MET wild-type NSCLC groups.
Main Results:
- MET alterations were identified in a small subset of NSCLC patients (METex14: 1.53%, high METamp: 0.76%, low METamp: 0.35%).
- MET-altered NSCLC patients showed distinct demographic and clinical characteristics compared to wild-type.
- METex14 tumors had lower tumor mutational burden (TMB) and neoantigen tumor burden (NTB), while MET amplification (METamp) tumors showed altered immune cell proportions (lower CD4+, higher NK cells).
- Higher PD-L1 positivity rates were observed in MET-altered groups compared to MET wild-type.
Conclusions:
- METex14 mutations and MET amplification significantly alter the genomic and immune landscape of NSCLC.
- Distinct immune profiles associated with MET alterations suggest differential responses to immunotherapy.
- Further research is warranted to elucidate the impact of these variations on immunotherapy selection and treatment outcomes in MET-altered NSCLC.
