Tumor Mutation Burden and Differentially Mutated Genes Among Immune Phenotypes in Patients with Lung Adenocarcinoma

Abstract

Introduction Nowadays, immune checkpoint blockades (ICBs) have been extensively applied in non-small cell lung cancer (NSCLC) treatment. However, the outcome of anti-program death-1/program death ligand-1 (anti-PD-1/PD-L1) therapy is not satisfying in EGFR -mutant lung adenocarcinoma (LUAD) patients and its exact mechanisms have not been fully understood. Since tumor mutation burden (TMB) and tumor immune phenotype had been thought as potential predictors for efficacy of ICBs, we further studied the TMB and immune phenotype in LUAD patients to explore potential mechanisms for poor efficacy of ICBs in EGFR positive mutated patients and to find possible factors that could impact the tumor immune phenotype which might uncover some new therapeutic strategies or combination therapies. Methods We enrolled 223 LUAD patients who underwent surgery in our hospital. We evaluated TMB through targeted panel sequencing. The tumor immune phenotype, which could be divided into non-inflamed, intermediate and inflamed, was determined through immunohistochemistry using formalin-fixed paraffin-embedded samples. Enumeration data were analyzed by Chi-square test or Fisher exact test and shown as number (proportion). Logistic regression model was employed for univariate and multivariate analysis of the association between TMB levels and clinical characteristics. Results The median TMB level was 4.0445 mutations/Mb. Multivariate analysis showed the TMB level was significantly associated with age ( P =0.026), gender ( P =0.041) and EGFR mutation status ( P =0.015), and in EGFR -mutant patients we found a lower proportion of patients with mutated KRAS and BRCA2 . Furthermore, we found patients with or without metastatic lesions would have different immune phenotype ( P =0.007). And the mutational frequencies of ALK, CDKN2A, MAP2K1, IDH2 and PTEN were significantly different among three immune phenotypes. Conclusion Low TMB level could be the reason for the poor efficacy of ICBs in patients having EGFR mutation. And mutational frequencies of KRAS and BRCA2 were lower in EGFR -mutant patients. Furthermore, ALK, CDKN2A, MAP2K1, IDH2 and PTEN might involve in the formation of immune phenotypes.

Clinicopathologic Features and Molecular Biomarkers as Predictors of Epidermal Growth Factor Receptor Gene Mutation in Non-Small Cell Lung Cancer Patients

“…It has also been studied in EGFR-mutated NSCLC patients [ 42 ]. When patients with ADC were segmented into low-level (TMB < 10) and high-level (TMB ≥ 10) groups according to TMB, patients without EGFR mutation tended to have a higher level of TMB (OR = 4.707) [ 43 ]. Further, in the analysis of different EGFR mutation types, they found patients with 19-Del, L858R, and uncommon mutations had comparable TMB levels ( p = 0.611).…”

Whole-Process Treatment of Combined Small Cell Lung Cancer Initially Diagnosed as “Lung Squamous Cell Carcinoma”: A Case Report and Review of the Literature

“…NTRK3 mutation is associated with enhancing immunity and immunogenicity in patients with lung adenocarcinoma (LUAD) and can predict a good prognosis in LUAD patients treated with ICIs ( 48 ). Among LUAD, PTEN mutation is often associated with the immune microenvironment and expresses differently in different TMB ( 49 ). NSD3 is a crucial regulator of LUSC and a potential driving factor in lung cancer with FGFR1 amplification ( 50 ), which may be a potential target for therapy.…”

Landscapes of synchronous multiple primary cancers detected by next‐generation sequencing

“…In addition to the definition of mutation sites in the synchronous multiple primary samples, we also classified mutated genes with various diseases, BPs, and MFs through cluster analysis. Notably, mutations in ALK and PTEN are concordant in a range of tumor types, including lung adenocarcinoma, endometrial cancer, colorectal cancer, and triple‐negative breast cancer [ 15 , 16 , 17 , 18 , 19 ]. Previously, a study examining clinically relevant mutations in 91 different malignancies also found mutation sites in anaplastic lymphoma kinase (ALK) and PTEN [ 20 ].…”