A 20-gene mutation signature predicts the efficacy of immune checkpoint inhibitor therapy in advanced non-small cell lung cancer patients.

BACKGROUND: There is an unmet need to identify novel predictive biomarkers that enable more accurate identification of individuals who can benefit from immune checkpoint inhibitor (ICI) therapy. The US FDA recently approved tumor mutational burden (TMB) score of ≥ 10 mut/Mb as a threshold for pembrolizumab treatment of solid tumors. Our study aimed to test the hypothesis that specific gene mutation signature may predict the efficacy of ICI therapy more precisely than high TMB (≥ 10). METHODS: We selected 20 candidate genes that may predict for the efficacy of ICI therapy by the analysis of data from a published cohort of 350 advanced non-small cell lung cancer (NSCLC) patients. Then, we compared the influences of various gene mutation signatures on the efficacy of ICI treatment. They were also compared with PD-L1 and TMB. The Kaplan-Meier method was utilized to evaluate the prognosis univariates, while selected univariates were adopted to develop a systematic nomogram. RESULTS: A high mutation signature, where three or more of the 20 selected genes were mutated, was associated with the significant benefits of ICI therapy. Specifically, patients with high mutation signature were confirmed to have better prognosis for ICI treatment, compared with those with wild type (the median PFS: 7.17 vs. 2.90 months, p = 0.0004, HR = 0.47 (95% [CI]:0.32-0.68); the median OS: unreached vs. 9 months, p = 1.8E-8, HR = 0.17 (95% [CI]:0.11-0.25)). Moreover, those patients with the high mutation signature achieved significant ICI treatment benefits, while there was no difference of OS and PFS between patients without the signature but TMB-H (≥ 10) and those without the signature and low TMB(< 10). Finally, we constructed a novel nomogram to evaluate the efficacy of ICI therapy. CONCLUSION: A high mutational signature with 3 or more of the 20-gene panel could provide more accurate predictions for the outcomes of ICI therapy than TMB ≥ 10 in NSCLC patients.

The role of ERBB4 mutations in the prognosis of advanced non-small cell lung cancer treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have witnessed the achievements of convincing clinical benefits that feature the significantly prolonged overall survival (OS) of patients suffering from advanced non-small cell lung cancer (NSCLC), according to reports recently. Sensitivity to immunotherapy is related to several biomarkers, such as PD-L1 expression, TMB level, MSI-H and MMR. However, a further investigation into the novel biomarkers of the prognosis on ICIs treatment is required. In addition, there is an urgent demand for the establishment of a systematic hazard model to assess the efficacy of ICIs therapy for advanced NSCLC patients. METHODS: In this study, the gene mutation and clinical data of NSCLC patients was obtained from the TCGA database, followed by the analysis of the detailed clinical information and mutational data relating to two advanced NSCLC cohorts receiving the ICIs treatment from the cBioPortal of Cancer Genomics. The Kaplan-Meier plot method was used to perform survival analyses, while selected variables were adopted to develop a systematic nomogram. The prognostic significance of ERBB4 in pan-cancer was analyzed by another cohort from the cBioPortal of Cancer Genomics. RESULTS: The mutation frequencies of TP53 and ERBB4 were 54% and 8% in NSCLC, respectively. The mutual exclusive analysis in cBioPortal has indicated that ERBB4 does show co-occurencing mutations with TP53. Patients with ERBB4 mutations were confirmed to have better prognosis for ICIs treatment, compared to those seeing ERBB4 wild type (PFS: exact p = 0.017; OS: exact p < 0.01) and only TP53 mutations (OS: p = 0.021). The mutation status of ERBB4 and TP53 was tightly linked to DCB of ICIs treatment, PD-L1 expression, TMB value, and TIICs. Finally, a novel nomogram was built to evaluate the efficacy of ICIs therapy. CONCLUSION: ERBB4 mutations could serve as a predictive biomarker for the prognosis of ICIs treatment. The systematic nomogram was proven to have the great potential for evaluating the efficacy of ICIs therapy for advanced NSCLC patients.

Major Facilitator Superfamily Domain Containing 12 Is Overexpressed in Lung Cancer and Exhibits an Oncogenic Role in Lung Adenocarcinoma Cells.

Major facilitator superfamily domain containing 12 (MFSD12) regulates lysosomal cysteine import and promotes the proliferation and survival of melanoma cells. However, the expression and function of MFSD12 in other cancers, particularly in lung cancer, remain unclear. The expression of MFSD12 across various types of cancers and corresponding control tissues was examined using TIMER. MFSD12 expression in lung adenocarcinoma (LUAD) and its correlation with distinct clinicopathological features of LUAD patients were analyzed with UALCAN. The correlation between MFSD12 expression and survival of LUAD patients was assessed using the R package, survival, and the relationship between MFSD12 expression and immune infiltration status in LUAD was investigated using CIBERSORT. In addition, MFSD12 expression was knocked down in PC9 LUAD cells and their proliferation, capacity for expansion, cell cycle, apoptosis, and migration/invasion were evaluated through CCK-8 assays, colony formation assays, 7-AAD staining, Annexin V/PI staining, and Transwell assays, respectively. The stemness of these PC9 cells was determined through Western blotting, flow cytometry, and tumor sphere formation assays. MFSD12 mRNA levels were significantly elevated in multiple types of cancers, including LUAD. MFSD12 expression was also positively correlated with cancer stage, nodal metastasis, and infiltration of various immune cells in LUAD, and high MFSD12 levels predicted poor survival among LUAD patients. Knockdown of MFSD12 in PC9 cells resulted in decreased proliferation, attenuated colony formation capacity, cell cycle arrest, elevated apoptosis, impaired migration/invasion, and reduced stemness in PC9 cells. MFSD12 is an oncogene in LUAD.

Positron emission tomography/computed tomography and endobronchial ultrasound-guided transbronchial needle aspiration to evaluate the status of N2 in preoperative non-small cell lung cancer: a diagnostic test.

Background: As a minimally invasive method, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was more accurate than non-invasive methods such as positron emission tomography (PET) and computed tomography (CT) to evaluate the lymph nodes in preoperative non-small cell lung cancer (NSCLC). PET/CT has more anatomical advantages than PET scanning and is more accurate in lung cancer staging. However, no relevant studies have comparatively evaluated PET/CT and EBUS-TBNA for NSCLC patients. Methods: A total of 112 patients were included in this retrospective analysis. The golden diagnosis of N2 status was postoperative pathological results. In EBUS-TBNA puncture specimens, if clear malignant tumor cells could be seen, the results were taken as positive. In PET/CT image analysis, the CT values, short diameter, and maximum standardized uptake value (SUVmax) of each lymph node were recorded to evaluate N2 status. The results of PET/CT and EBUS-TBNA were compared with the final pathological results, and respective sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated. - Then, the patients were divided into adenocarcinoma group and squamous cell carcinoma group -and the results were calculated and compared with the above method. Results: The results showed that EBUS-TBNA had a higher diagnostic value for mediastinal lymph nodes than PET/CT, and the difference was statistically significant (P<0.001). In NSCLC patients, the results showed that the sensitivity (P=0.013), specificity (P<0.001), PPV (P<0.001), NPV (P<0.001), and accuracy (P<0.001) of EBUS-TBNA were higher than that of PET/CT (AUC =0.954 and 0.636, respectively). In adenocarcinoma cases, specificity (P<0.001), PPV (P<0.001), NPV (P<0.001), and accuracy (P<0.001) of EBUS-TBNA were higher than that of PET/CT (AUC =0.957 and 0.596, respectively).In cases with squamous cell carcinoma, specificity (P=0.003), PPV (P<0.001), and accuracy (P<0.001) of EBUS-TBNA were higher than PET/CT (AUC =0.952 and 0.657, respectively). Conclusions: For preoperative diagnosis of mediastinal lymph node metastases in NSCLC, EBUS-TBNA is more accurate than PET/CT. For those patients with suspected mediastinal lymph node metastasis, EBUS-TBNA should be preferred method to evaluate the status of mediastinal lymph nodes.

[A Review of Epigenetic Modifications Regulate MicroRNA Expression in Lung Cancer].

Lung cancer is one of the primary causes of cancer-induced death among the world. Although the network of molecular implicated in lung cancer is gradually revealed, the exact molecular mechanism of its occurrence and development has not been fully elucidated. As a class of small and endogenous single-stranded non-coding RNAs, microRNAs (miRNAs) are found in a wide range of organisms from plants, viruses to humans. miRNAs involve various functions in normal lung tissue development. They take part in a large amount of biological processes including cell growth, metabolism, proliferation and differentiation. However, aberrant expression of miRNAs could induce the occurrence, development, invasion and metastasis of lung tumor, so it is deemed the novel biomarkers. Similar to that of protein-coding genes, expression and function of miRNA are regulated by various factors and the epigenetic network which includes DNA methylation and histone modification. Moreover, key enzymes driving epigenetic modifications are regulated by miRNAs. Therefore, better understanding of inextricable linkage between miRNAs and epigenome will provides a basis for the feasibility of miRNA-orientated diagnostic, therapeutic and prognostic strategies related to lung cancer in future.