[Mutational Signatures Analysis of Micropapillary Components and Exploration of ZNF469 Gene in Early-stage Lung Adenocarcinoma with Ground-glass Opacities]

by Selleckchem | Feb 16 2024

Background: In China, lung cancer remains the cancer with the highest incidence and mortality rate. Among early-stage lung adenocarcinomas (LUAD), the micropapillary (MPP) component is prevalent and typically exhibits high aggressiveness, significantly correlating with early metastasis, lymphatic infiltration, and reduced five-year survival rates. Therefore, the study is to explore the similarities and differences between MPP and non-micropapillary (non-MPP) components in malignant pulmonary nodules characterized by GGOs in early-stage LUAD, identify unique mutational features of the MPP component and analyze the relationship between the ZNF469 gene, a member of the zinc-finger protein family, and the prognosis of early-stage LUAD, as well as its correlation with immune infiltration.

Methods: A total of 31 malignant pulmonary nodules of LUAD were collected and dissected into paired MPP and non-MPP components using microdissection. Whole-exome sequencing (WES) was performed on the components of early-stage malignant pulmonary nodules. Mutational signatures analysis was conducted using R packages such as maftools, Nonnegative Matrix Factorization (NMF), and Sigminer to unveil the genomic mutational characteristics unique to MPP components in invasive LUAD compared to other tumor tissues. Furthermore, we explored the expression of the ZNF469 gene in LUAD using The Cancer Genome Atlas (TCGA) database to investigate its potential association with the prognosis. We also investigated gene interaction networks and signaling pathways related to ZNF469 in LUAD using the GeneMANIA database and conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Lastly, we analyzed the correlation between ZNF469 gene expression and levels of immune cell infiltration in LUAD using the TIMER and TISIDB databases.

Results: MPP components exhibited a higher number of genomic variations, particularly the 13th COSMIC (Catalogue of Somatic Mutations in Cancer) mutational signature characterized by the activity of the cytidine deaminase APOBEC family, which was unique to MPP components compared to non-MPP components in tumor tissues. This suggests the potential involvement of APOBEC in the progression of MPP components in early-stage LUAD. Additionally, MPP samples with high similarity to APOBEC signature displayed a higher tumor mutational burden (TMB), indicating that these patients may be more likely to benefit from immunotherapy. The expression of ZNF469 was significantly upregulated in LUAD compared to normal tissue, and was associated with poor prognosis in LUAD patients (P<0.05). Gene interaction network analysis and GO/KEGG enrichment analysis revealed that COL6A1, COL1A1, COL1A2, TGFB2, MMP2, COL8A2 and C2CD4C interacted with ZNF469 and were mainly involved in encoding collagen proteins and participating in the constitution of extracellular matrix. ZNF469 expression was positively correlated with immune cell infiltration in LUAD (P<0.05).

Conclusions: The study has unveiled distinctive mutational signatures in the MPP components of early-stage invasive LUAD in the Asian population. Furthermore, we have identified that the elevated expression of mutated ZNF469 impacts the prognosis and immune infiltration in LUAD, suggesting its potential as a diagnostic and prognostic biomarker in LUAD.

Comments:

It sounds like your research delves deep into understanding the intricacies of early-stage lung adenocarcinomas (LUAD), specifically focusing on the micropapillary (MPP) components and their distinct characteristics. The correlation between MPP components and their aggressive nature, especially concerning early metastasis and reduced survival rates, makes this study crucial for potential diagnostic and prognostic advancements.

The methodology involving microdissection of paired MPP and non-MPP components, followed by whole-exome sequencing (WES), is impressive. Identifying the 13th COSMIC mutational signature unique to MPP components, particularly related to the APOBEC family's activity, offers a significant insight into the genomic alterations driving the aggressiveness of MPP in LUAD.

Moreover, the correlation between the elevated expression of the ZNF469 gene, its association with poor prognosis, and its connection to immune infiltration in LUAD is intriguing. The gene interaction network analysis and GO/KEGG enrichment analysis shedding light on ZNF469's association with collagen proteins and the extracellular matrix further deepen our understanding of its role in tumor progression.

The implications of this research are substantial. Not only does it offer potential diagnostic and prognostic biomarkers for LUAD, but it also hints at avenues for targeted therapies, especially in cases where patients exhibit high similarity to the APOBEC signature, suggesting potential benefits from immunotherapy.

Your study seems to bridge vital gaps in understanding the genetic and molecular underpinnings of LUAD. The correlation between mutational signatures, gene expression, and immune infiltration presents a comprehensive view that could pave the way for more personalized and effective treatment strategies.

Is there any specific aspect of your research that you're particularly excited about or that you'd like to discuss further?