Comprehensive profiling of genomic and transcriptomic differences between risk groups of lung adenocarcinoma and lung squamous cell carcinoma

Abstract

Lung cancer is the second frequently diagnosed cancer type and responsible for the highest number of cancer deaths worldwide. Lung adenocarcinoma and lung squamous cell carcinoma are subtypes of non-small cell lung cancer which has the highest frequency of lung cancer cases. We aimed to analyze genomic and transcriptomic variations including simple nucleotide variations (SNVs), copy number variations (CNVs) and differential expressed genes (DEGs) in order to find key genes and pathways for diagnostic and prognostic prediction for lung adenocarcinoma and lung squamous cell carcinoma. We performed univariate cox model and then lasso regularized cox model with leave-one-out cross-validation using TCGA gene expression data in tumor samples. We generated a 35-gene signature and a 33-gene signature for prognostic risk prediction based on the overall survival time of the patients with LUAD and LUSC, respectively. When we clustered patients into high-risk and low-risk groups, the survival analysis showed highly significant results with high prediction power for both training and test datasets. Then we characterized the differences including significant SNVs, CNVs, DEGs, active subnetworks, and the pathways. We described the results for the risk groups and cancer subtypes separately to identify specific genomic alterations between both high-risk groups and cancer subtypes. Both LUAD and LUSC high-risk groups have more down-regulated immune pathways and upregulated metabolic pathways. On the other hand, low-risk groups have both upregulated and downregulated genes on cancer-related pathways. Both LUAD and LUSC have important gene alterations such as CDKN2A and CDKN2B deletions with different frequencies. SOX2 amplification occurs in LUSC and PSMD4 amplification in LUAD. EGFR and KRAS mutations are mutually exclusive in LUAD samples. EGFR, MGA, SMARCA4, ATM, RBM10, and KDM5C genes are mutated only in LUAD but not in LUSC. CDKN2A, PTEN, and HRAS genes are mutated only in LUSC samples. Low-risk groups of both LUAD and LUSC, tend to have a higher number of SNVs, CNVs, and DEGs. The signature genes and altered genes have the potential to be used as diagnostic and prognostic biomarkers for personalized oncology.

Prognostic and Immunological Role of FAT Family Genes in Non-Small Cell Lung Cancer

“…LUAD and LUSC are distinct in disease pathology, molecular mechanisms, immunogenic features and patient outcomes. 43,44 We found that, in LUSC, there was no significant correlation between patients with mutant FATs than in those with wildtype FATs in OS, PFS and immune checkpointrelated genes. Moreover, FAT1/2/3/4 mutations showed no positive correlation with infiltration level of CD8 + T-cells and CD4 + T-cells in LUSC.…”

AC099850.3/NCAPG Axis Predicts Poor Prognosis and is Associated with Resistance to EGFR Tyrosine-Kinase Inhibitors in Lung Adenocarcinoma

“…LUAD and LUSC differ with regards to disease pathology, molecular mechanisms, EGFR mutational status and patient outcomes. 49,50 Correlations between NCAPG tumor aggressiveness and survival outcomes in LUSC were insignificant. These findings imply differences in the significance of NCAPG in development and progression of LUAD and LUSC, and that NCAPG may be a promising molecular target in LUAD, but not in LUSC.…”

Down-regulation of interleukin-2 predicts poor prognosis and associated with immune escape in lung adenocarcinoma

“…The most commonly mutated genes in LUAD include oncogenes (KRAS and EGFR) and tumor suppressor genes (TP53, KEAP1, STK11 and NF1) [19,20]. The JAK-STAT signaling pathway and PI3K-Akt signaling pathway can facilitate the proliferation, migration, and invasion in lung adenocarcinoma [21,22].…”