Abstract
Aberrant N6-methyladenosine (m6A) RNA methylation regulatory genes and related gene alternative splicing (AS) could be used to predict the prognosis of non–small cell lung carcinoma. This study focused on 13 m6A regulatory genes (METTL3, METTL14, WTAP, KIAA1429, RBM15, ZC3H13, YTHDC1, YTHDC2, YTHDF1, YTHDF2, HNRNPC, FTO, and ALKBH5) and expression profiles in TCGA-LUAD (n = 504) and TCGA-LUSC (n = 479) datasets from the Cancer Genome Atlas database. The data were downloaded and bioinformatically and statistically analyzed, including the gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. There were 43,948 mRNA splicing events in lung adenocarcinoma (LUAD) and 46,020 in lung squamous cell carcinoma (LUSC), and the data suggested that m6A regulators could regulate mRNA splicing. Differential HNRNPC and RBM15 expression was associated with overall survival (OS) of LUAD and HNRNPC and METTL3 expression with the OS of LUSC patients. Furthermore, the non–small cell lung cancer prognosis-related AS events signature was constructed and divided patients into high- vs. low-risk groups using seven and 14 AS genes in LUAD and LUSC, respectively. The LUAD risk signature was associated with gender and T, N, and TNM stages, but the LUSC risk signature was not associated with any clinical features. In addition, the risk signature and TNM stage were independent prognostic predictors in LUAD and the risk signature and T stage were independent prognostic predictors in LUSC after the multivariate Cox regression and receiver operating characteristic analyses. In conclusion, this study revealed the AS prognostic signature in the prediction of LUAD and LUSC prognosis.
Highlights
Lung cancer is still the most significant health burden in the world, accounting for 14% of all newly diagnosed cancer cases as the second most common cancer and 18% of all cancer-related deaths as the leading cause of cancer death globally in 2018 and 2020 (de Martel et al, 2020; Sung et al, 2021)
The gene alternative splicing (GAS) events in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) were download from The Cancer Genome Atlas (TCGA) Splice Seq and calculated for the percent spliced in index (PSI) value, a quantifiable GAS indicator after the comparison of single and multiple samples between subgroups, that is, calculation of the percentage of GAS value for each GAS event, which was typically used to quantify GAS events according to a previous study (Lin and Krainer, 2019)
We found that the risk signature and the TNM stage were independent prognostic factors of LUAD, while the risk signature and T stage were independent prognostic factors in LUSC (Figures 7A,B, Table 2)
Summary
Lung cancer is still the most significant health burden in the world, accounting for 14% of all newly diagnosed cancer cases as the second most common cancer and 18% of all cancer-related deaths as the leading cause of cancer death globally in 2018 and 2020 (de Martel et al, 2020; Sung et al, 2021). Lung cancer can be divided into small cell lung cancer and non–small cell lung cancer (NSCLC), and the latter accounts for 85% of all lung cancer cases, and the overall 5year survival rate of lung cancer remains to be approximately 15% (Balata et al, 2019). Treatment of NSCLC is dependent on the stage of disease at diagnosis, and early-staged NSCLC could be surgically cured, whereas the advanced staged diseases can only be subjected to chemotherapy, radiation therapy, immunotherapy, and/or targeted therapy (Maconachie et al, 2019; Planchard et al, 2018) and their prognosis is, still poor, approximately less than 5–7% at the best according to the American Cancer Society data (https://www.cancer.org/cancer/ lung-cancer/detection-diagnosis-staging/survival-rates.html) or after advanced therapy (Zhang et al, 2021). The search and development of biomarkers for early detection and prediction of prognosis and treatment outcome are urgently needed to effectively conquer this deadly disease clinically
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