Differences in the expression profiles of m6A-related genes and the prognostic role in immunotherapy for lung adenocarcinoma patients

Zhizhao Zhang^1,2Yuanhui Yang³Guangyang Bai^1,2Chen Xue⁴Xikun Zhang^4*

• ¹Shandong Provincial Hospital, Jinan, China
• ²Shandong First Medical University, Jinan, China
• ³Henan University of Science and Technology, Luoyang, China
• ⁴Qinghai Provincial People's Hospital, Xining, China

Abstract Background Lung adenocarcinoma (LUAD) is the predominant subtype of non-small cell lung cancer (NSCLC) and is linked to elevated mortality rates. Nonetheless, effective approaches to direct clinical therapy techniques for LUAD remain insufficient. This study aimed to systematically investigate the biological functions of m6A methylation regulators, and examine their relationships with tumor immunity in LUAD, thereby providing a theoretical foundation for clinical treatment strategies. Methods RNA sequencing data for 20 m6A methylation regulators and clinical data for LUAD patients were obtained from TCGA and GEO databases. The relationship between IGF2BP1 and immunological infiltrates in LUAD was examined using CIBERSORT. The "GSVA" R package (version 1.38.2) was utilized to GSVA. The PPI network of these m6A-related genes was established using the STRING database. The TIDE algorithm was utilized to forecast the clinical response to immune checkpoint inhibitors, whereas the R package oncoPredict was employed to assess the chemotherapeutic response. We gathered clinical specimens to validate Kaplan–Meier survival calculations and using immunohistochemistry to differentiate between high and low expression cohorts. Results Univariate COX and LASSO logistic regression analysis indicated that IGF2BP1 was the sole independent predictor of LUAD after controlling for common clinical markers. The mutation rates of m6A modification regulators in LUAD were below 10%. Subsequent study demonstrated that IGF2BP1 expression was substantially associated with immune infiltration, the expression of immunological checkpoints, the efficacy of immunotherapy in LUAD patients, and the incidence, progression, metastasis, and treatment resistance of lung adenocarcinoma. Furthermore, patients in the high expression group of IGF2BP1 exhibited a worse prognosis. We developed a nomogram by integrating IGF2BP1 expression with eight additional predictive risk variables. The ROC curves and calibration curves indicated that the nomogram was well-calibrated and effectively differentiated between high-expression and low-expression LUAD patients. The outcomes of the clinical validation cohort were consistent with the aforementioned analyses. Conclusions Our findings indicate that the m6A alteration is involved in the regulation of the tumor microenvironment, and that IGF2BP1 serves as an independent predictor associated with immunotherapy response in LUAD, potentially representing an innovative biomarker for LUAD prognosis and tumor immunity status.