Abstract
Background: Clear cell renal cell carcinoma (ccRCC) is a prevalent and aggressive form of kidney cancer with a poor prognosis. The tumor mutational burden (TMB) has been a subject of considerable interest in various cancer studies. However, the relationship between TMB and ccRCC has been inadequately explored. This study aimed to elucidate the role of TMB-related immune genes in ccRCC and the underlying molecular mechanisms. Methods: Somatic mutation data from 336 ccRCC patients were downloaded from The Cancer Genome Atlas (TCGA). The mutational spectrum was analyzed using the maftools software package. Based on the TCGA ccRCC cohort, we summarized the gene mutation profile. The TMB was calculated, and samples were categorized into high- and low-TMB groups. We then investigated the relationship between TMB and clinical characteristics. Additionally, we identified TMB-related immune genes by intersecting TMB-related differentially expressed genes with immune-related genes. Finally, we selected the immune genes most strongly associated with TMB and examined their expression levels in ccRCC cancer tissues. We further explored their roles and potential molecular mechanisms both in vivo and in vitro. Results: The most common mutations in the variant classification, variant type, and single nucleotide variant classes in ccRCC were analyzed bioinformatically. We found that a higher TMB was associated with poorer overall survival outcomes, younger age, and lower grade. Furthermore, we identified a novel TMB-related immune gene in ccRCC: the progestagen-associated endometrial protein (PAEP) gene. This gene was significantly overexpressed in ccRCC tissues and strongly associated with patient prognosis. Additionally, we observed that knockdown of PAEP significantly inhibited proliferation, migration, and invasion while promoting apoptosis in the 786-O and ACHN ccRCC cell lines. In vivo, the growth rate of subcutaneous xenografts in nude mice was significantly slowed after PAEP knockout. Mechanistically, the anti-cancer effects of PAEP knockout may be related to inhibition of the PI3K/Akt/NF-κB signaling pathway. Conclusion: Our study suggests that PAEP may be a potential therapeutic target for ccRCC, providing a new theoretical basis for ccRCC clinical immunotherapy.