BackgroundPost-renal transplant patients have a high likelihood of developing renal cancer. However, the underlying biological mechanisms behind the development of renal cancer in post-kidney transplant patients remain to be elucidated. Therefore, this study aimed to investigate the underlying biological mechanism behind the development of renal cell carcinoma in post-renal transplant patients.MethodsNext-generation sequencing data and corresponding clinical information of patients with clear cell renal cell carcinoma (ccRCC) were obtained from The Cancer Genome Atlas Program (TCGA) database. The microarray data of kidney transplant patients with or without rejection response was obtained from the Gene Expression Omnibus (GEO) database. In addition, statistical analysis was conducted in R software.ResultsWe identified 55 upregulated genes in the transplant patients with rejection from the GEO datasets (GSE48581, GSE36059, and GSE98320). Furthermore, we conducted bioinformatics analyses, which showed that all of these genes were upregulated in ccRCC tissue. Moreover, a prognosis model was constructed based on four rejection-related genes, includingPLAC8,CSTA,AIM2, andLYZ. The prognosis model showed excellent performance in prognosis prediction in a ccRCC cohort. In addition, the machine learning algorithms identified 19 rejection-related genes, includingPLAC8, involved in ccRCC occurrence. Finally, thePLAC8was selected for further research, including its clinical and biological role.ConclusionIn all, our study provides novel insight into the transition from the rejection of renal transplant to renal cancer. Meanwhile,PLAC8could be a potential biomarker for ccRCC diagnosis and prognosis in post-kidney transplant patients.