Acquired cystic disease (ACD)-associated renal cell carcinoma (RCC) develops uniquely and frequently in patients receiving long-term dialysis for end-stage renal disease (ESRD). In our previous study, the molecular alteration profiles of ACD-associated RCC were partially similar to those of papillary RCC (PRCC). However, the specific profiles of molecular alterations in ACD-associated RCC and their pathogenic mechanisms remain largely unknown. Therefore, we compared genome-wide transcription and DNA methylation profiles of 12 ACD-associated RCC and 26 PRCC samples, which comprised eight ESRD-induced and 18 sporadic (arising in non-dialysis kidney) PRCC samples. RNA-seq and Infinium Methylation EPIC were used to identify the unique genetic and epigenetic profiles in ACD-associated RCC. ACD-associated RCC harboured a unique expression profile from that of PRCC. Its profile was characterised by the upregulation of pathways related to amino acid metabolism. In addition, ACD-associated RCC exhibited a unique DNA methylation profile that was characterised by the hypomethylation of pathways related to amino acid metabolism. This reflected a significant difference between the expression profiles of ACD-associated RCC and PRCC. The present genome-wide transcriptome and DNA methylome profiling revealed that aberrant activation of amino acid metabolism-related pathways, potentially induced by DNA hypomethylation, may be involved in the pathogenesis of ACD-associated RCC.