Abstract 6629: Spatial immunogenomic analysis of the transformation process in acquired cystic disease of the kidney

Abstract Chronic kidney disease (CKD) is one of the leading causes of death, affecting more than 10 % of the general population worldwide. When CKD progresses to the advanced stage known as end-stage renal disease (ESRD), patients require kidney replacement therapy such as dialysis or kidney transplantation. The prevalence of dialysis patients in Japan is 2,535 per million population, which is much higher than those in Western countries, mainly due to the low number of kidney transplants in Japan. One of the critical complications of dialysis is the high incidence of kidney cancer, which is approximately 15 times higher than in the general population. More than 90 % of patients on dialysis for more than 10 years develop acquired cystic kidney disease (ACKD), which has been reported to be associated with the development of kidney cancer. However, the molecular mechanism underlying ACKD-associated RCC(ACD-RCC) has not been elucidated. We performed multi-omic analyses of ACKD especially from a spatial immunogenomic perspective. We collected the data of 26 single-cell transcriptomes and 26 spatial transcriptomes using 10x Genomics platform as well as 42 exome sequencing and 86 RNA sequencing for renal cysts and tumors from ACKD patients. Normal kidney tissues from non-dialysis patients were also analyzed. The mutational landscape of ACD-RCC and ESRD-clear cell renal cell carcinoma(ccRCC) was totally different from that of the sporadic ccRCC. Specifically, ccRCC in ACKD patients was characterized by a higher incidence of TCEB1 mutations (35.3%). Analysis on the noncancerous tissues in ACKD revealed the unique transcriptomic features of renal cysts in ACKD with a characteristic of inflammatory signaling activation. Specifically, unique immune cell infiltration patterns of lymphocytes and macrophages in ACKD were identified, which are distinct from those in normal kidney tissue. Our integrative single cell and spatial analyses identified renal cyst cluster which is characterized by activation of proximal tubular genes, and our data support that renal cysts and subsequent dialysis-related tumors both originate from proximal tubular cells. Also, we estimated copy number variation in renal cysts and found shared copy number variation with tumors. Furthermore, we identified specific mutations concentrated in the cyst wall using laser capture microdissection, suggesting that a single cyst may have arisen from a single clone. Also, we analyzed intercellular communication and identified important pathways for nurturing cysts formation including signaling pathway. Collectively, our results will contribute to the suppression of cystic kidney and renal tumors, and pave the way for improving the prognosis of patients with ACKD. Citation Format: Jun TAKAHASHI, Yosuke Tanaka, Yusuke Sato, Tetsuo Ushiku, Hiroyoshi Nishikawa, Haruki Kume, Hiroyuki Mano. Spatial immunogenomic analysis of the transformation process in acquired cystic disease of the kidney [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6629.