Abstract 6066: Genomic analysis of end-stage renal disease

Abstract Background: Chronic kidney disease is frequently associated with persistent inflammation, which results in fibrosis in the stroma, a reduced number of renal tubules, the formation of multiple cystic lesions, ultimately terminating in renal failure and hemodialysis. Given the high incidence of renal cell carcinoma (RCC) in hemodialysis patients, suggesting a relationship between tissue remodeling by chronic inflammation and carcinogenesis. However, little is known about the genetic background of cancer development from remaining tubules and cystic lesions in hemodialysis patients. Method: We enrolled 5 patients under hemodialysis who were accompanied by acquired cystic kidney disease and underwent radical nephrectomy for RCC. Surgical specimens were fixed with alcohol-based solution and paraffin-embedded, and after H&E staining, subjected to laser capture microdissection (LCM) to collect remaining tubules and cysts containing approximately 200 cells. DNA was extracted and analyzed for somatic mutations and copy number alteration by whole-exome sequencing. Result: In total, we collected 161 LCM samples, including 118 from proximal tubules, 17 from collecting ducts, and 26 from cysts. Median variant allele frequencies of detected mutations were 0.237 in proximal tubules, 0.133 in collecting duct, and 0.381 in cysts, indicating larger clonal expansion in proximal tubules and cysts than in collecting ducts. Proximal tubules and cysts contained recurrent mutations in FAT1 (11% and 8%, respectively), STAG2 (5% and 8%), and PTEN (3% and 4%), whereas no recurrent driver mutations were identified in collecting ducts. In copy number analysis, 26% of proximal tubules, 35% of collecting ducts, and 80% of cysts had copy number alterations. Of note, samples from cysts had more copy number alterations compared to remaining tubules (on average, 2.3 vs. 1.1). Proximal tubules had recurrent copy number gains of chromosomes 3, 7, 10, 18, and 20, and loss of chromosome 22 and samples from collecting ducts showed gains of chromosome 7 and loss of chromosome 18. In cysts, gains of chromosomes 2, 3, 7, 10, 12, and 16 and loss of chromosomes 15, 16, 21, and 22 were frequently observed. Copy number profile in cysts was similar to that of papillary RCC and acquired cystic disease-associated RCC. Conclusion: In the end-stage cystic kidney, proximal tubules and cysts showed an enrichment of driver mutations commonly found in papillary RCC and RCC with acquired cystic disease, reflecting the fact that the incidence of these two types of RCC increases as the duration of dialysis becomes longer. In addition, clear cell RCC drivers, such as VHL mutation and loss of chromosome 3, were not observed, possibly explaining the rare occurrence of clear cell RCC in hemodialysis patients. Since cysts had more frequent copy number alterations than remaining tubules, cysts in the end-stage kidney might be precursor lesions of RCC. Citation Format: Kosuke Ieiri, Nobuyuki Kakiuchi, Tomonori Hirano, Tomomi Nishimura, Koichi Watanabe, Hiroko Tanaka, Satoru Miyano, Dai Takamatsu, Keisuke Monji, Eiji Kashiwagi, Masaki Shiota, Junichi Inokuchi, Masatoshi Eto, Seishi Ogawa. Genomic analysis of end-stage renal disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6066.