Whole-Exome Sequencing Identified Mutational Profiles of Urothelial Carcinoma post Kidney Transplantation

Abstract

Background: Kidney transplantation is a lifesaving option of selected patients with end-stage kidney disease (ESKD). Urothelial carcinoma (UC) is the most common de novo cancer after kidney transplantation in Taiwan. UC has the characteristics of high mutational burden and elevated degree of molecular heterogeneity compared with other solid tumors. However, there are limited research exploring the genomic alterations in UC after kidney transplantation. Methods: In this study, we performed whole exome sequencing (WES) to compare the genetic alterations between UC developed after kidney transplantation (UCKT) and UC from hemodialysis patients (UCHD). After mapping and variant calling, a total of 18,733 and 11,093 mutations were identified from UCKT and UCHD patients, respectively. We first excluded known SNPs and then retained genes that were annotated in Cosmic, Intogen, and TCGA bladder databases for onco-driver genes. Seventeen UCKT unique genes with recurrent SNPs in more than two patients were subjected for further analysis. IPA pathway analysis was used to explore the interconnections among these genes. Results: 17 novel mutations of BTK, CARD11, ELL, FNBP1, GNAQ, HOXD13, IKZF1, MAX, MLLT10, NTRK3, PAX5, SEPTIN6, SEPTIN9, SH3GL1, SLC34A2, TAL1 , and TRAF7 were identified UCKT groups, and none of the genes had been reported in the genomes of patients with UC. Among the affected genes, GNAQ, IKZF1, and NTRK3 were potentially involved in the signaling network of UCKT. Conclusion : Our findings provide information for understanding the mutational landscape of UC developed after kidney transplantation, and a gene list that may be of great importance in related molecular mechanisms. Genetic analysis in malignancy after transplantation may help to identify high risk patients in post-transplant care and also illuminate a fundamental aspect of the molecular pathogenesis of post-transplantation UC.