Whole-exome Sequencing Identified Mutational Profiles of De Novo Urothelial Carcinoma After Kidney Transplantation

Abstract

Introduction Urothelial carcinoma (UC) has the characteristic of high mutational burden and elevated degree of molecular heterogeneity compared with other solid tumor. Rapid development in whole exome sequencing (WES) have identified drivers and somatic alteration of UC. In Taiwan, UC is the most common de novo cancer after kidney transplantation. There are limited reports exploring the genomic alteration in UC after kidney transplantation. In this study we perform WES of UC developed after kidney transplantation in an effort to discover the molecular genetics of UC and their association with immunosuppressive regiment used. Materials and Methods Formalin-fixed paraffin-embedded archival samples of UC from 5 kidney transplant patients from the Kaohsiung Medical University Hospital Taiwan were obtained. Kidney transplant patients with UC diagnosed before the transplant surgery were excluded. All of the patients were sporadic, without any family history of UC. For control group, we selected 5 hemodialysis patients with UC diagnosed after the commencement of dialysis treatment. The patient medical history was confirmed by chart review. DNA was extracted for WES analysis. Results Our WES data is matched with the Cosmic, Intogen, and TCGA database for onco-driver genes. We newly identified nine genes, including BRIP1, GNAQ, IKZF1, MLLT10, NTRK3, SEPT6, SH3GL1, SLC34A2, TSC2 which have mutations specifically in kidney transplant recipients in this study. These patients received conventional immunosuppressive agents, including Tacrolimus, mycophenolate mofetil, mammalian target of rapamycin inhibitor (mTORi) and steroid as maintenance therapy. Discussion and Conclusion This preliminary data provides clues for understanding the mutational landscape of UC developed after kidney transplantation. Genetic analysis in malignancy after transplantation may help to identify high risk patients in post-transplant care and also illuminate a fundamental aspects of the molecular pathogenesis of post-transplantation UC.