Project description:This study presents a comprehensive multi-omic analysis of upper urinary tract urothelial tumours (UTUC) and urines of patients with past exposure to carcinogenic aristolochic acid (AA). We determined complex miRNA:mRNA tumor networks and their key protein components. Tumor exome and transcriptome sequencing revealed a burden of AA-specific mutations in UTUC and identified deleteriously mutated genes and their mRNA transcripts. A subset of identified urinary miRNAs presents potential biomarkers of UTUC development or presence. Recurrent upper urinary tract carcinomas (UTUC) arise in the context of nephropathy linked to exposure to the herbal carcinogen aristolochic acid (AA). We aimed to delineate the detailed biological programs underlying UTUC tumorigenesis in patients from endemic aristolochic acid nephropathy (AAN) regions in Southern Europe, by using an integrative multi-omics analysis of UTUCs, corresponding unaffected tissues and of patient urines. Quantitative miRNA and mRNA expression profiling, immunohistochemical analysis by tissue microarrays, and exome and transcriptome sequencing were performed in UTUC and non-tumor tissues. Urinary miRNAsof cases undergoing surgery were profiled before and after UTUC resection. RNA and protein levels were analyzed using appropriate statistical tests and trend assessment. Dedicated bioinformatic tools were used for analysis of pathways, mutational signatures and result visualization. The results delineate UTUC-specific miRNA:mRNA networks comprising 89 miRNAs associated with 1862 target mRNAs and involving deregulation of cell cycle, DNA damage response, DNA repair, bladder cancer, oncogenes, tumor suppressors, chromatin structure regulators and developmental signaling pathways. Key UTUC-specific transcriptome components were confirmed at the protein level. Exome and transcriptome sequencing of UTUC revealed AA-specific COSMIC mutational signature 22, with 68-76% AA-specific, deleterious mutations propagated at the mRNA level. We next identified a signature of UTUC-specific miRNAs consistently more abundant in the patients’ urine prior to tumor resection. The gene regulation programs of AAN-associated UTUC tumors are highly complex and involve regulatory miRNAs prospectively applicable to non-invasive urine-based screening of AAN patients for cancer recurrence.

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Differential miRNA expression profiling of urinary exosomes from normo- and microalbuminuric type 1 diabetic patients

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