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Recurrent upper tract urothelial carcinomas (UTUCs) arise in the context of nephropathy linked to exposure to the herbal carcinogen aristolochic acid (AA). Here we delineated the molecular programs underlying UTUC tumorigenesis in patients from endemic aristolochic acid nephropathy (AAN) regions in Southern Europe. We applied an integrative multiomics analysis of UTUCs, corresponding unaffected tissues and of patient urines. Quantitative microRNA (miRNA) and messenger ribonucleic acid (mRNA) expression profiling, immunohistochemical analysis by tissue microarrays and exome and transcriptome sequencing were performed in UTUC and nontumor tissues. Urinary miRNAs of cases undergoing surgery were profiled before and after tumor resection. Ribonucleic acid (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 1, 862 target mRNAs, involving deregulation of cell cycle, deoxyribonucleic acid (DNA) damage response, DNA repair, bladder cancer, oncogenes, tumor suppressors, chromatin structure regulators and developmental signaling pathways. Key UTUC- specific transcripts were confirmed at the protein level. Exome and transcriptome sequencing of UTUCs revealed AA-specific mutational signature SBS22, with 68% to 76% AA-specific, deleterious mutations propagated at the transcript level, a possible basis for neoantigen formation and immunotherapy targeting. We next identified a signature of UTUC- specific miRNAs consistently more abundant in the patients' urine prior to tumor resection, thereby defining biomarkers of tumor presence. The complex gene regulation programs of AAN-associated UTUC tumors involve regulatory miRNAs prospectively applicable to noninvasive urine-based screening of AAN patients for cancer presence and recurrence.

Endemska nefropatija (EN) kronična je tubulointersticijska nefropatija aristolohične kiseline (AAN) koja se javlja u stanovnika određenih sela u dolinama velikih pritoka Dunava na jugoistoku Europe uključujući i Hrvatsku. Oboljeli od EN-a imaju znatno veću učestalost karcinoma prijelaznog epitela mokraćovoda nego opća populacija. Danas se smatra da je A:T transverzija gena p53 »potpisna« mutacija za aristolohičnu kiselinu koja je uzrok endemske nefropatije. Postojeći kriteriji za EN su zastarjeli, neujednačeni (tri vrste kriterija) te nisu u skladu s novim preporukama za klasifikaciju bubrežnih bolesti. Stoga su na temelju sadašnjih znanja i stručnosti grupe znanstvenika i stručnjaka iz svih zemalja s EN-om, kao i svijeta u kojem je AAN opisan stvoreni novi dijagnostički kriteriji i nova klasifikacija stanovništva endemskih sela na simpoziju o EN-u. EN je velik javnozdravstveni problem pa bi nam sadašnja znanja o ovoj bolesti, kao i novi dijagnostički kriteriji trebali pomoći u njezinu ranom otkrivanju i liječenju, a možda u nekoj bližoj budućnosti i njezinoj eradikaciji., Endemic nephropathy (EN) is a chronic tubulointerstitial aristolochic acid nephropathy (AAN) affecting residents of the certain villages in the valleys of the major tributaries of the Danube river in the south-east Europe including Croatia. Patients with EN have a significantly higher incidence of transitional cell carcinoma of the ureter than the general population. A-T transversion of the p53 gene is now considered to be a mutational »signature« of aristolochic acid, which is a cause of endemic nephropathy. Currently used diagnostic criteria for EN are outdated, uneven (three types of criteria) and are not in agreement with proposed new guidelines for kidney diseases. Therefore, based on current knowledge and expertise of a group of scientists and experts from all countries with EN as well as world where AAN has been reported, new diagnostic criteria and the new classification of the population of endemic villages were created at a symposium on EN. EN presents a major public health problem and current knowledge about this disease as well as new diagnostic criteria should help us in its early detection and treatment and maybe in a near future its eradication.