Molecular profiles and urinary biomarkers of upper tract urothelial carcinomas associated with aristolochic acid exposure.

Recurrent upper urinary tract carcinomas (UTUC) 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 multi-omics analysis of UTUCs, corresponding unaffected tissues and of patient urines. Quantitative miRNA and mRNA expression profiling, immuno-histochemical analysis by tissue microarrays, and exome and transcriptome sequencing were performed in UTUC and non-tumor tissues. Urinary miRNAs of cases undergoing surgery were profiled before and after tumor 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, 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 transcripts were confirmed at the protein level. Exome and transcriptome sequencing of UTUCs revealed AA-specific mutational signature SBS22, with 68-76% 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 non-invasive urine-based screening of AAN patients for cancer presence and recurrence. This article is protected by copyright. All rights reserved.

International journal of cancer. 2021 Sep 27 [Epub ahead of print]

Sandra KaranoviĆ, Maude Ardin, Zuojian Tang, Karla TomiĆ, Stephanie Villar, Claire Renard, Elisa Venturini, Adam H Lorch, Daniel S Lee, Želimir StipančiĆ, Neda Slade, Ivana VukoviĆ Brinar, Damir Dittrich, Krešimir KarloviĆ, Fran Borovečki, Kathleen G Dickman, Magali Olivier, Arthur P Grollman, Bojan JelakoviĆ, Jiri Zavadil

School of Medicine University of Zagreb, Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb, Zagreb, Croatia., Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, WHO, Lyon, France., Institute for Systems Genetics, New York University Langone Medical Center, New York, NY, USA., Department of Pathology, General Hospital Dr. Josip BenčeviĆ, Slavonski Brod, Croatia., Office for Collaborative Science, New York University Langone Medical Center, New York, NY, USA., Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Department for Dialysis Odžak, County Hospital Orašje, Odžak, Bosnia and Herzegovina., Division of Molecular Medicine, Institute Ruđer BoškoviĆ|, Zagreb, Croatia., Department of Urology, General Hospital Dr. Josip BenčeviĆ, Slavonski Brod, Croatia., Department for Functional Genomics, Center for Translational and Clinical Research, University Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia., Department of Medicine, Stony Brook University, Stony Brook, NY, USA.