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

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...

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Published in:International journal of cancer 2022-01, Vol.150 (2), p.374-386
Main Authors: Karanović, Sandra, Ardin, Maude, Tang, Zuojian, Tomić, Karla, Villar, Stephanie, Renard, Claire, Venturini, Elisa, Lorch, Adam H., Lee, Daniel S., Stipančić, Želimir, Slade, Neda, Vuković Brinar, Ivana, Dittrich, Damir, Karlović, Krešimir, Borovečki, Fran, Dickman, Kathleen G., Olivier, Magali, Grollman, Arthur P., Jelaković, Bojan, Zavadil, Jiri
Format: Article
Language:English
Subjects:
Aristolochic acid
Aristolochic Acids - adverse effects
Biomarkers
Biomarkers, Tumor - genetics
Biomarkers, Tumor - urine
Bladder cancer
Cancer
Carcinogens
Carcinoma, Transitional Cell - chemically induced
Carcinoma, Transitional Cell - genetics
Carcinoma, Transitional Cell - pathology
Carcinoma, Transitional Cell - urine
Cell cycle
Chromatin
Deoxyribonucleic acid
DNA
DNA damage
DNA microarrays
DNA repair
Exome
Follow-Up Studies
Gene expression
Gene Expression Regulation, Neoplastic - drug effects
Gene regulation
Humans
Immunotherapy
massively parallel sequencing
Medical research
MicroRNAs
MicroRNAs - urine
miRNA
Mutation
Neoantigens
Nephropathy
Patients
Prognosis
Proteome - analysis
Proteome - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
Statistical analysis
Transcription
transcriptome profiling
Transcriptomes
Tumorigenesis
upper tract urothelial carcinoma
Urinary Bladder Neoplasms - chemically induced
Urinary Bladder Neoplasms - genetics
Urinary Bladder Neoplasms - pathology
Urinary Bladder Neoplasms - urine
urine miRNA
Urothelial carcinoma
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Summary: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. What's new? Ingestion of aristolochic acid (AA) via contaminated wheat‐containing food products is a major cause of endemic neuropathy and urologic carcinogenesis in southeastern Europe. Here, using integrated multi‐omics analysis, the authors identified molecular programs underlying upper tract urothelial tumors (UTUC) in patients in Southern Europe with past carcinogenic AA exposure. Analyses reveal associations between 89 miRNAs and 1,862 target mRNAs, with confirmation of UTUC‐specific transc
ISSN:0020-7136
1097-0215
1097-0215
DOI:10.1002/ijc.33827