Molecular profiles and urinary biomarkers of upper tract urothelial carcinomas associated with aristolochic acid exposure
| Autor: | Kathleen G. Dickman, Ivana Vuković Brinar, Damir Dittrich, Elisa Venturini, Fran Borovečki, Sandra Karanović, Daniel S. Lee, Stephanie Villar, Želimir Stipančić, Magali Olivier, Karla Tomić, Bojan Jelaković, Jiri Zavadil, Claire Renard, Arthur P. Grollman, Krešimir Karlović, Adam Lorch, Zuojian Tang, Neda Slade, Maude Ardin |
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| Jazyk: | chorvatština |
| Rok vydání: | 2022 |
| Předmět: |
Cancer Research
Proteome Aristolochic acid Context (language use) Biology medicine.disease_cause upper tract urothelial carcinoma aristolochic acid nephropathy urinary biomarkers 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine microRNA Clinical Medical Sciences Biomarkers Tumor medicine Humans Exome RNA Messenger 030304 developmental biology Carcinoma Transitional Cell 0303 health sciences Tissue microarray Cancer Basic Medical Sciences Prognosis medicine.disease 3. Good health Gene Expression Regulation Neoplastic Gene expression profiling MicroRNAs Urinary Bladder Neoplasms Oncology chemistry 030220 oncology & carcinogenesis Mutation Cancer research Aristolochic Acids Carcinogenesis Follow-Up Studies |
| Zdroj: | International Journal of Cancer |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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