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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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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8627473/
https://www.ncbi.nlm.nih.gov/pubmed/34569060
http://dx.doi.org/10.1002/ijc.33827
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author 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
author_facet 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
author_sort Karanović, Sandra
collection PubMed
description 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.
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spelling pubmed-86274732022-10-14 Molecular profiles and urinary biomarkers of upper tract urothelial carcinomas associated with aristolochic acid exposure 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 Int J Cancer Tumor Markers and Signatures 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. John Wiley & Sons, Inc. 2021-10-15 2022-01-15 /pmc/articles/PMC8627473/ /pubmed/34569060 http://dx.doi.org/10.1002/ijc.33827 Text en © 2021 IARC. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Tumor Markers and Signatures
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
Molecular profiles and urinary biomarkers of upper tract urothelial carcinomas associated with aristolochic acid exposure
title Molecular profiles and urinary biomarkers of upper tract urothelial carcinomas associated with aristolochic acid exposure
title_full Molecular profiles and urinary biomarkers of upper tract urothelial carcinomas associated with aristolochic acid exposure
title_fullStr Molecular profiles and urinary biomarkers of upper tract urothelial carcinomas associated with aristolochic acid exposure
title_full_unstemmed Molecular profiles and urinary biomarkers of upper tract urothelial carcinomas associated with aristolochic acid exposure
title_short Molecular profiles and urinary biomarkers of upper tract urothelial carcinomas associated with aristolochic acid exposure
title_sort molecular profiles and urinary biomarkers of upper tract urothelial carcinomas associated with aristolochic acid exposure
topic Tumor Markers and Signatures
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8627473/
https://www.ncbi.nlm.nih.gov/pubmed/34569060
http://dx.doi.org/10.1002/ijc.33827
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