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Mutational signature and clonal relatedness of recurrent urothelial carcinomas with aristolochic acid
Urothelial carcinomas (UCs) are malignant tumors that arise from the lower and upper urinary tract and are characterized by multiple recurrences. Aristolochic acid (AA) is a potent nephrotoxin and human carcinogen associated with UC. East Asian populations with a high UC prevalence have an unusual g...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9516318/ https://www.ncbi.nlm.nih.gov/pubmed/36185218 http://dx.doi.org/10.3389/fonc.2022.990023 |
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author | Zhu, Jie Ai, Qing Cheng, Qiang Shen, Dan Dong, Zhouhuan Li, Jie Shen, Donglai Wang, Wei Zhang, Xu Li, Hongzhao |
author_facet | Zhu, Jie Ai, Qing Cheng, Qiang Shen, Dan Dong, Zhouhuan Li, Jie Shen, Donglai Wang, Wei Zhang, Xu Li, Hongzhao |
author_sort | Zhu, Jie |
collection | PubMed |
description | Urothelial carcinomas (UCs) are malignant tumors that arise from the lower and upper urinary tract and are characterized by multiple recurrences. Aristolochic acid (AA) is a potent nephrotoxin and human carcinogen associated with UC. East Asian populations with a high UC prevalence have an unusual genome-wide AA-induced mutational pattern. To address the genomic differences and clonal relatedness between primary and recurrent tumors in the UCs with AA pattern, we investigated the genomic differences and tumor microenvironment (TME) of AA and non-AA UCs. 17 UC patients were recruited, with nine documented AA exposure. Eleven of them showed recurrence. After-surgery tissues of primary and paired recurrent tumors were collected. Capture-based targeted deep sequencing was performed using a commercial panel consisting of 520 cancer-related genes. Tumor-infiltrating lymphocytes (TILs) were identified with an immunofluorescence-based microenvironment analysis panel (MAP). Hierarchical clustering based on the COSMIC signatures confirmed two significant subtypes: AA Sig and non-AA Sig. AA Sig was associated with AA-containing herbal drug intake, recurrence, and higher tumor mutation burden (TMB). The clonal architecture of UCs revealed three types of clonal evolution patterns. Non-AA Sig cohort showed shared clonal origin of primary and recurrent tumors. AA Sig showed heterogeneity and had multiple independent origins. Recurrent tumors as second primary tumors in AA Sig showed immunoreactive TME, indicating a better response with immune checkpoint inhibitor therapy. The AA mutational signature and unique immune profiles are helpful molecular markers to distinguish AA exposure from other carcinogens. These results also provide new insights into the origin of recurrent UCs that could affect treatment strategies. |
format | Online Article Text |
id | pubmed-9516318 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-95163182022-09-29 Mutational signature and clonal relatedness of recurrent urothelial carcinomas with aristolochic acid Zhu, Jie Ai, Qing Cheng, Qiang Shen, Dan Dong, Zhouhuan Li, Jie Shen, Donglai Wang, Wei Zhang, Xu Li, Hongzhao Front Oncol Oncology Urothelial carcinomas (UCs) are malignant tumors that arise from the lower and upper urinary tract and are characterized by multiple recurrences. Aristolochic acid (AA) is a potent nephrotoxin and human carcinogen associated with UC. East Asian populations with a high UC prevalence have an unusual genome-wide AA-induced mutational pattern. To address the genomic differences and clonal relatedness between primary and recurrent tumors in the UCs with AA pattern, we investigated the genomic differences and tumor microenvironment (TME) of AA and non-AA UCs. 17 UC patients were recruited, with nine documented AA exposure. Eleven of them showed recurrence. After-surgery tissues of primary and paired recurrent tumors were collected. Capture-based targeted deep sequencing was performed using a commercial panel consisting of 520 cancer-related genes. Tumor-infiltrating lymphocytes (TILs) were identified with an immunofluorescence-based microenvironment analysis panel (MAP). Hierarchical clustering based on the COSMIC signatures confirmed two significant subtypes: AA Sig and non-AA Sig. AA Sig was associated with AA-containing herbal drug intake, recurrence, and higher tumor mutation burden (TMB). The clonal architecture of UCs revealed three types of clonal evolution patterns. Non-AA Sig cohort showed shared clonal origin of primary and recurrent tumors. AA Sig showed heterogeneity and had multiple independent origins. Recurrent tumors as second primary tumors in AA Sig showed immunoreactive TME, indicating a better response with immune checkpoint inhibitor therapy. The AA mutational signature and unique immune profiles are helpful molecular markers to distinguish AA exposure from other carcinogens. These results also provide new insights into the origin of recurrent UCs that could affect treatment strategies. Frontiers Media S.A. 2022-09-14 /pmc/articles/PMC9516318/ /pubmed/36185218 http://dx.doi.org/10.3389/fonc.2022.990023 Text en Copyright © 2022 Zhu, Ai, Cheng, Shen, Dong, Li, Shen, Wang, Zhang and Li https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Zhu, Jie Ai, Qing Cheng, Qiang Shen, Dan Dong, Zhouhuan Li, Jie Shen, Donglai Wang, Wei Zhang, Xu Li, Hongzhao Mutational signature and clonal relatedness of recurrent urothelial carcinomas with aristolochic acid |
title | Mutational signature and clonal relatedness of recurrent urothelial carcinomas with aristolochic acid |
title_full | Mutational signature and clonal relatedness of recurrent urothelial carcinomas with aristolochic acid |
title_fullStr | Mutational signature and clonal relatedness of recurrent urothelial carcinomas with aristolochic acid |
title_full_unstemmed | Mutational signature and clonal relatedness of recurrent urothelial carcinomas with aristolochic acid |
title_short | Mutational signature and clonal relatedness of recurrent urothelial carcinomas with aristolochic acid |
title_sort | mutational signature and clonal relatedness of recurrent urothelial carcinomas with aristolochic acid |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9516318/ https://www.ncbi.nlm.nih.gov/pubmed/36185218 http://dx.doi.org/10.3389/fonc.2022.990023 |
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