Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhu, Jie, Ai, Qing, Cheng, Qiang, Shen, Dan, Dong, Zhouhuan, Li, Jie, Shen, Donglai, Wang, Wei, Zhang, Xu, Li, Hongzhao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
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
_version_ 1784798682377355264
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
work_keys_str_mv AT zhujie mutationalsignatureandclonalrelatednessofrecurrenturothelialcarcinomaswitharistolochicacid
AT aiqing mutationalsignatureandclonalrelatednessofrecurrenturothelialcarcinomaswitharistolochicacid
AT chengqiang mutationalsignatureandclonalrelatednessofrecurrenturothelialcarcinomaswitharistolochicacid
AT shendan mutationalsignatureandclonalrelatednessofrecurrenturothelialcarcinomaswitharistolochicacid
AT dongzhouhuan mutationalsignatureandclonalrelatednessofrecurrenturothelialcarcinomaswitharistolochicacid
AT lijie mutationalsignatureandclonalrelatednessofrecurrenturothelialcarcinomaswitharistolochicacid
AT shendonglai mutationalsignatureandclonalrelatednessofrecurrenturothelialcarcinomaswitharistolochicacid
AT wangwei mutationalsignatureandclonalrelatednessofrecurrenturothelialcarcinomaswitharistolochicacid
AT zhangxu mutationalsignatureandclonalrelatednessofrecurrenturothelialcarcinomaswitharistolochicacid
AT lihongzhao mutationalsignatureandclonalrelatednessofrecurrenturothelialcarcinomaswitharistolochicacid