Mutational signature and clonal relatedness of recurrent urothelial carcinomas with aristolochic acid
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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.Keywords:
Aristolochic Acid
Chinese Herbs Nephropathy has made global focuses on the nephrotoxicity of aristolochic acid(AA).More studies found that patients who had aristolochic acid nephropathy were complicated by urothelial cancer,therefore driving more resources on elucidation of the molecular mechanism of mutagenesis and carcinogenesis by aristolochic acid.Two major components,aristolochic acid I and aristolochic acid II,are considered as genotoxic mutagens.This paper discusses the mechanism of mutagenesis and carcinogenesis of these two components,involving the formation of AA-DNA adducts,metabolic activation,the distribution in vivo and oncogene mutation of AA-DNA adducts.
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Abstract Each hepatocellular carcinoma displays dozens of mutations in driver and passenger genes. The analysis of the types of substitutions and their trinucleotide context defines mutational signatures that recapitulate the endogenous and exogenous mutational processes operative in tumor cells. Aristolochic acid is present in plants from the genus Aristolochia and causes chronic nephropathy. Moreover, aristolochic acid has genotoxic properties responsible for the occurrence of urothelial carcinoma. Metabolites of aristolochic acid form DNA adducts on adenine residues leading to a specific mutational signature with almost exclusively A:T to T:A transversions, preferentially in a CTG trinucleotide context. Interestingly, this mutational fingerprint has been identified in a subset of hepatocellular carcinomas suggesting that aristolochic acid is a new risk factor for hepatocellular carcinoma. More data are warranted to capture the real impact of exposure to aristolochic acid in hepatocellular carcinoma occurrence worldwide.
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There have been numerous domestic and international reports of nephrotoxicity associated with botanical products found to contain aristolochic acid. Many investigations disclosed cases of nephropathy and end-stage renal diseases associated with ingestion of products containing aristolochic acid. Of further concern is carcinogenic potential of aristolochic acid. Aristolochic acid, when tested for carcinogenicity by oral administration in mice and rats,induced chronically toxicity,and led to local and systemic tumors. Furthermore,patients taking aristolochic acid may be at increased risk of developing malignancies. The toxic effects of aristolochic acid in animals have been inferred from effects seen in patients suffering from kidney nephropathy as a result of consuming herbal mixtures containing aristolochic acid. Concerns about botanical-containing products known or suspected of containing aristolochic acid will bring to our attention important safety information relative to nephrotoxicity associated with aristolochic acid and rationality to utilize traditional Chinese medicine.
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국내 유통 중인 한약재에 발암물질로 알려진 aristolochic acid 함유 여부를 검사하고자 방기, 목통, 목향, 마두령, 세신, 청목향 등을 대상으로 aristolochic acid 검출 유무 및 정량분석을 수행하였다. 시료에 대한 TLC와 C_(18) column을 이용한 HPLC의 aristolochic acid 최적 분석 조건을 수립하였고 aristolochic acid 정량분석 결과 방기 type II에는 3.9 mg/g, 마두령에는 2.3 mg/g이 함유되어 있는 것으로 나타났다. 그외 목향, 목통, 세신, 청목향 등 시료에서는 aristolochic acid가 검출되지 않았다.
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Covering: 1960 to 2013
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Endemic nephropathy is a syndrome that comprises two entities: chronic interstitial nephropathy and urothelial cell cancers predominantly of the upper urinary tract. The etiological agent for the disease is aristolochic acid, a compound found in the plants of Aristolochia spp. The development of urothelial cancers is characterized by the formation of aristolactam DNA adducts leading to mutations, predominantly A: T->T: A transversions. In order to comprehensively understand the gene regulation programs in upper urothelial cancers we performed integrated miRNA and mRNA expression profiling of paired tumours and unaffected urothelium samples. The obtained data will help us to understand the carcinogenesis caused by aristolochic acid and might be the source for the design of a diagnostic biomarker.
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Aristolochic acid nephropathy is a chronic, fibrosing, interstitial nephritis caused by aristolochic acid (AA), which is a component of the plants of Aristolochiacae family. It was first reported in 1993, in Belgium as a Chinese herb nephropathy, in patients who received a slimming regimen containing AA. The term aristolochic acid nephropathy also includes Balcan endemic nephropathy and other endemic tubulointerstitial fibrosis. Moreover, AA is a human carcinogen which induces urothelial cancer. The AA-containing herbs are banned in many countries and FDA published the warnings concerning the safety of AA-containing botanical remedies in 2000. Regarding the increasing interest in herbal medicines, uncontrolled access to botanical remedies and replacement of one herb by another AA-containing compounds makes thousands of people all around the world at risk of this grave disease.
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