Aristolochic acid mutational signature defines the low-risk subtype in upper tract urothelial carcinoma

Lü, Huan; Yuan, Liang; Guan, Bao; Shi, Yue; Gong, Yanqing; Li, Juan; Kong, Wenwen; Liu, Jin; Fang, Dong; Li, Libo; He, Qun; Shakeel, Muhammad; Li, Xuesong; Zhou, Liqun; Ci, Weimin

doi:10.7150/thno.43251

Cited by 42 publications

(79 citation statements)

References 44 publications

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“…Conversely, defective DNA mismatch repair mutational signature was only seen in the UCB cohorts. Consistent with our conclusion, several reports have demonstrated that AA mutational signature was present for the upper urinary tract instead of the lower urinary tract (31,34,35). However, Poon et al…”

Section: Discussionsupporting

confidence: 92%

“…To our knowledge, we are the rst to report that the 5-methylcytosine mutational signature was the predominant mutational signature seen in UTUC cohorts. Lu et al demonstrated that the AA mutational signature was associated with AA exposure, which could be a screening tool de ning low-risk UTUC with therapeutic relevance (31). POLE encodes subunits of Polε DNA polymerase enzyme complex, which serves the major catalytic and proofreading and replicates the leading strand during DNA replication.…”

Section: Discussionmentioning

confidence: 99%

“…One explanation for these nding is the difference in the enrolled population, because exposure to aristolochic acid is associated with other cancer types in addition to UC, such as cancers of the kidney, bile duct, and liver (37). Similarly, POLE mutational signature and defective DNA mismatch repair mutational signature are controversial (26,31,38,39). These studies suggest that mutational characteristics may be in uenced by a variety of factors and be used as a screening tool to assist clinical differential diagnosis between UTUC and UCB.…”

Section: Discussionmentioning

confidence: 99%

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Comparison of Genomic Characterization in Upper Tract Urothelial Carcinoma and Urothelial Carcinoma of the Bladder

Yang

Liu

et al. 2021

Preprint

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Background: Different genomic characterization in urothelial carcinoma (UC) by site of origin, may imply contrasting therapeutic opportunities and pathogenetic mechanisms. The aim of this study was to investigate whether the differences between upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) result from intrinsic biological diversity.Methods: We prospectively sequenced 118 tumors and matched blood DNA from Chinese UC patients using next-generation sequencing (NGS) techniques, including 45 UTUC and 73 UCB.Results: There were marked disparities in the mutational landscape for UC according to race and site of origin. Signature 22 for exposure to aristolochic acid (AA) and signature 10 for defects in polymerase POLE were only observed in the UTUC cohort. Conversely, signature 6 for defective DNA mismatch repair only existed in the UCB cohort. Compared to UCB, UTUC had higher clonal (p<0.001) and subclonal mutation numbers (p=0.015). TP53, PIK3CA, and FGFR3 mutations may be the driver genes for UTUC, whereas for UCB, the driver gene may be BRCA1. UTUC patients had lower PD-L1 than UCB patients. There was no significant difference in the number of DDR mutations, copy number variation (CNV) counts, tumor mutational burden (TMB) or clinical actionability between UTUC and UCB.Conclusions: UTUC and UCB exhibit significant differences in the prevalence of common genomic landscape and carcinogenesis. Consequently, molecular subtypes differ according to location, and these results may have important implications for the site-specific management of patients with urothelial carcinoma. Mutational signature may be used as a screening tool to assist clinical differential diagnosis between UTUC and UCB.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Comparison of Genomic Characterization in Upper Tract Urothelial Carcinoma and Urothelial Carcinoma of the Bladder

Yang

Liu

et al. 2021

Preprint

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“…36,37 AA-related UTUC with unique underlying pathogenesis may have distinct profiles of prognosis and therapeutic strategy. As previously reported, increased gene mutational burden and neoantigen load were observed in patients with AA exposure, 38,39 which can be recognized by T cells and generate antibodies. AA UTUC may then be hypothesized as a good candidate for immune checkpoint blockade therapy.…”

Section: Discussionsupporting

confidence: 70%

Prognostic role of stromal tumor-infiltrating lymphocytes in locally advanced upper tract urothelial carcinoma: A retrospective multicenter study (TSU-02 study)

et al. 2021

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“…From a clinical standpoint, AA-associated UTUC is diagnosed through deep sequencing of urinary sediment DNA, designed to detect a set of known oncogenic mutations and chromosomal aneuploidies [35]. Additionally, cell-free urinary DNA can be sequenced and specific mutational patterns identified [36].…”

Section: Genomics Of Aristolochic Acid-associated Upper Urinary Tractmentioning

confidence: 99%

Current Knowledge on Genomic Profiling of Upper Tract Urothelial Carcinoma

Lorenzis

Albo

Longo

et al. 2021

Genes

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Recent research in next-generation sequencing characterized the genomic landscape of urothelial cancer. However, the majority of the studies focused on bladder cancer (BC). Upper urinary tract urothelial carcinomas (UTUC) and BC share some histological characteristics, but, considering the differences in terms of embryologic precursors, epidemiology, genetics, medical and surgical management and response to therapy, UTUC and BC should be considered as two distinct diseases. Our objective is to analyze through a literature search the latest updates and the current knowledge about the genomics of UTUC. We also evaluate genetic differences between BC and UTUC and the potential implications for systemic therapy. Molecular subtyping and variant histology and their correlation with response to chemotherapy were also explored. In summary, the most frequent genomic variations in UTUC included FGFR3, chromatin remodeling genes, TP53/MDM2 and other tumor suppressors/oncogenes. The genomics of UTUC, integrated with clinical data, could drive the selection of patients who could benefit from targeted therapy or off-label treatment. Routine implementation of tumor genomic characterization in UTUC patients should therefore be contemplated and evaluated prospectively.

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Aristolochic acid mutational signature defines the low-risk subtype in upper tract urothelial carcinoma

Cited by 42 publications

References 44 publications

Comparison of Genomic Characterization in Upper Tract Urothelial Carcinoma and Urothelial Carcinoma of the Bladder

Comparison of Genomic Characterization in Upper Tract Urothelial Carcinoma and Urothelial Carcinoma of the Bladder

Prognostic role of stromal tumor-infiltrating lymphocytes in locally advanced upper tract urothelial carcinoma: A retrospective multicenter study (TSU-02 study)

Current Knowledge on Genomic Profiling of Upper Tract Urothelial Carcinoma

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