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Huina Wang
Acornmed Biotechnology CO., Ltd.
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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.
Keywords
upper tract urothelial carcinoma, urothelial carcinoma of the bladder, genomic characterization, mutational signature, marker
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Figure 6
This is a list of supplementary files associated with this preprint. Click to download.
- FigureS1.jpg
Figure S1 Differences in the prevalence of gene mutations by stage, comparison between UTUC and UCB. (A) Differences for genes with a significant difference between UTUC and UCB in various stages. (B) Top 5 genes for various stages. The frequently mutated genes in (C) UTUC stage ≤2, (D) UTUC stage >2 (E) UCB stage ≤2. (F) UCB stage >2. Names of the top 5 mutated genes (left), frequency of the top 20 mutated genes (right), TMB (above), and mutation type for each sample (bottom). a represents a significant difference in mutation frequency between UTUC and UBC. b represents a significant difference in mutation frequency in various UCB stages.
- FigureS2.jpg
Figure S2 Correlation between observed and expected co-occurrence of mutations for (A) UTUC and (B) UCB.
- figureS3.jpg
Figure S3 Landscapes of frequent clonal (A) and subclonal mutations (B) of UTUC and UCB.
- figureS4.jpg
Figure S4 Landscapes of frequent genes for CNV in different locations of UC. The most frequently mutated genes in (A) UTUC, (B) UCB. Names of the top 20 mutated genes (left), Frequency of the top 20 mutated genes (right).
- figureS5.jpg
Figure S5 Relationship among those immune markers. (A) Relationship between DDR genes and CNV in UTUC and UCB. (B) Relationship between DDR gene mutation and TMB in UTUC and UCB. (C) Relationship between CNV and TMB in UTUC and UCB. (D) Relationship between DDR gene mutation and PD-L1 in UTUC and UCB. (E) Relationship between CNV and PD-L1 in UTUC and UCB. (F) Relationship between TMB and PD-L1 in UTUC and UCB.
- tableS1.docx
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A new preprint design is coming!
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This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research
Huina Wang
Acornmed Biotechnology CO., Ltd.
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
View the published article at The Oncologist.
Version 1
Posted 05 Jan, 2021
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cancer Biology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at The Oncologist.
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.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
This is a list of supplementary files associated with this preprint. Click to download.
- FigureS1.jpg
Figure S1 Differences in the prevalence of gene mutations by stage, comparison between UTUC and UCB. (A) Differences for genes with a significant difference between UTUC and UCB in various stages. (B) Top 5 genes for various stages. The frequently mutated genes in (C) UTUC stage ≤2, (D) UTUC stage >2 (E) UCB stage ≤2. (F) UCB stage >2. Names of the top 5 mutated genes (left), frequency of the top 20 mutated genes (right), TMB (above), and mutation type for each sample (bottom). a represents a significant difference in mutation frequency between UTUC and UBC. b represents a significant difference in mutation frequency in various UCB stages.
- FigureS2.jpg
Figure S2 Correlation between observed and expected co-occurrence of mutations for (A) UTUC and (B) UCB.
- figureS3.jpg
Figure S3 Landscapes of frequent clonal (A) and subclonal mutations (B) of UTUC and UCB.
- figureS4.jpg
Figure S4 Landscapes of frequent genes for CNV in different locations of UC. The most frequently mutated genes in (A) UTUC, (B) UCB. Names of the top 20 mutated genes (left), Frequency of the top 20 mutated genes (right).
- figureS5.jpg
Figure S5 Relationship among those immune markers. (A) Relationship between DDR genes and CNV in UTUC and UCB. (B) Relationship between DDR gene mutation and TMB in UTUC and UCB. (C) Relationship between CNV and TMB in UTUC and UCB. (D) Relationship between DDR gene mutation and PD-L1 in UTUC and UCB. (E) Relationship between CNV and PD-L1 in UTUC and UCB. (F) Relationship between TMB and PD-L1 in UTUC and UCB.
- tableS1.docx
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