The evolving genomic landscape of urothelial carcinoma

Glaser, Alexander; Fantini, Damiano; Shilatifard, Ali; Schaeffer, Edward M.; Meeks, Joshua J.

doi:10.1038/nrurol.2017.11

Cited by 101 publications

(81 citation statements)

References 123 publications

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“…APOBEC3B expression is upregulated in breast cancer and is associated with overall mutations 15 . Our group also demonstrated the relationship between APOBEC3B expression and mutations in bladder cancer 37 . Overexpression of APOBEC3B in breast cancer cell lines results in DNA fragmentation, increased C>T mutations, delayed cell cycle arrest, and eventual cell death 15 .…”

Section: Discussionsupporting

confidence: 55%

APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response

Glaser

Fantini²,

Rimar³

et al. 2017

Preprint

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BackgroundThe APOBEC family of enzymes is responsible for a mutation signature characterized by a TCW>T/G mutation. APOBEC-mediated mutagenesis is implicated in a wide variety of tumors, including bladder cancer. In this study, we explore the APOBEC mutational signature in bladder cancer and the relationship with specific mutations, molecular subtype, gene expression, and survival. We hypothesized that tumors with high levels of APOBEC-mediated mutagenesis would be enriched for mutations in DNA damage response genes and associated with higher expression of genes related to activation of the immune system.MethodsGene expression (n=408) and mutational (n=395) data from the Cancer Genome Atlas (TCGA) bladder urothelial carcinoma provisional dataset was utilized for analysis. Tumors were split into “APOBEC-high” and “APOBEC-low” tumors based on APOBEC enrichment score. Analysis was performed with R.FindingsPatients with APOBEC-high tumors have better overall survival compared to those with APOBEC-low tumors (38.2 vs 18.5 months, p=0.005). Tumors enriched for APOBEC mutagenesis are more likely to have mutations in DNA damage response genes (TP53, ATR, BRCA2), and chromatin regulatory genes (MLL, MLL3), while APOBEC-low tumors are more likely to have mutations in FGFR3 and KRAS. APOBEC3A and APOBEC3B expression correlates with total mutational burden, regardless of bladder tumor molecular subtype. APOBEC mutagenesis and enrichment is associated with increased expression of immune-related genes, including interferon signaling.InterpretationTumors enriched for APOBEC mutagenesis are more likely to have mutations in DNA damage response genes and chromatin regulatory genes, potentially providing more single-strand DNA substrate for APOBEC3A and APOBEC3B, leading to a hypermutational phenotype and the subsequent immune response.HighlightsABPOEC enzymes, particularly APOBEC3A and APOBEC3B, are responsible for the predominant pattern of mutagenesis in bladder cancerTumors enriched for APOBEC-mediated mutagenesis are more likely to have mutations in DNA damage response genes and chromatin regulatory genes, while tumors not enriched for APOBEC-mediated mutagenesis are more likely to have mutations in KRAS and FGFR3APOBEC enrichment is associated with upregulation of genes involved in the immune response

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Section: Discussionsupporting

confidence: 55%

APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response

Glaser

Fantini²,

Rimar³

et al. 2017

Preprint

Self Cite

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“…A future genome‐wide screening in tissue samples from women might, in addition, identify target sites which are more specific for females. Furthermore, numerous somatic mutations have been identified in UCa whose suitability as diagnostic UCa‐markers might be elevated at the level of circulating tumor DNA . In this context, it is interesting to mention that differences between male and female UCa patients in the mutational patterns of selected genes have been recently identified .…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, numerous somatic mutations have been identified in UCa whose suitability as diagnostic UCa-markers might be elevated at the level of circulating tumor DNA. 27,28 In this context, it is interesting to mention that differences between male and female UCa patients in the mutational patterns of selected genes have been recently identified. 29 Consequently, the respective targets might be more suitable as diagnostic markers in female UCa patients.…”

Section: Discussionmentioning

confidence: 99%

Noninvasive diagnosis of urothelial cancer in urine using DNA hypermethylation signatures—Gender matters

Köhler

Bonberg

Ahrens

et al. 2019

Intl Journal of Cancer

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Urothelial cancer (UCa) is the most predominant cancer of the urinary tract and noninvasive diagnosis using hypermethylation signatures in urinary cells is promising. Here, we assess gender differences in a newly identified set of methylation biomarkers. UCa‐associated hypermethylated sites were identified in urine of a male screening cohort (n = 24) applying Infinium‐450K‐methylation arrays and verified in two separate mixed‐gender study groups (n = 617 in total) using mass spectrometry as an independent technique. Additionally, tissue samples (n = 56) of mixed‐gender UCa and urological controls (UCt) were analyzed. The hypermethylation signature of UCa in urine was specific and sensitive across all stages and grades of UCa and independent on hematuria. Individual CpG sensitivities reached up to 81.3% at 95% specificity. Albeit similar methylation differences in tissue of both genders, differences were less pronounced in urine from women, most likely due to the frequent presence of squamous epithelial cells and leukocytes. Increased repression of methylation levels was observed at leukocyte counts ≥500/μl urine which was apparent in 30% of female and 7% of male UCa cases, further confirming the significance of the relative amounts of cancerous and noncancerous cells in urine. Our study shows that gender difference is a most relevant issue when evaluating the performance of urinary biomarkers in cancer diagnostics. In case of UCa, the clinical benefits of methylation signatures to male patients may outweigh those in females due to the general composition of women's urine. Accordingly, these markers offer a diagnostic option specifically in males to decrease the number of invasive cystoscopies.

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“…We identified nine potential driver genes ( STAG2 , EME1 , AKAP9 , DST , ZNF91 , PARD3 , ZFP36L2 , METTL3 , and POLR3B ) whose mutations were negatively associated with bladder cancer recurrence ( P < 0.05, Table and Supporting Information Supplemental Table ). Among these nine genes, STAG2 was one of the most commonly mutated genes in bladder cancer and a potential predictor of recurrence for bladder cancer . STAG2 protein is a component of the cohesin complex, and predominantly functions in sister chromatid cohesion and segregation, DNA repair and gene expression .…”

Section: Discussionmentioning

confidence: 99%

Identification of a nine‐gene panel as a prognostic indicator for recurrence with muscle‐invasive bladder cancer

Han

Zheng

Tian

et al. 2019

Journal of Surgical Oncology

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Background and Objectives Bladder cancer is one of the most common and highly recurrent cancers worldwide. Recurrence‐associated genes may potentially predict cancer recurrence. We aimed to construct a recurrence‐associated gene panel to improve the prognostic prediction of bladder cancer. Methods Based on DNA sequencing and clinical data from the TCGA‐BLCA project, we identified 10 potential driver genes significantly associated with recurrence of bladder cancer. We performed multivariable logistic regression analysis to construct an optimized recurrence prediction model with nine recurrence‐associated genes (EME1, AKAP9, ZNF91, PARD3, STAG2, ZFP36L2, METTL3, POLR3B, and MUC7) and clinical information as the independent variables. Results The area under the receiver operating characteristic (ROC) curve was 0.80 in this model, much higher than that of the baseline model (AUC = 0.73) and the same trend was also validated in its subset. Decision curve analysis also revealed that there is a significant net benefit gained by adding nine genes mutation to the baseline model. Furthermore, Kaplan‐Meier survival analysis showed that eight out of the nine genes (excluding MUC7) had good effects on the overall prognosis of patients. Conclusions This nine‐gene panel will most likely be a useful tool for prognostic evaluation and will facilitate the personalized management of patients with bladder cancer.

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The evolving genomic landscape of urothelial carcinoma

Cited by 101 publications

References 123 publications

APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response

APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response

Noninvasive diagnosis of urothelial cancer in urine using DNA hypermethylation signatures—Gender matters

Identification of a nine‐gene panel as a prognostic indicator for recurrence with muscle‐invasive bladder cancer

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