Genomic heterogeneity in bladder cancer: challenges and possible solutions to improve outcomes

Meeks, Joshua J.; Al‐Ahmadie, Hikmat; Faltas, Bishoy; Taylor, John A.; Flaig, Thomas W.; DeGraff, David J.; Christensen, Emil; Woolbright, Benjamin L.; McConkey, David J.; Dyrskjøt, Lars

doi:10.1038/s41585-020-0304-1

Cited by 127 publications

(129 citation statements)

References 134 publications

(172 reference statements)

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“…The intratumoral and intertumoral heterogeneity at the genomic, transcriptional and cellular levels contribute to the capricious outcomes of UBC patients 4 . Even the pathologically similar, the intrinsic molecular and genetic events were quite different; thus, a number of groups used gene expression patterns to reveal the molecular subtypes which traverse stage and grade classification 5 - 10 .…”

Section: Introductionmentioning

confidence: 99%

Identification of glycogene-type and validation of ST3GAL6 as a biomarker predicts clinical outcome and cancer cell invasion in urinary bladder cancer

Dalangood

Zhu

et al. 2020

Theranostics

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Background: Urinary bladder cancer (UBC) is one of the most common causes of morbidity and mortality worldwide characterized by a high risk of invasion and metastasis; however, the molecular classification biomarkers and underlying molecular mechanisms for UBC patient stratification on clinical outcome need to be investigated. Methods: A systematic transcriptomic analysis of 185 glycogenes in the public UBC datasets with survival information and clinicopathological parameters were performed using unsupervised hierarchical clustering. The gene signature for glycogene-type classification was identified using Limma package in R language, and correlated to 8 known molecular features by Gene Set Variation Analysis (GSVA). The clinical relevance and function of a glycogene was characterized by immunohistochemistry in UBC patient samples, and quantitative RT-PCR, Western blotting, promoter activity, MAL II blotting, immunofluorescence staining, wound healing, and transwell assays in UBC cells. Results: A 14-glycogene signature for glycogene-type classification was identified. Among them, ST3GAL6, a glycotransferase to transfer sialic acid to 3'-hydroxyl group of a galactose residue, showed a significant negative association with the subtype with luminal feature in UBC patients (n=2,130 in total). Increased ST3GAL6 was positively correlated to tumor stage, grade, and survival in UBCs from public datasets or our cohort (n=52). Transcription factor GATA3, a luminal-specific marker for UBC, was further identified as a direct upstream regulator of ST3GAL6 to negatively regulate its transactivation. ST3GAL6 depletion decreased MAL II level, cell invasion and migration in 5637 and J82 UBC cells. ST3GAL6 could reverse the effects of GATA3 on global sialylation and cell invasion in SW780 cells. Conclusions: Herein, we successfully identified a novel 14-gene signature for glycogene-type classification of UBC patients. ST3GAL6 gene, from this signature, was demonstrated as a potential biomarker for poor outcomes and cell invasion in UBCs.

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Section: Introductionmentioning

confidence: 99%

Identification of glycogene-type and validation of ST3GAL6 as a biomarker predicts clinical outcome and cancer cell invasion in urinary bladder cancer

Dalangood

Zhu

et al. 2020

Theranostics

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“…BlCa is one of the most frequent malignancies of the male urinary tract and is considered to be a highly heterogeneous disease both in molecular/cellular extent and in patients' treatment outcome [35]. Currently, the lack of accurate prognostic tools leads to the non-personalized active treatment and lifelong surveillance of the patients, making BlCa the most expensive per patient-to-treat malignancy for healthcare systems [36,37].…”

Section: Discussionmentioning

confidence: 99%

tRNA-Derived Fragments (tRFs) in Bladder Cancer: Increased 5′-tRF-LysCTT Results in Disease Early Progression and Patients’ Poor Treatment Outcome

Papadimitriou

Avgeris

Levis

et al. 2020

Cancers

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The heterogeneity of bladder cancer (BlCa) prognosis and treatment outcome requires the elucidation of tumors’ molecular background towards personalized patients’ management. tRNA-derived fragments (tRFs), although originally considered as degradation debris, represent a novel class of powerful regulatory non-coding RNAs. In silico analysis of the TCGA-BLCA project highlighted 5′-tRF-LysCTT to be significantly deregulated in bladder tumors, and 5′-tRF-LysCTT levels were further quantified in our screening cohort of 230 BlCa patients. Recurrence and progression for non-muscle invasive (NMIBC) patients, as well as progression and patient’s death for muscle-invasive (MIBC) patients, were used as clinical endpoint events. TCGA-BLCA were used as validation cohort. Bootstrap analysis was performed for internal validation and the clinical net benefit of 5′-tRF-LysCTT on disease prognosis was assessed by decision curve analysis. Elevated 5′-tRF-LysCTT was associated with unfavorable disease features, and significant higher risk for early progression (multivariate Cox: HR = 2.368; p = 0.033) and poor survival (multivariate Cox: HR = 2.151; p = 0.032) of NMIBC and MIBC patients, respectively. Multivariate models integrating 5′-tRF-LysCTT with disease established markers resulted in superior risk-stratification specificity and positive prediction of patients’ progression. In conclusion, increased 5′-tRF-LysCTT levels were strongly associated with adverse disease outcome and improved BlCa patients’ prognostication.

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“…In addition, we observed a high concordance of mutational status between tumors and matched urine samples in DIAGURO BC cases with analytical sensitivities of 98.6% for UroMuTERT and 97.2% for ddPCR assays and therefore only a small fraction of false negatives, likely reflecting in such cases the existence of minor tumoral TERT mutated clones (MAF < 1%) undetectable in urine samples. Bladder tumors are characterized by intra-and inter-tumoral heterogeneity both at the molecular and cellular levels [33,34]. The co-existence of multiple sub-clonal populations, including multiple TERT mutated clones has been also reported in bladder tumors [11,24].…”

Section: Discussionmentioning

confidence: 99%

Development of Sensitive Droplet Digital PCR Assays for Detecting Urinary TERT Promoter Mutations as Non-Invasive Biomarkers for Detection of Urothelial Cancer

Hosen

Forey

Durand

et al. 2020

Cancers

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Somatic mutations in the telomerase reverse transcriptase (TERT) promoter regions are frequent events in urothelial cancer (UC) and their detection in urine (supernatant cell-free DNA or DNA from exfoliated cells) could serve as putative non-invasive biomarkers for UC detection and monitoring. However, detecting these tumor-borne mutations in urine requires highly sensitive methods, capable of measuring low-level mutations. In this study, we developed sensitive droplet digital PCR (ddPCR) assays for detecting TERT promoter mutations (C228T, C228A, CC242-243TT, and C250T). We tested the C228T and C250T ddPCR assays on all samples with sufficient quantity of urinary DNA (urine supernatant cell-free DNA (US cfDNA) or urine pellet cellular DNA (UP cellDNA)) from the DIAGURO (n = 89/93 cases and n = 92/94 controls) and from the IPO-PORTO (n = 49/50 cases and n = 50/50 controls) series that were previously screened with the UroMuTERT assay and compared the performance of the two approaches. In the DIAGURO series, the sensitivity and specificity of the ddPCR assays for detecting UC using either US cfDNA or UP cellDNA were 86.8% and 92.4%. The sensitivity was slightly higher than that of the UroMuTERT assay in the IPO-PORTO series (67.4% vs. 65.3%, respectively), but not in the DIAGURO series (86.8% vs. 90.7%). The specificity was 100% in the IPO-PORTO controls for both the UroMuTERT and ddPCR assays, whereas in the DIAGURO series, the specificity dropped for ddPCR (92.4% versus 95.6%). Overall, an almost perfect agreement between the two methods was observed for both US cfDNA (n = 164; kappa coefficient of 0.91) and UP cellDNA (n = 280; kappa coefficient of 0.94). In a large independent series of serial urine samples from DIAGURO follow-up BC cases (n = 394), the agreement between ddPCR and UroMuTERT was (i) strong (kappa coefficient of 0.87), regardless of urine DNA types (kappa coefficient 0.89 for US cfDNA and 0.85 for UP cellDNA), (ii) the highest for samples with mutant allelic fractions (MAFs) > 2% (kappa coefficient of 0.99) and (iii) only minimal for the samples with the lowest MAFs (< 0.5%; kappa coefficient 0.32). Altogether, our results indicate that the two methods (ddPCR and UroMuTERT) for detecting urinary TERT promoter mutations are comparable and that the discrepancies relate to the detection of low-allelic fraction mutations. The simplicity of the ddPCR assays makes them suitable for implementation in clinical settings.

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Genomic heterogeneity in bladder cancer: challenges and possible solutions to improve outcomes

Cited by 127 publications

References 134 publications

Identification of glycogene-type and validation of ST3GAL6 as a biomarker predicts clinical outcome and cancer cell invasion in urinary bladder cancer

Identification of glycogene-type and validation of ST3GAL6 as a biomarker predicts clinical outcome and cancer cell invasion in urinary bladder cancer

tRNA-Derived Fragments (tRFs) in Bladder Cancer: Increased 5′-tRF-LysCTT Results in Disease Early Progression and Patients’ Poor Treatment Outcome

Development of Sensitive Droplet Digital PCR Assays for Detecting Urinary TERT Promoter Mutations as Non-Invasive Biomarkers for Detection of Urothelial Cancer

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