Spectrum of genetic mutations in de novo PUNLMP of the urinary bladder

Peña, Maria Del Carmen Rodriguez; Tregnago, Aline C.; Eich, Marie‐Lisa; Springer, Simeon; Wang, Yuxuan; Taheri, Diana; Ertoy, Dilek; Fujita, Kazutoshi; Bezerra, Stephania M.; Cunha, Isabela W.; Raspollini, Maria Rosaria; Yu, Lingfei; Bivalacqua, Trinity J.; Papadopoulos, Nickolas; Kinzler, Kenneth W.; Vogelstein, Bert; Netto, George J.

doi:10.1007/s00428-017-2164-5

Cited by 27 publications

(16 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TERT promoter mutations occur in up to 80% of invasive urothelial carcinomas of the bladder and in several of their histologic variants ( Allory et al, 2014 ; Cowan et al, 2016 ; Killela et al, 2013 ; Kinde et al, 2013 ; Nguyen et al, 2016 ). Moreover, TERT promoter mutations occur in 60–80% of BC precursors, including papillary urothelial neoplasms of low malignant potential ( Rodriguez Pena et al, 2017 ), non-invasive low-grade papillary urothelial carcinoma, non-invasive high-grade papillary urothelial carcinoma and ‘flat’ carcinoma in situ (CIS), as well as in urinary cells from a subset of these patients ( Kinde et al, 2013 ). TERT promoter mutations have thus been established as a common genetic alteration in urothelial neoplasms ( Cheng et al, 2017 ; Killela et al, 2013 ; Kinde et al, 2013 ; Yuan et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy

Springer

Chen

Peña

et al. 2018

eLife

Self Cite

135

157

View full text Add to dashboard Cite

Current non-invasive approaches for detection of urothelial cancers are suboptimal. We developed a test to detect urothelial neoplasms using DNA recovered from cells shed into urine. UroSEEK incorporates massive parallel sequencing assays for mutations in 11 genes and copy number changes on 39 chromosome arms. In 570 patients at risk for bladder cancer (BC), UroSEEK was positive in 83% of those who developed BC. Combined with cytology, UroSEEK detected 95% of patients who developed BC. Of 56 patients with upper tract urothelial cancer, 75% tested positive by UroSEEK, including 79% of those with non-invasive tumors. UroSEEK detected genetic abnormalities in 68% of urines obtained from BC patients under surveillance who demonstrated clinical evidence of recurrence. The advantages of UroSEEK over cytology were evident in low-grade BCs; UroSEEK detected 67% of cases whereas cytology detected none. These results establish the foundation for a new non-invasive approach for detection of urothelial cancer.

show abstract

Section: Introductionmentioning

confidence: 99%

Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy

Springer

Chen

Peña

et al. 2018

eLife

Self Cite

135

157

View full text Add to dashboard Cite

show abstract

“…To some extent, UTUC shares the same gene alterations as UBC, so this method might also be a useful tool for detecting UBC for bladder surveillance after RNU. In bladder tumors, the TERT promoter mutation occurs frequently in precancerous lesions and in low‐grade UBC, high‐grade UBC, squamous cell carcinoma of the urinary bladder, adenocarcinoma of the urinary bladder, micropapillary urothelial carcinoma and plasmacytoid urothelial carcinoma . Thus, the TERT promoter mutation has been established as a common genetic alteration in UC.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic potential of TERT promoter and FGFR3 mutations in urinary cell‐free DNA in upper tract urothelial carcinoma

et al. 2019

Self Cite

View full text Add to dashboard Cite

Most upper tract urothelial carcinomas ( UTUC ) are muscle invasive at the time of diagnosis. Current standard methods for the diagnosis of UTUC are invasive. Urine cytology is the only non‐invasive test for detecting UTUC , but its sensitivity is low. A novel non‐invasive assay for UTUC detection would improve patient outcome. This study aimed to investigate the mutation of cell‐free DNA (cf DNA ) in urine supernatant to develop a reliable diagnostic biomarker for UTUC patients. We studied urinary cf DNA from 153 individuals, including 56 patients with localized UTUC , and carried out droplet digital PCR assay for TERT promoter and FGFR 3 hotspot mutations. We could detect mutations of TERT C228T in 22/56 (39.3%), TERT C250T in 4/56 (7.1%), and FGFR 3 S249C in 9/56 (16.1%) patients. FGFR 3 mutation was detected only in ≤ pT 1 tumors (positive predictive value: 100.0%). In combination with cytology results, the sensitivity was 78.6%, and the specificity was 96.0%. Although these data need to be validated in a larger‐scale cohort, mutation analysis of TERT promoter and FGFR 3 in urinary cf DNA has the potential to be a non‐invasive diagnostic marker and reliable factor for tumor staging.

show abstract

“…Mutation and data analysis was performed as previously described [19, 20, 25, 26]. In brief, purified DNA was submitted for SafeSeqS analysis, a sequencing error-reduction technique capable of discriminating mutations from artifactual sequencing variants introduced during the sequencing process [27, 28].…”

Section: Methodsmentioning

confidence: 99%

Incidence and distribution of UroSEEK gene panel in a multi-institutional cohort of bladder urothelial carcinoma

et al. 2019

Self Cite

View full text Add to dashboard Cite

Non-invasive approaches for early detection of bladder cancer are actively being investigated. We recently developed a urine based molecular assay for the detection and surveillance of bladder neoplasms (UroSEEK). UroSEEK is designed to detect alterations in 11 genes that includes most common genetic alterations in bladder cancer. In this study we analyzed 527 cases including 373 non-invasive and 154 invasive urothelial carcinomas of bladder from trans-urethral resections or cystectomies performed at 4 institutions (1991–2016). Two different mutational analysis assays of a representative tumor area were performed: first, a singleplex PCR assay for evaluation of the TERT promoter region (TERTSeqS) and second, a multiplex PCR assay using primers designed to amplify regions of interest of 10 (FGFR3, PIK3CA, TP53, HRAS, KRAS, ERBB2, CDKN2A, MET, MLL, and VHL) genes (UroSeqS). Overall 92% of all bladder tumors were positive for at least one genetic alteration in the UroSEEK panel. We found TERT promoter mutations in 77% of low-grade non-invasive papillary carcinomas with relatively lower incidence of 65% in high-grade non-invasive papillary carcinomas and carcinomas in situ; p=0.017. Seventy-two percent of pT1 and 63% of muscle-invasive bladder tumors harbored TERT promoter mutations with g.1295228C>T alteration being the most common in all groups. FGFR3 and PIK3CA mutations were more frequent in low-grade non-invasive papillary carcinomas compared to high-grade non-invasive papillary carcinomas and carcinomas in situ (p<0.0001), while the opposite was true for TP53 (p<0.0001). Significantly higher rates of TP53 and CDKN2A mutation rates (p=0.005 and 0.035, respectively) were encountered in muscle-invasive bladder tumors compared to those of pT1 stage. The overwhelming majority of all investigated tumors showed at least one mutation among UroSEEK assay genes confirming the comprehensive coverage of the panel and supporting its potential utility as a non-invasive urine based assay.

show abstract

Spectrum of genetic mutations in de novo PUNLMP of the urinary bladder

Cited by 27 publications

References 24 publications

Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy

Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy

Diagnostic potential of TERT promoter and FGFR3 mutations in urinary cell‐free DNA in upper tract urothelial carcinoma

Incidence and distribution of UroSEEK gene panel in a multi-institutional cohort of bladder urothelial carcinoma

Contact Info

Product

Resources

About