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

Springer, Simeon; Chen, Chung‐Hsin; Peña, Maria Del Carmen Rodriguez; Lü, Li; Douville, Christopher; Wang, Yuxuan; Cohen, Joshua D.; Taheri, Diana; Silliman, Natalie; Schaefer, Joy; Ptak, Janine; Dobbyn, Lisa; Papoli, Maria; Kinde, Isaac; Afsari, Bahman; Tregnago, Aline C.; Bezerra, Stephania M.; VandenBussche, Christopher; Fujita, Kazutoshi; Ertoy, Dilek; Cunha, Isabela W.; Yu, Lingfei; Bivalacqua, Trinity J.; Grollman, Arthur P.; Díaz, Luis A.; Karchin, Rachel; Danilova, Ludmila; Huang, Chao Yuan; Shun, Chia‐Tung; Turesky, Robert J.; Yun, Byeong Hwa; Rosenquist, Thomas A.; Pu, Yeong-Shiau; Hruban, Ralph H.; Tomasetti, Cristian; Papadopoulos, Nickolas; Kinzler, Ken W; Vogelstein, Bert; Dickman, Kathleen G.; Netto, George J.

doi:10.7554/elife.32143

Cited by 138 publications

(177 citation statements)

References 93 publications

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“…Springer et al reported that mutant DNA in urinary pellets from UTUC patients in Taiwan could be detected by NGS at rates of 25.0% ( TERT C228T), 7.1% ( TERT C250T), 10.7% ( FGFR3 S249C), and 5.4% ( PIK3CA E545K). In the current study, we could detect mutations at rates of 39.3% ( TERT C228T), 7.1% ( TERT C250T), 16.1% ( FGFR3 S249C), and 8.9% ( PIK3CA E545K) in urinary cfDNA in Japanese patients.…”

Section: Discussionmentioning

confidence: 99%

“…The mutant TERT promoter allele alters the binding site, recruits transcription factor GABPA, and engages in long‐range chromatin interactions, subsequently stimulating increased TERT promoter activity and enabling tumors to overcome the end‐replication problem and avoid senescence . Springer et al reported the clinical potential of mutant DNA derived from urinary cells (pellets) by targeted sequencing in patients with UBC or UTUC for cancer detection and surveillance. In UBC patients, urinary cfDNA has a higher tumor genomic burden and greater detection potential as a genomic biomarker than urinary pellets .…”

Section: Introductionmentioning

confidence: 99%

“…Next-generation sequencing has shown genomic alterations and transcriptional subtypes in UTUC and UBC tissue. [13][14][15][16] Hotspot mutations of TERT promoter and FGFR3 (S249C) are frequently identified in UTUC specimens. Mutations in the upstream promoter of the TERT gene predominantly affect two hotspots, g.1295228 C>T and g.1295250 C>T, 17,18 hereafter referred to as C228T and C250T, respectively.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…Furthermore, bladder cancer is innately exposed to urine, which is also a resource for liquid biopsy. UroSEEK is one of such tests and is a urine‐based molecular assay designed to detect mutations in 11 genes and copy number changes on 39 chromosome arms for the detection and surveillance of bladder cancer . The 11 genes included drug‐targetable genes, such as FGFR3 , ERBB2 and PIK3CA .…”

Section: New Technologiesmentioning

confidence: 99%

Predictive biomarkers for drug response in bladder cancer

Yoshida¹,

Kates

Fujita

et al. 2019

Int J of Urology

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Bladder cancer is a heterogeneous disease. Interpatient heterogeneity in response to a drug limits treatment options and impairs improvement of patient survival. For example, approximately half of patients do not respond to cisplatin‐based combination chemotherapy, although it is the standard of care for muscle‐invasive and metastatic bladder cancer. The development of robust predictive biomarkers is expected to improve outcomes by enabling clinicians to use chemotherapy only in the patients who will benefit from it. Recent advances in the molecular characterization of bladder cancer showed that the basal subtype of bladder cancer and tumors with inactivating mutations in DNA damage repair genes were associated with greater benefit from cisplatin‐based chemotherapy. The present review summarizes current efforts to develop predictive biomarkers for drug response in bladder cancer, focusing on those that predict the response to cisplatin‐based chemotherapy for advanced bladder cancer. We also review the current situation with regard to the identification of predictive biomarkers for response to intravesical therapy, immune checkpoint inhibitors and molecularly‐targeted drugs. We also discuss the future applications of new technologies, including liquid biopsies and patient‐derived organoids that will also serve as resources for the identification of biomarkers in bladder cancer.

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“…Although they are thought to share common pathways of carcinogenesis, UTUCs are more invasive at the time of diagnosis, which indicates a more aggressive genetic phenotype. The use of next‐generation sequencing in the detection of mutation in UTUC definitely accelerates and facilitates the understanding of the genomic level in UTUC …”

Section: Etiologymentioning

confidence: 99%

Recent advances in upper tract urothelial carcinomas: From bench to clinics

2018

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Urothelial carcinoma in the upper tract is rare and often discussed separately. Many established risk factors were identified for the disease, including genetic and external risk factors. Radiographic survey, endoscopic examination and urine cytology remained the most important diagnostic modalities. In localized upper tract urothelial carcinomas, radical nephroureterectomy with bladder cuff excision are the gold standard for large, high‐grade and suspected invasive tumors of the renal pelvis and proximal ureter, whereas kidney‐sparing surgeries should be considered in patients with low‐risk disease. Advances in technology have given endoscopic surgery an important role, not only in diagnosis, but also in treatment. Although platinum‐based combination chemotherapy is efficacious in advanced or metastatic disease, current established chemotherapy regimens are toxic and lack a sustained response. Immune checkpoint inhibitors have led to a new era of treatment for advanced or metastatic urothelial carcinomas. The remarkable results achieved thus far show that immunotherapy will likely be the future treatment paradigm. The combination of immune checkpoint inhibitors and other agents is another inspiring avenue to explore that could benefit even more patients. With respect to the high incidence rate and different clinical appearance of upper tract urothelial carcinomas in Taiwan, a possible correlation exists between exposure to certain external risk factors, such as arsenic in drinking water and aristolochic acid in Chinese herbal medicine. As more gene sequencing differences between upper tract urothelial carcinomas and various disease causes are detailed, this has warranted the era of individualized screening and treatment for the disease.

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

Cited by 138 publications

References 93 publications

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

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

Predictive biomarkers for drug response in bladder cancer

Recent advances in upper tract urothelial carcinomas: From bench to clinics

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