In:
BJU International, Wiley, Vol. 124, No. 3 ( 2019-09), p. 532-544
Abstract:
To develop a focused panel of somatic mutations ( SM s) present in the majority of urothelial bladder cancers ( UBC s), to investigate the diagnostic and prognostic utility of this panel, and to compare the identification of SM s in urinary cell‐pellet (cp) DNA and cell‐free (cf) DNA as part of the development of a non‐invasive clinical assay. Patients and Methods A panel of SM s was validated by targeted deep‐sequencing of tumour DNA from 956 patients with UBC . In addition, amplicon and capture‐based targeted sequencing measured mutant allele frequencies ( MAF s) of SM s in 314 urine cp DNA s and 153 urine cf DNA s. The association of SM s with grade, stage, and clinical outcomes was investigated by univariate and multivariate Cox models. Concordance between SM s detected in tumour tissue and cp DNA and cf DNA was assessed. Results The panel comprised SM s in 23 genes: TERT (promoter), FGFR 3 , PIK 3 CA , TP 53 , ERCC 2 , RHOB , ERBB 2 , HRAS , RXRA , ELF 3 , CDKN 1A , KRAS , KDM 6A , AKT 1 , FBXW 7 , ERBB 3 , SF 3B1 , CTNNB 1 , BRAF , C3orf70 , CREBBP , CDKN 2A , and NRAS ; 93.5–98.3% of UBC s of all grades and stages harboured ≥1 SM (mean: 2.5 SM s/tumour). RAS mutations were associated with better overall survival ( P = 0.04). Mutations in RXRA , RHOB and TERT (promoter) were associated with shorter time to recurrence ( P 〈 0.05). MAF s in urinary cf DNA and cp DNA were highly correlated; using a capture‐based approach, 〉 94% of tumour SM s were detected in both cpDNA and cf DNA . Conclusions SM s are reliably detected in urinary cp DNA and cf DNA . The technical capability to identify very low MAF s is essential to reliably detect UBC , regardless of the use of cp DNA or cf DNA . This 23‐gene panel shows promise for the non‐invasive diagnosis and risk stratification of UBC .
Type of Medium:
Online Resource
ISSN:
1464-4096
,
1464-410X
Language:
English
Publisher:
Wiley
Publication Date:
2019
detail.hit.zdb_id:
2019983-1
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