Targeted deep sequencing of urothelial bladder cancers and associated urinary DNA: a 23-gene panel with utility for non-invasive diagnosis and risk stratification

Autor:	Ward, Douglas G., Gordon, Naheema S., Boucher, Rebecca H., Pirrie, Sarah J., Baxter, Laura, Ott, Sascha, Silcock, Lee, Whalley, Celina M., Stockton, Joanne D., Beggs, Andrew D., Griffiths, Mike, Abbotts, Ben, Ijakipour, Hanieh, Latheef, Fathimath N., Robinson, Robert A., White, Andrew J., James, Nicholas D., Zeegers, Maurice P., Cheng, K. K., Bryan, Richard T.
Přispěvatelé:	Complexe Genetica, RS: NUTRIM - R3 - Respiratory & Age-related Health, RS: CAPHRI - R5 - Optimising Patient Care
Rok vydání:	2019
Předmět:	Adult Male CARCINOMA diagnosis BIOMARKERS detection GUIDELINES Risk Assessment #blcsm Databases Genetic Humans RECURRENCE Aged Aged 80 and over Carcinoma Transitional Cell #BladderCancer High-Throughput Nucleotide Sequencing DNA DNA Neoplasm Sequence Analysis DNA Middle Aged mutations Prognosis urine TERT PROMOTER MUTATIONS Urinary Bladder Neoplasms Mutation Translational Science Female LIQUID BIOPSIES
Zdroj:	Bju International BJU International, 124(3), 532-544. Wiley
ISSN:	1464-410X 1464-4096
Popis:	Objectives To develop a focused panel of somatic mutations (SMs) present in the majority of urothelial bladder cancers (UBCs), to investigate the diagnostic and prognostic utility of this panel, and to compare the identification of SMs 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 SMs 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 (MAFs) of SMs in 314 urine cpDNAs and 153 urine cfDNAs. The association of SMs with grade, stage, and clinical outcomes was investigated by univariate and multivariate Cox models. Concordance between SMs detected in tumour tissue and cpDNA and cfDNA was assessed. Results The panel comprised SMs in 23 genes: TERT (promoter), FGFR3, PIK3CA, TP53, ERCC2, RHOB, ERBB2, HRAS, RXRA, ELF3, CDKN1A, KRAS, KDM6A, AKT1, FBXW7, ERBB3, SF3B1, CTNNB1, BRAF, C3orf70, CREBBP, CDKN2A, and NRAS; 93.5-98.3% of UBCs of all grades and stages harboured >= 1 SM (mean: 2.5 SMs/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 94% of tumour SMs were detected in both cpDNA and cfDNA. Conclusions SMs are reliably detected in urinary cpDNA and cfDNA. The technical capability to identify very low MAFs is essential to reliably detect UBC, regardless of the use of cpDNA or cfDNA. This 23-gene panel shows promise for the non-invasive diagnosis and risk stratification of UBC.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::feada36f84757b87073fa0b6be19c5d9 https://pubmed.ncbi.nlm.nih.gov/31436040 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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