Urinary TERT promoter mutations as non-invasive biomarkers for the comprehensive detection of urothelial cancer.

Adult Aged Aged, 80 and over Algorithms Biomarkers, Tumor Case-Control Studies Circulating Tumor DNA DNA Mutational Analysis Disease Management Female Humans Liquid Biopsy Male Middle Aged Mutation Promoter Regions, Genetic Sensitivity and Specificity Telomerase / genetics Tomography, X-Ray Computed Urologic Neoplasms / diagnosis

Blood Cell DNA Cell-free DNA TERT mutations Urine Urothelial cancer detection

Journal

EBioMedicine

ISSN: 2352-3964

Titre abrégé: EBioMedicine

Pays: Netherlands

ID NLM: 101647039

Informations de publication

Date de publication:
Jun 2019

Historique:

received: 18 04 2019

revised: 02 05 2019

accepted: 02 05 2019

pubmed: 28 5 2019

medline: 18 12 2019

entrez: 25 5 2019

Statut: ppublish

Résumé

Recurrent mutations in the promoter of the telomerase reverse transcriptase (TERT) gene (C228T and C250T) detected in tumours and cells shed into urine of urothelial cancer (UC) patients are putative biomarkers for UC detection and monitoring. However, the possibility of detecting these mutations in cell-free circulating DNA (cfDNA) in blood and urine, or DNA from urinary exfoliated cells (cellDNA) with a single-gene sensitive assay has never been tested in a case-control setting. We developed a single-plex assay (UroMuTERT) for the detection of low-abundance TERT promoter mutations. We tested 93 primary and recurrent UC cases and 94 controls recruited in France (blood, urine samples and tumours for the cases), and 50 primary UC cases and 50 controls recruited in Portugal (urinary exfoliated cell samples). We compared our assay with urine cytology. In the French series, C228T or C250T were detected in urinary cfDNA or cellDNA in 81 cases (87·1%; 95% CI 78·6-93·2), and five controls (Specificity 94·7%; 95%CI 88·0-98·3), with 98·6% (95% CI 92·5-99·96) concordance in matched tumours. Detection rate in plasma cfDNA among cases was 7·1%. The UroMuTERT sensitivity was (i) highest for urinary cfDNA and cellDNA combined, (ii) consistent across primary and recurrent cases, tumour stages and grades, (iii) higher for low-risk non-muscle invasive UC (86·1%) than urine cytology (23·0%) (P < 0·0001) and (iv) 93·9% when combined with cytology. In the Portuguese series - the sensitivity and specificity for detection of UC with urinary cellDNA was 68·0% (95% CI 53·3-80·5) and 98·0% (95% CI 89·3-100·0). TERT promoter mutations detected by the UroMuTERT assay in urinary DNA (cfDNA or cellDNA) show excellent sensitivity and specificity for the detection of UC, significantly outperforming that of urine cytology notably for detection of low-grade early stages UC. FUND: French Cancer League; French Foster Research in Molecular Biology and European Commission FP7 Marie Curie COFUND.

Sections du résumé

BACKGROUND BACKGROUND

METHODS METHODS

We developed a single-plex assay (UroMuTERT) for the detection of low-abundance TERT promoter mutations. We tested 93 primary and recurrent UC cases and 94 controls recruited in France (blood, urine samples and tumours for the cases), and 50 primary UC cases and 50 controls recruited in Portugal (urinary exfoliated cell samples). We compared our assay with urine cytology.

FINDINGS RESULTS

In the French series, C228T or C250T were detected in urinary cfDNA or cellDNA in 81 cases (87·1%; 95% CI 78·6-93·2), and five controls (Specificity 94·7%; 95%CI 88·0-98·3), with 98·6% (95% CI 92·5-99·96) concordance in matched tumours. Detection rate in plasma cfDNA among cases was 7·1%. The UroMuTERT sensitivity was (i) highest for urinary cfDNA and cellDNA combined, (ii) consistent across primary and recurrent cases, tumour stages and grades, (iii) higher for low-risk non-muscle invasive UC (86·1%) than urine cytology (23·0%) (P < 0·0001) and (iv) 93·9% when combined with cytology. In the Portuguese series - the sensitivity and specificity for detection of UC with urinary cellDNA was 68·0% (95% CI 53·3-80·5) and 98·0% (95% CI 89·3-100·0).

INTERPRETATION CONCLUSIONS

TERT promoter mutations detected by the UroMuTERT assay in urinary DNA (cfDNA or cellDNA) show excellent sensitivity and specificity for the detection of UC, significantly outperforming that of urine cytology notably for detection of low-grade early stages UC. FUND: French Cancer League; French Foster Research in Molecular Biology and European Commission FP7 Marie Curie COFUND.

Identifiants

DOI: 10.1016/j.ebiom.2019.05.004 PMID: 31122840 PMC: PMC6603852

pubmed: 31122840

pii: S2352-3964(19)30305-6

doi: 10.1016/j.ebiom.2019.05.004

pmc: PMC6603852

pii:

doi:

Substances chimiques

Biomarkers, Tumor 0

Circulating Tumor DNA 0

TERT protein, human EC 2.7.7.49

Telomerase EC 2.7.7.49

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

431-438