Detection of multiple mutations in urinary exfoliated cells from male bladder cancer patients at diagnosis and during follow-up.
Most bladder cancer (BC) patients need life-long, invasive and expensive monitoring and treatment, making it a serious burden on the health system. Thus, there is a pressing need for an accurate test to assist diagnosis and surveillance of BC as an alternative to cystoscopy. Mutations in human TERT, FGFR3, PIK3CA, and RAS genes have been proposed as potential molecular markers in bladder tumor. Their concomitant presence in urine samples has not been fully explored.We investigated a panel of mutations in DNA from exfoliated urinary cells of 255 BC patients at diagnosis. Forty-one mutations in TERT, FGFR3, PIK3CA, and RAS were analyzed by SNaPshot assay in relation to clinical outcome. In 81 of these patients under surveillance, the same set of mutations was screened in additional 324 samples prospectively collected.The most common mutations detected in urine at diagnosis were in the TERT promoter. In non-invasive BC, these mutations were related to high risk and grade (p<0.0001) as well as progression to muscle-invasive disease (p=0.01), whereas FGFR3 mutations were observed in low-grade BC (p=0.02) and patients with recurrences (p=0.05). Stronger associations were observed for combined TERT and FGFR3 mutations and number of recurrences (OR: 4.54 95% CI: 1.23-16.79, p=0.02). Analyses of the area under the curve for combinations of mutations detected at diagnosis and follow-up showed an accuracy of prediction of recurrence of 0.80 (95% CI: 0.71-0.89).Mutations in urine of BC patients may represent reliable biomarkers. In particular, TERT and FGFR3 mutations have a good accuracy of recurrence prediction.
Molecular and Genetic Epidemiology Unit, Human Genetics Foundation, Turin, Italy.
Rossana
R
Critelli
Department of Medical Sciences, University of Turin, Turin, Italy.
Francesca
F
Fasanelli
Department of Surgical Sciences, Urology, University of Turin, Turin, Italy.
Marco
M
Oderda
Molecular and Genetic Epidemiology Unit, Human Genetics Foundation, Turin, Italy.
Silvia
S
Polidoro
Molecular and Genetic Epidemiology Unit, Human Genetics Foundation, Turin, Italy.
Manuela Bianca
MB
Assumma
Department of Medical Sciences, University of Turin, Turin, Italy.|Genomic Variation in Human Populations and Complex Diseases Unit, Human Genetics Foundation, Turin, Italy.
Clara
C
Viberti
Department of Surgical Sciences, Urology, University of Turin, Turin, Italy.
Mirko
M
Preto
Department of Surgical Sciences, Urology, University of Turin, Turin, Italy.
Paolo
P
Gontero
Department of Urology, Humanitas Cellini, Turin, Italy.
Giuseppina
G
Cucchiarale
Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
Irene
I
Lurkin
Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
Ellen C
EC
Zwarthoff
Molecular and Genetic Epidemiology Unit, Human Genetics Foundation, Turin, Italy.|Department of Surgery and Cancer, Imperial College London, London, UK.
Paolo
P
Vineis
Unit of Cancer Epidemiology, Centre for Cancer Prevention (CPO-Piemonte), Turin, Italy.
Carlotta
C
Sacerdote
Department of Medical Sciences, University of Turin, Turin, Italy.|Genomic Variation in Human Populations and Complex Diseases Unit, Human Genetics Foundation, Turin, Italy.
Giuseppe
G
Matullo
Molecular and Genetic Epidemiology Unit, Human Genetics Foundation, Turin, Italy.
Alessio
A
Naccarati
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000235:genetics / Q000652:urine*; D002295:Carcinoma, Transitional Cell / Q000175:diagnosis* / Q000235:genetics* / Q000652:urine; D004252:DNA Mutational Analysis / Q000379:methods; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000235:genetics / Q000652:urine; D012372:ROC Curve; D012680:Sensitivity and Specificity; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000652:urine
D014408:Biomarkers, Tumor
TERT; bladder cancer; recurrence; urine mutation analyses