Research Papers:

Detection of multiple mutations in urinary exfoliated cells from male bladder cancer patients at diagnosis and during follow-up

Rossana Critelli, Francesca Fasanelli, Marco Oderda, Silvia Polidoro, Manuela Bianca Assumma, Clara Viberti, Mirko Preto, Paolo Gontero, Giuseppina Cucchiarale, Irene Lurkin, Ellen C. Zwarthoff, Paolo Vineis, Carlotta Sacerdote, Giuseppe Matullo and Alessio Naccarati _

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Oncotarget. 2016; 7:67435-67448. https://doi.org/10.18632/oncotarget.11883

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Rossana Critelli1, Francesca Fasanelli2, Marco Oderda3, Silvia Polidoro1, Manuela Bianca Assumma1, Clara Viberti2,4, Mirko Preto3, Paolo Gontero3, Giuseppina Cucchiarale5, Irene Lurkin6, Ellen C. Zwarthoff6, Paolo Vineis1,7, Carlotta Sacerdote8, Giuseppe Matullo2,4, Alessio Naccarati1

1Molecular and Genetic Epidemiology Unit, Human Genetics Foundation, Turin, Italy

2Department of Medical Sciences, University of Turin, Turin, Italy

3Department of Surgical Sciences, Urology, University of Turin, Turin, Italy

4Genomic Variation in Human Populations and Complex Diseases Unit, Human Genetics Foundation, Turin, Italy

5Department of Urology, Humanitas Cellini, Turin, Italy

6Department of Pathology, Erasmus MC, Rotterdam, The Netherlands

7Department of Surgery and Cancer, Imperial College London, London, UK

8Unit of Cancer Epidemiology, Centre for Cancer Prevention (CPO-Piemonte), Turin, Italy

Correspondence to:

Alessio Naccarati, email: [email protected]

Keywords: bladder cancer, urine mutation analyses, TERT, recurrence

Received: May 27, 2016    Accepted: August 25, 2016    Published: September 07, 2016


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.

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