Promoter hypermethylation of HS3ST2, SEPTIN9 and SLIT2 combined with FGFR3 mutations as a sensitive/specific urinary assay for diagnosis and surveillance in patients with low or high-risk non-muscle-invasive bladder cancer

Handle URI:
http://hdl.handle.net/10754/621987
Title:
Promoter hypermethylation of HS3ST2, SEPTIN9 and SLIT2 combined with FGFR3 mutations as a sensitive/specific urinary assay for diagnosis and surveillance in patients with low or high-risk non-muscle-invasive bladder cancer
Authors:
Roperch, Jean-Pierre; Grandchamp, Bernard; Desgrandchamps, François; Mongiat-Artus, Pierre; Ravery, Vincent; Ouzaid, Idir; Roupret, Morgan; Phe, Véronique; Ciofu, Calin; Tubach, Florence; Cussenot, Olivier; Incitti, Roberto
Abstract:
Background: Non-muscle-invasive bladder cancer (NMIBC) is a high incidence form of bladder cancer (BCa), where genetic and epigenetic alterations occur frequently. We assessed the performance of associating a FGFR3 mutation assay and a DNA methylation analysis to improve bladder cancer detection and to predict disease recurrence of NMIBC patients. Methods: We used allele specific PCR to determine the FGFR3 mutation status for R248C, S249C, G372C, and Y375C. We preselected 18 candidate genes reported in the literature as being hypermethylated in cancer and measured their methylation levels by quantitative multiplex-methylation specific PCR. We selected HS3ST2, SLIT2 and SEPTIN9 as the most discriminative between control and NMIBC patients and we assayed these markers on urine DNA from a diagnostic study consisting of 167 NMIBC and 105 controls and a follow-up study consisting of 158 NMIBC at diagnosis time's and 425 at follow-up time. ROC analysis was performed to evaluate the diagnostic accuracy of each assay alone and in combination. Results: For Diagnosis: Using a logistic regression analysis with a model consisting of the 3 markers' methylation values, FGFR3 status, age and known smoker status at the diagnosis time we obtained sensitivity/specificity of 97.6 %/84.8 % and an optimism-corrected AUC of 0.96. With an estimated BCa prevalence of 12.1 % in a hematuria cohort, this corresponds to a negative predictive value (NPV) of 99.6 %. For Follow-up: Using a logistic regression with FGFR3 mutation and the CMI at two time points (beginning of the follow-up and current time point), we got sensitivity/specificity/NPV of 90.3 %/65.1 %/97.0 % and a corrected AUC of 0.84. We also tested a thresholding algorithm with FGFR3 mutation and the two time points as described above, obtaining sensitivity/specificity/NPV values of, respectively, 94.5 %/75.9 %/98.5 % and an AUC of 0.82. Conclusions: We showed that combined analysis of FGFR3 mutation and DNA methylation markers on urine can be a useful strategy in diagnosis, surveillance and for risk stratification of patients with NMIBC. These results provide the basis for a highly accurate noninvasive test for population screening and allowing to decrease the frequency of cystoscopy, an important feature for both patient quality of life improvement and care cost reduction. © 2016 The Author(s).
KAUST Department:
Computational Bioscience Research Center (CBRC)
Citation:
Roperch J-P, Grandchamp B, Desgrandchamps F, Mongiat-Artus P, Ravery V, et al. (2016) Promoter hypermethylation of HS3ST2, SEPTIN9 and SLIT2 combined with FGFR3 mutations as a sensitive/specific urinary assay for diagnosis and surveillance in patients with low or high-risk non-muscle-invasive bladder cancer. BMC Cancer 16. Available: http://dx.doi.org/10.1186/s12885-016-2748-5.
Publisher:
Springer Nature
Journal:
BMC Cancer
Issue Date:
2-Sep-2016
DOI:
10.1186/s12885-016-2748-5
Type:
Article
ISSN:
1471-2407
Sponsors:
The authors thank the Assistance Publique-Hôpitaux de Paris (AP-HP) for providing the samples obtained from a collection code-named AUVES (project reference RECF0998-PHRC 2003). We also warmly thank Agoranov start-up incubator for their help in the implementation of our work.This work was partly supported by a grant from Bpifrance (project reference PIA1 A1407120Q 2014).
Is Supplemented By:
Roperch, J.-P., Grandchamp, B., Desgrandchamps, F., Mongiat-Artus, P., Ravery, V., Idir Ouzaid, … Incitti, R. (2016). Promoter hypermethylation of HS3ST2, SEPTIN9 and SLIT2 combined with FGFR3 mutations as a sensitive/specific urinary assay for diagnosis and surveillance in patients with low or high-risk non-muscle-invasive bladder cancer. Figshare. https://doi.org/10.6084/m9.figshare.c.3619151; DOI:10.6084/m9.figshare.c.3619151; HANDLE:http://hdl.handle.net/10754/624134
Additional Links:
http://bmccancer.biomedcentral.com/articles/10.1186/s12885-016-2748-5
Appears in Collections:
Articles; Computational Bioscience Research Center (CBRC)

Full metadata record

DC FieldValue Language
dc.contributor.authorRoperch, Jean-Pierreen
dc.contributor.authorGrandchamp, Bernarden
dc.contributor.authorDesgrandchamps, Françoisen
dc.contributor.authorMongiat-Artus, Pierreen
dc.contributor.authorRavery, Vincenten
dc.contributor.authorOuzaid, Idiren
dc.contributor.authorRoupret, Morganen
dc.contributor.authorPhe, Véroniqueen
dc.contributor.authorCiofu, Calinen
dc.contributor.authorTubach, Florenceen
dc.contributor.authorCussenot, Olivieren
dc.contributor.authorIncitti, Robertoen
dc.date.accessioned2016-12-08T13:54:25Z-
dc.date.available2016-12-08T13:54:25Z-
dc.date.issued2016-09-02en
dc.identifier.citationRoperch J-P, Grandchamp B, Desgrandchamps F, Mongiat-Artus P, Ravery V, et al. (2016) Promoter hypermethylation of HS3ST2, SEPTIN9 and SLIT2 combined with FGFR3 mutations as a sensitive/specific urinary assay for diagnosis and surveillance in patients with low or high-risk non-muscle-invasive bladder cancer. BMC Cancer 16. Available: http://dx.doi.org/10.1186/s12885-016-2748-5.en
dc.identifier.issn1471-2407en
dc.identifier.doi10.1186/s12885-016-2748-5en
dc.identifier.urihttp://hdl.handle.net/10754/621987-
dc.description.abstractBackground: Non-muscle-invasive bladder cancer (NMIBC) is a high incidence form of bladder cancer (BCa), where genetic and epigenetic alterations occur frequently. We assessed the performance of associating a FGFR3 mutation assay and a DNA methylation analysis to improve bladder cancer detection and to predict disease recurrence of NMIBC patients. Methods: We used allele specific PCR to determine the FGFR3 mutation status for R248C, S249C, G372C, and Y375C. We preselected 18 candidate genes reported in the literature as being hypermethylated in cancer and measured their methylation levels by quantitative multiplex-methylation specific PCR. We selected HS3ST2, SLIT2 and SEPTIN9 as the most discriminative between control and NMIBC patients and we assayed these markers on urine DNA from a diagnostic study consisting of 167 NMIBC and 105 controls and a follow-up study consisting of 158 NMIBC at diagnosis time's and 425 at follow-up time. ROC analysis was performed to evaluate the diagnostic accuracy of each assay alone and in combination. Results: For Diagnosis: Using a logistic regression analysis with a model consisting of the 3 markers' methylation values, FGFR3 status, age and known smoker status at the diagnosis time we obtained sensitivity/specificity of 97.6 %/84.8 % and an optimism-corrected AUC of 0.96. With an estimated BCa prevalence of 12.1 % in a hematuria cohort, this corresponds to a negative predictive value (NPV) of 99.6 %. For Follow-up: Using a logistic regression with FGFR3 mutation and the CMI at two time points (beginning of the follow-up and current time point), we got sensitivity/specificity/NPV of 90.3 %/65.1 %/97.0 % and a corrected AUC of 0.84. We also tested a thresholding algorithm with FGFR3 mutation and the two time points as described above, obtaining sensitivity/specificity/NPV values of, respectively, 94.5 %/75.9 %/98.5 % and an AUC of 0.82. Conclusions: We showed that combined analysis of FGFR3 mutation and DNA methylation markers on urine can be a useful strategy in diagnosis, surveillance and for risk stratification of patients with NMIBC. These results provide the basis for a highly accurate noninvasive test for population screening and allowing to decrease the frequency of cystoscopy, an important feature for both patient quality of life improvement and care cost reduction. © 2016 The Author(s).en
dc.description.sponsorshipThe authors thank the Assistance Publique-Hôpitaux de Paris (AP-HP) for providing the samples obtained from a collection code-named AUVES (project reference RECF0998-PHRC 2003). We also warmly thank Agoranov start-up incubator for their help in the implementation of our work.This work was partly supported by a grant from Bpifrance (project reference PIA1 A1407120Q 2014).en
dc.publisherSpringer Natureen
dc.relation.urlhttp://bmccancer.biomedcentral.com/articles/10.1186/s12885-016-2748-5en
dc.rightsThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectDiagnosisen
dc.subjectGenetic and Epigenetic DNA biomarkersen
dc.subjectNon-muscle-invasive bladder canceren
dc.subjectSurveillanceen
dc.subjectUrine-based assayen
dc.titlePromoter hypermethylation of HS3ST2, SEPTIN9 and SLIT2 combined with FGFR3 mutations as a sensitive/specific urinary assay for diagnosis and surveillance in patients with low or high-risk non-muscle-invasive bladder canceren
dc.typeArticleen
dc.contributor.departmentComputational Bioscience Research Center (CBRC)en
dc.identifier.journalBMC Canceren
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionOncoDiag SAS, Agoranov, Paris, Franceen
dc.contributor.institutionSaint-Louis Hospital, Departement of Urology, Paris, Franceen
dc.contributor.institutionBichat-Claude Bernard Hospital, Departement of Urology, Paris, Franceen
dc.contributor.institutionGRC-05, University Institute of Oncology, University Paris-6, Paris, Franceen
dc.contributor.institutionPitié Hospital, Department of Urology, Paris, Franceen
dc.contributor.institutionTenon Hospital, Department of Urology, Paris, Franceen
dc.contributor.institutionINSERM, ECEVE, UMR 1123, CIC-EC 11425, Paris, Franceen
dc.contributor.institutionUniversity Paris Diderot, ECEVE, UMR 1123, Sorbonne Paris Cité, Paris, Franceen
dc.contributor.institutionBichat-Claude Bernard Hospital, Department of Epidemiology and Clinical Research, Paris, Franceen
kaust.authorIncitti, Robertoen
dc.relation.isSupplementedByRoperch, J.-P., Grandchamp, B., Desgrandchamps, F., Mongiat-Artus, P., Ravery, V., Idir Ouzaid, … Incitti, R. (2016). Promoter hypermethylation of HS3ST2, SEPTIN9 and SLIT2 combined with FGFR3 mutations as a sensitive/specific urinary assay for diagnosis and surveillance in patients with low or high-risk non-muscle-invasive bladder cancer. Figshare. https://doi.org/10.6084/m9.figshare.c.3619151en
dc.relation.isSupplementedByDOI:10.6084/m9.figshare.c.3619151en
dc.relation.isSupplementedByHANDLE:http://hdl.handle.net/10754/624134en
All Items in KAUST are protected by copyright, with all rights reserved, unless otherwise indicated.