Integrated genetic and epigenetic analysis of bladder cancer reveals an additive diagnostic value of <i>FGFR3</i> mutations and hypermethylation events

Serizawa, Reza; Ralfkiær, Ulrik; Steven, Kenneth; Lam, Gitte Wrist; Schmiedel, Sven; Schüz, Joachim; Hansen, Alastair; Horn, Thomas; Guldberg, Per

doi:10.1002/ijc.25651

Cited by 93 publications

(102 citation statements)

References 47 publications

(64 reference statements)

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“…Our three-gene methylation panel consisting of OTX1, ONECUT2, and OSR1 had a sensitivity of 68% and 74% in the test and validation set respectively with a specificity of 90% for the detection of recurrent bladder tumors in voided urine. Previously, we and Serizawa and colleagues, (34) showed an inverse correlation between FGFR3 mutation and methylation, therefore a combination of these assays could increase sensitivity for the detection of recurrent bladder cancer. We therefore combined the 3-plex methylation assay with the FGFR3 mutation assay.…”

Section: Discussionmentioning

confidence: 82%

A 3-Plex Methylation Assay Combined with the FGFR3 Mutation Assay Sensitively Detects Recurrent Bladder Cancer in Voided Urine

Kandimalla

Masius

Beukers

et al. 2013

Clinical Cancer Research

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Purpose: DNA methylation is associated with bladder cancer and these modifications could serve as useful biomarkers. FGFR3 mutations are present in 60% to 70% of non-muscle invasive bladder cancer (NMIBC). Low-grade bladder cancer recurs in more than 50% of patients. The aim of this study is to determine the sensitivity and specificity of a urine assay for the diagnosis of recurrences in patients with a previous primary NMIBC G1/G2 by using cystoscopy as the reference standard.Experimental Design: We selected eight CpG islands (CGI) methylated in bladder cancer from our earlier genome-wide study. Sensitivity of the CGIs for recurrences detection was investigated on a test set of 101 preTUR urines. Specificity was determined on 70 urines from healthy males aged more than 50 years. A 3-plex assay for the best combination was developed and validated on an independent set of 95 preTUR, recurrence free, and nonmalignant urines (n ¼ 130).Results: The 3-plex assay identified recurrent bladder cancer in voided urine with a sensitivity of 74% in the validation set. In combination with the FGFR3 mutation assay, a sensitivity of 79% was reached (specificity of 77%). Sensitivity of FGFR3 and cytology was 52% and 57%, respectively.Conclusion: The combination of methylation and FGFR3 assays efficiently detects recurrent bladder cancer without the need for stratification of patients regarding methylation/mutation status of the primary tumor. We conclude that the sensitivity of this combination is in the same range as cystoscopy and paves the way for a subsequent study that investigates a modified surveillance protocol consisting of the urine test followed by cystoscopy only when the urine test is positive.

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Section: Discussionmentioning

confidence: 82%

A 3-Plex Methylation Assay Combined with the FGFR3 Mutation Assay Sensitively Detects Recurrent Bladder Cancer in Voided Urine

Kandimalla

Masius

Beukers

et al. 2013

Clinical Cancer Research

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“…Of the 63 reports selected for detailed evaluation, 33 were excluded as duplications or because they lacked key data. The final meta-analysis was carried out on the remaining 30 studies (Billerey et al, 2001;Kimura et al, 2001;Bakkar et al, 2003;Rieger-Christ et al, 2003;van Rhijn et al, 2003van Rhijn et al, , 2004Hernández et al, 2005;Jebar et al, 2005;van der Aa et al, 2005;Wallerand et al, 2005;Hernández et al, 2006;Lindgren et al, 2006;Tomlinson et al, 2007;van Oers et al, 2007;Burger et al, 2008;Junker et al, 2008;Eltze et al, 2009;Ouerhani et al, 2009;van Oers et al, 2009;Zieger et al, 2009;Bakkar et al, 2010;Bodoor et al, 2010;Kompier et al, 2010;Miyake et al, 2010;van Rhijn et al, 2010;Al-Ahmadie et al, 2011;Dodurga et al, 2011;Serizawa et al, 2011;Sjödahl et al, 2011;van Rhijn et al, 2012). Twenty-five of the studies (Table 1A) investigated the association between FGFR3 mutations and grade or stage, while the other 13 studies (Table 1B) investigated the prognostic value of FGFR3 mutations for BC.…”

Section: Resultsmentioning

confidence: 99%

Clinical significance of fibroblast growth factor receptor-3 mutations in bladder cancer: a systematic review and meta-analysis

et al. 2014

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ABSTRACT. Mutations in the fibroblast growth factor receptor-3 (FGFR3) gene are frequently found in bladder cancer, but their prognostic value remains controversial. To globally summarize the association between FGFR3 mutations and the grade and stage of bladder cancer, and to analyze the predictive role of FGFR3 mutations with respect to survival, eligible studies were identified and assessed for quality through multiple search strategies. Risk ratio (RR) data were collected from studies comparing the number of FGFR3 mutants among low-grade and early-stage bladder cancer patients to the number among high-grade and late-stage patients. Hazard ratio (HR) data were collected from studies comparing survival in patients with mutant FGFR3 genes to those with wild-type genes. Studies were pooled, and the RRs of grade and stage and the HRs of survival were

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“…Many genes have been reported to be hypermethylated in bladder cancer, but it is just recently that studies with new screening approaches have identified methylation markers with high sensitivity and specificity (14,34,35,39,40). Using the Infinium array, we identified genes being hypoor hypermethylated in bladder cancer (Supplementary Table S10).…”

Section: Discussionmentioning

confidence: 99%

“…All studies mentioned above have a higher sensitivity than cytology and specificity equal or slightly lower than cytology. One way of improving the already sensitive bladder cancer detection assay is to combine methylation and mutational analysis as done by Serizawa and colleagues (35). In their study, they discovered an inverse correlation between methylation and FGFR3 mutations.…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive Genome Methylation Analysis in Bladder Cancer: Identification and Validation of Novel Methylated Genes and Application of These as Urinary Tumor Markers

Reinert

Modin

Castaño

et al. 2011

Clinical Cancer Research

181

161

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Purpose: Epigenetic alterations are common and can now be addressed in a parallel fashion. We investigated the methylation in bladder cancer with respect to location in genome, consistency, variation in metachronous tumors, impact on transcripts, chromosomal location, and usefulness as urinary markers.Experimental Design: A microarray assay was utilized to analyze methylation in 56 samples. Independent validation was conducted in 63 samples by a PCR-based method and bisulfite sequencing. The methylation levels in 174 urine specimens were quantified. Transcript levels were analyzed using expression microarrays and pathways were analyzed using dedicated software.Results: Global methylation patterns were established within and outside CpG islands. We validated methylation of the eight tumor markers genes ZNF154 (P < 0.0001), HOXA9 (P < 0.0001), POU4F2 (P < 0.0001), EOMES (P ¼ 0.0005), ACOT11 (P ¼ 0.0001), PCDHGA12 (P ¼ 0.0001), CA3 (P ¼ 0.0002), and PTGDR (P ¼ 0.0110), the candidate marker of disease progression TBX4 (P < 0.04), and other genes with stage-specific methylation. The methylation of metachronous tumors was stable and targeted to certain pathways. The correlation to expression was not stringent. Chromosome 21 showed most differential methylation (P < 0.0001) and specifically hypomethylation of keratins, which together with keratin-like proteins were epigenetically regulated. In DNA from voided urine, we detected differential methylation of ZNF154 (P < 0.0001), POU4F2 (P < 0.0001), HOXA9 (P < 0.0001), and EOMES (P < 0.0001), achieving 84% sensitivity and 96% specificity.Conclusions: We initiated a detailed mapping of the methylome in metachronous bladder cancer. Novel genes with tumor, chromosome, as well as pathway-specific differential methylation in bladder cancer were identified. The methylated genes were promising cancer markers for early detection of bladder cancer. Clin Cancer Res; 17(17); 5582-92. Ó2011 AACR.

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Integrated genetic and epigenetic analysis of bladder cancer reveals an additive diagnostic value of FGFR3 mutations and hypermethylation events

Cited by 93 publications

References 47 publications

A 3-Plex Methylation Assay Combined with the FGFR3 Mutation Assay Sensitively Detects Recurrent Bladder Cancer in Voided Urine

A 3-Plex Methylation Assay Combined with the FGFR3 Mutation Assay Sensitively Detects Recurrent Bladder Cancer in Voided Urine

Clinical significance of fibroblast growth factor receptor-3 mutations in bladder cancer: a systematic review and meta-analysis

Comprehensive Genome Methylation Analysis in Bladder Cancer: Identification and Validation of Novel Methylated Genes and Application of These as Urinary Tumor Markers

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