Defining Molecular Profiles of Poor Outcome in Patients With Invasive Bladder Cancer Using Oligonucleotide Microarrays

Sänchez‐Carbayo, Marta; Socci, Nicholas D.; Lozano, Juanjo; Saint, F.; Cordon‐Cardo, Carlos

doi:10.1200/jco.2005.03.2375

Cited by 488 publications

(448 citation statements)

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“…To our knowledge, there was no data suggesting that SOX9 could be epigenetically modified by methylation in human cancer. This gene was chosen once we observed significant statistical associations of its decreasing transcript levels with increasing tumour stage (Po0.005) after analysing a previously reported transcript profiling data of our group (Sanchez-Carbayo et al, 2006), suggesting their involvement in bladder cancer progression. This clinical observation excluded the need to estimate multiple testing and false discovery thresholds for SOX9, a common strategy undertaken for candidate selection in high-throughput studies.…”

Section: Discussionmentioning

confidence: 99%

“…nitrogen immediately after resection and stored at À801C until processing. Bladder tissues embedded in OCT were macrodissected to ensure a minimum of 75% of tumour or normal urothelium counterpart cell subpopulations (Sanchez-Carbayo et al, 2006). Genomic DNA was extracted using a non-organic method (Oncor, Gaithersburg, MD, USA).…”

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confidence: 99%

“…For CpG methylation arrays, invasive bladder tumours (n ¼ 10) were compared to their paired normal urothelium. An independent series of 101 bladder tumours (non-muscle invasive (n ¼ 56): pTa (n ¼ 24), pT1 (n ¼ 32); and muscle invasive (n ¼ 45): pT2 (n ¼ 16), pT3 (n ¼ 25), pT4 (n ¼ 4)) was utilised to validate the relevance of methylation candidates in bladder cancer progression (Sanchez-Carbayo et al, 2006). Human bladder cancer cell lines (n ¼ 11) were obtained from the American Type Culture Collection (Rockland, MD, USA) (Sanchez-Carbayo et al, 2002) and from the European Collection of Cell Cultures (Salisbury, United Kingdom).…”

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Identification of DNA hypermethylation of SOX9 in association with bladder cancer progression using CpG microarrays

et al. 2007

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CpG island arrays represent a high-throughput epigenomic discovery platform to identify global disease-specific promoter hypermethylation candidates along bladder cancer progression. DNA obtained from 10 pairs of invasive bladder tumours were profiled vs their respective normal urothelium using differential methylation hybridisation on custom-made CpG arrays (n ¼ 12 288 clones). Promoter hypermethylation of 84 clones was simultaneously shown in at least 70% of the tumours. SOX9 was selected for further validation by bisulphite genomic sequencing and methylation-specific polymerase chain reaction in bladder cancer cells (n ¼ 11) and primary bladder tumours (n ¼ 101). Hypermethylation was observed in bladder cancer cells and associated with lack of gene expression, being restored in vitro by a demethylating agent. In primary bladder tumours, SOX9 hypermethylation was present in 56.4% of the cases. Moreover, SOX9 hypermethylation was significantly associated with tumour grade and overall survival. Thus, this high-throughput epigenomic strategy has served to identify novel hypermethylated candidates in bladder cancer. In vitro analyses supported the role of methylation in silencing SOX9 gene. The association of SOX9 hypermethylation with tumour progression and clinical outcome suggests its relevant clinical implications at stratifying patients affected with bladder cancer.

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confidence: 99%

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Identification of DNA hypermethylation of SOX9 in association with bladder cancer progression using CpG microarrays

et al. 2007

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“…It has also permitted the development of novel noninvasive detection and surveillance strategies and revealed potential therapeutic targets [131][132][133][134][135][136]. The absence of multi-institutional randomized prospective trials, however, has delayed the validation of these prognostic and predictive markers for routine clinical use.…”

Section: Genomics Of Urothelial Carcinomamentioning

confidence: 99%

The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs—Part B: Prostate and Bladder Tumours

et al. 2016

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It has been 12 yr since the publication of the last World Health Organization (WHO) classification of tumours of the prostate and bladder. During this time, significant new knowledge has been generated about the pathology and genetics of these tumours. Intraductal carcinoma of the prostate is a newly recognized entity in the 2016 WHO classification. In most cases, it represents intraductal spread of aggressive prostatic carcinoma and should be separated from high-grade prostatic intraepithelial neoplasia. New acinar adenocarcinoma variants are microcystic adenocarcinoma and pleomorphic giant cell adenocarcinoma. Modifications to the Gleason grading system are incorporated into the 2016 WHO section on grading of prostate cancer, and it is recommended that the percentage of pattern 4 should be reported for Gleason score 7. The new WHO classification further recommends the recently developed prostate cancer grade grouping with five grade groups. For bladder cancer, the 2016 WHO classification continues to recommend the 1997 International Society of Urological Pathology grading classification. Newly described or better defined noninvasive urothelial lesions include urothelial dysplasia and urothelial proliferation of uncertain malignant potential, which is frequently identified in patients with a prior history of urothelial carcinoma. Invasive urothelial carcinoma with divergent differentiation refers to tumours with some percentage of "usual type" urothelial carcinoma combined with other morphologies. Pathologists should mention the percentage of divergent histologies in the pathology report. PATIENT SUMMARY Intraductal carcinoma of the prostate is a newly recognized entity in the 2016 World Health Organization classification. Better defined noninvasive urothelial lesions include urothelial dysplasia and urothelial proliferation of uncertain malignant potential. v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j AbstractIt has been 12 yr since the publication of the last World Health Organization (WHO) classification of tumours of the prostate and bladder. During this time, significant new knowledge has been generated about the pathology and genetics of these tumours.

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“…The four investigated genes, TBX2, TBX3, GATA2, and ZIC4, encode transcription factors that are important in the regulation of developmental processes and gene expression is more frequent in nonmuscle-invasive bladder cancer compared with muscle-invasive disease. 19,20 This could be linked to our results in which aggressive tumors that progressed to muscle-invasive bladder cancer showed more methylation than the non-progressive tumors. Furthermore, the most significant markers, TBX2 and TBX3, downregulate the p53-pathway by inhibiting the expression of the ARF and CIP1 gene.…”

Section: Discussionmentioning

confidence: 53%

Stratification based on methylation of TBX2 and TBX3 into three molecular grades predicts progression in patients with pTa-bladder cancer

et al. 2015

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The potential risk of recurrence and progression in patients with non-muscle-invasive bladder cancer necessitates followup by cystoscopy. The risk of progression to muscle-invasive bladder cancer is estimated based on the European Organisation of Research and Treatment of Cancer score, a combination of several clinicopathological variables. However, pathological assessment is not objective and reproducibility is insufficient. The use of molecular markers could contribute to the estimation of tumor aggressiveness. We recently demonstrated that methylation of GATA2, TBX2, TBX3, and ZIC4 genes could predict progression in Ta tumors. In this study, we aimed to validate the markers in a large patient set using DNA from formalin-fixed and paraffin-embedded tissue. PALGA: the Dutch Pathology Registry was used for patient selection. We included 192 patients with pTaG1/2 bladder cancer of whom 77 experienced progression. Methylation analysis was performed and log-rank analysis was used to calculate the predictive value of each methylation marker for developing progression over time. This analysis showed better progression-free survival in patients with low methylation rates compared with the patients with high methylation rates for all markers (Po0.001) during a followup of ten-years. The combined predictive effect of the methylation markers was analyzed with the Coxregression method. In this analysis, TBX2, TBX3, and ZIC4 were independent predictors of progression. On the basis of methylation status of TBX2 and TBX3, patients were divided into three new molecular grade groups. Survival analysis showed that only 8% of patients in the low molecular grade group progressed within 5 years. This was 29 and 63% for the intermediate-and high-molecular grade groups. In conclusion, this new moleculargrade based on the combination of TBX2 and TBX3 methylation is an excellent marker for predicting progression to muscle-invasive bladder cancer in patients with primary pTaG1/2 bladder cancer.

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Defining Molecular Profiles of Poor Outcome in Patients With Invasive Bladder Cancer Using Oligonucleotide Microarrays

Abstract: Gene profiling provides a genomic-based classification scheme of diagnostic and prognostic utility for stratifying advanced bladder cancer. Identification of this poor outcome profile could assist in selecting patients who may benefit from more aggressive therapeutic intervention.

Cited by 488 publications

References 27 publications

Identification of DNA hypermethylation of SOX9 in association with bladder cancer progression using CpG microarrays

Identification of DNA hypermethylation of SOX9 in association with bladder cancer progression using CpG microarrays

The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs—Part B: Prostate and Bladder Tumours

Stratification based on methylation of TBX2 and TBX3 into three molecular grades predicts progression in patients with pTa-bladder cancer

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