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Liu HP, Jia W, Kadeerhan G, Xue B, Guo W, Niu L, Wang X, Wu X, Li H, Tian J, Wang D, Lai HM. Individualized prognosis stratification in muscle invasive bladder cancer: A pairwise TP53-derived transcriptome signature. Transl Oncol 2023; 29:101629. [PMID: 36689862 PMCID: PMC9873666 DOI: 10.1016/j.tranon.2023.101629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/03/2023] [Accepted: 01/16/2023] [Indexed: 01/22/2023] Open
Abstract
TP53 is the most frequently mutated gene in muscle invasive bladder cancer (MIBC) and there are two gene signatures regarding TP53 developed for MIBC prognosis. However, they are limited to immune genes only and unable to be used individually across platforms due to their quantitative manners. We used 827 gene expression profiles from seven MIBC cohorts with varied platforms to build a pairwise TP53-derived transcriptome signature, 13 gene pairs (13-GPs). Since the 13-GPs model is a single sample prognostic predictor, it can be applied individually in practice and is applicable to any gene-expression platforms without specific normalization requirements. Survival difference between high-risk and low-risk patients stratified by the 13-GPs test was statistically significant (HR range: 2.26-2.76, all P < .0001). Discovery and validation sets showed that the 13-GPs was an independent prognostic factor after adjusting other clinical features (HR range: 2.21-2.82, all P < .05). Moreover, it was a potential supplement to the consensus molecular classification of MIBC to further stratify the LumP subtype (patients with better prognoses). High- and low-risk patients by the 13-GPs model presented distinct immune microenvironment and DDR mutation rates, suggesting that it might have the potential for immunotherapy. Being a general approach to other cancer types, this study demonstrated how we integrated gene variants with pairwise gene panels to build a single sample prognostic test in translational oncology.
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Affiliation(s)
- Hua-Ping Liu
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
| | - Wei Jia
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
| | - Gaohaer Kadeerhan
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
| | - Bo Xue
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
| | - Wenmin Guo
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
| | - Lu Niu
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
| | - Xiaoliang Wang
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
| | - Xiaolin Wu
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
| | - Haitao Li
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
| | - Jun Tian
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
| | - Dongwen Wang
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China,Corresponding authors.
| | - Hung-Ming Lai
- Aiphaqua Genomics Research Unit, Taipei 111, Taiwan,Corresponding authors.
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Kocsmár I, Pajor G, Gyöngyösi B, Székely E, Varga M, Kocsmár É, Kenessey I, Beöthe T, Süle N, Majoros A, Szendrői A, Nyírády P, Kiss A, Riesz P, Lotz G. Development and Initial Testing of a Modified UroVysion-Based Fluorescence In Situ Hybridization Score for Prediction of Progression in Bladder Cancer. Am J Clin Pathol 2020; 153:274-284. [PMID: 31732739 DOI: 10.1093/ajcp/aqz165] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES Our aim was to predict progression of non-muscle-invasive bladder urothelial carcinomas (NMIUCs) into muscle-invasive disease by assessing cytogenetic abnormality of tumors with a new UroVysion scoring system. METHODS Seventy-five bladder cancer cases (including 57 NMIUCs) were classified according to the quantitatively assessed degree of UroVysion-detected chromosomal abnormalities into urine fluorescence in situ hybridization score (UFS) groups: UFS I, II, and III. Cox time-to-event, Kaplan-Meier, and C-statistics analyses were performed. RESULTS UFS proved to be an independent prognostic factor of progression-free survival (PFS) and time to progression (TTP). NMIUCs with UFS III had a 34.05-fold increased hazard for progression to muscle-invasive cancer (TTP; 95% confidence interval, 5.841-198.5; P < .001) in comparison with UFS I to II cases. The addition of UFS to conventional risk scores increased the C-index for PFS and TTP. CONCLUSIONS UFS can indicate an increased risk for progression into muscle-invasive disease in patients with NMIUC and improves prognostic accuracy of the current clinical risk assessment systems.
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Affiliation(s)
- Ildikó Kocsmár
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Gábor Pajor
- Department of Pathology, University of Pécs, Pécs, Hungary
| | - Benedek Gyöngyösi
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Eszter Székely
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Márton Varga
- Department of Pathology, Peterfy Sandor Municipal Hospital and Trauma Center, Budapest, Hungary
| | - Éva Kocsmár
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - István Kenessey
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Tamás Beöthe
- Department of Urology, Faculty of Medicine, University of Pécs, Pécs, Hungary
- Department of Urology, Peterfy Sandor Municipal Hospital and Trauma Center, Budapest, Hungary
| | - Norbert Süle
- Department of Pathology & Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, NY
| | - Attila Majoros
- Department of Urology, Semmelweis University, Budapest, Hungary
| | - Attila Szendrői
- Department of Urology, Semmelweis University, Budapest, Hungary
| | - Péter Nyírády
- Department of Urology, Semmelweis University, Budapest, Hungary
| | - András Kiss
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Péter Riesz
- Department of Urology, Semmelweis University, Budapest, Hungary
| | - Gábor Lotz
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
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Worst TS, Weis CA, Stöhr R, Bertz S, Eckstein M, Otto W, Breyer J, Hartmann A, Bolenz C, Wirtz RM, Erben P. CDKN2A as transcriptomic marker for muscle-invasive bladder cancer risk stratification and therapy decision-making. Sci Rep 2018; 8:14383. [PMID: 30258198 PMCID: PMC6158275 DOI: 10.1038/s41598-018-32569-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 09/10/2018] [Indexed: 12/22/2022] Open
Abstract
Deletions of the cell cycle control gene CDKN2A are described as progression markers of non-muscle invasive bladder cancer and to be associated with fibroblast growth factor 3 (FGFR3) mutations. The prognostic role of CDKN2A RNA expression in muscle invasive bladder cancer (MIBC) is under discussion. In 80 MIBC patients (m/f 60/20) who underwent radical cystectomy the expression of CDKN2A and FGFR3 was examined with qRT-PCR (test cohort). The MDA cohort (n = 57) and the TCGA cohort (n = 365) served for validation. The expression of drug target genes and TCGA molecular subtypes was correlated with CDKN2A expression. In the test cohort CDKN2Ahigh patients (n = 8; 10.0%) had a significantly shorter recurrence-free (p = 0.018) and disease-specific (p = 0.006) survival compared to the rest of the cohort. A similar stratification was seen in the validation cohorts (CDKN2Ahigh: n = 7, 12.3%, p = 0.001; n = 46, 12.6%, p = 0.011). In the TCGA cohort these patients had a comparably low expression of drug target genes. The expression of CDKN2A significantly differed among TGCA molecular subtypes. 71.7% of CDKN2Ahigh were TCGA basal squamous tumours but also show divergent molecular features compared to this group. In summary CDKN2A RNA expression-based risk stratification of MIBC allows the identification of a CDKN2Ahigh poor prognosis group with low expression of drug target genes.
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Affiliation(s)
- Thomas S Worst
- Department of Urology, University Medical Center Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
| | - Cleo-Aron Weis
- Institute of Pathology, University Medical Center Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Robert Stöhr
- Institute of Pathology, University of Erlangen-Nuremberg, Krankenhausstraße 8-10, 91054, Erlangen, Germany
| | - Simone Bertz
- Institute of Pathology, University of Erlangen-Nuremberg, Krankenhausstraße 8-10, 91054, Erlangen, Germany
| | - Markus Eckstein
- Institute of Pathology, University of Erlangen-Nuremberg, Krankenhausstraße 8-10, 91054, Erlangen, Germany
| | - Wolfgang Otto
- Department of Urology, University of Regensburg, Landshuter Straße 65, 93053, Regensburg, Germany
| | - Johannes Breyer
- Department of Urology, University of Regensburg, Landshuter Straße 65, 93053, Regensburg, Germany
| | - Arndt Hartmann
- Institute of Pathology, University of Erlangen-Nuremberg, Krankenhausstraße 8-10, 91054, Erlangen, Germany
| | - Christian Bolenz
- Department of Urology, University of Ulm, Prittwitzstraße 43, 89075, Ulm, Germany
| | - Ralph M Wirtz
- STRATIFYER Molecular Pathology GmbH, Werthmannstraße 1, 50935, Cologne, Germany
- Institute of Pathology at the St Elisabeth Hospital Köln-Hohenlind, Werthmannstraße 1, 50935, Cologne, Germany
| | - Philipp Erben
- Department of Urology, University Medical Center Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
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Yang T, Li Y, Li J, Liu J, Deng X, Wang G. Diagnostic Value Comparison of Urothelium Carcinoma Among Urine Exfoliated Cells Fluorescent In Situ Hybridization (FISH) Examination, Computerized Tomography (CT) Scan, and Urine Cytologic Examination. Med Sci Monit 2018; 24:5788-5792. [PMID: 30121694 PMCID: PMC6111772 DOI: 10.12659/msm.910134] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND This study aimed to compare the clinical effectiveness of urine exfoliated cells FISH examination, CT scan, and urine cytologic examination on the diagnosis of upper urinary tract urothelium carcinoma with hematuresis symptom. MATERIAL AND METHODS A total of 30 patients with suspicious upper urinary tract urothelium carcinoma between Aug 2010 and Aug 2011 were enrolled, including 23 males and 7 females. All the subjects received urine exfoliated cells FISH examination, CT scan, and urine cytologic examination. Twenty-one cases were diagnosed as urothelium carcinoma, including 14 cases of carcinoma of renal pelvis and 7 cases of carcinoma of ureter. There were 6 cases in stage Ta/T1, 12 cases in stage T2, and 3 cases in T3/T4. The other 9 cases consisted of 1 case of neuroendocrine carcinoma of the renal pelvis, 2 cases of nephrotuberculosis, and 6 cases of renal clear cell carcinoma. RESULTS The total sensitivity of FISH examination, CT scan, and urine cytologic examination on upper urinary tract urothelium carcinoma was 85.7%, 66.7%, and 28.6%, respectively (P<0.05). The tumor staging detection on Ta/T1, T2, and T3/T4 by FISH was 66.7%, 91.7%, 100%; by CT scan 33.3%, 75.0%, 100%; and by urine cytologic examination 0%, 25.0%, and 100%. Their diagnostic specificities were 88.9%, 77.8%, and 100%, respectively (P<0.05). CONCLUSIONS The diagnostic sensitivity on upper urinary tract urothelium carcinoma was highest in FISH examination, followed by CT scan and urine cytologic examination. FISH technique obviously improves the diagnosis of upper urinary tract urothelium carcinoma.
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Affiliation(s)
- Tao Yang
- Department of Urinary Surgery, Hebei General Hospital, Shijiazhuang, Hebei, China (mainland)
| | - Yan Li
- Department of Hematology, Hebei General Hospital, Shijiazhuang, Hebei, China (mainland)
| | - Jing Li
- Department of Hematology, Hebei Province Chinese Medicine Hospital, Shijiazhuang, Hebei, China (mainland)
| | - Junjiang Liu
- Department of Urinary Surgery, Hebei General Hospital, Shijiazhuang, Hebei, China (mainland)
| | - Xinna Deng
- Department of Oncology and Immunotherapy, Hebei General Hospital, Shijiazhuang, Hebei, China (mainland)
| | - Gang Wang
- Department of Urinary Surgery, Hebei General Hospital, Shijiazhuang, Hebei, China (mainland)
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Mao X, Li B, Liang Y, Li S, Zhou J, He Q, Jiang N, Chen Y, Sun Y, Cui Y, Jiang W, Wang H, Wang L, Ke Z. Auxiliary diagnostic value of p16 amplification combined with the detection of heterozygous and homozygous loss for urothelial carcinoma. Oncol Lett 2018; 15:6533-6540. [PMID: 29731855 DOI: 10.3892/ol.2018.8137] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 01/10/2018] [Indexed: 11/05/2022] Open
Abstract
The present study aimed to investigate the significance of detecting cyclin dependent kinase inhibitor 2A (p16) gene aberrations in the diagnosis of urothelial carcinoma (UC) using fluorescence in situ hybridization (FISH). A total of 77 voided urine specimens from 65 patients with UC and 12 patients with benign urinary disease were recruited into the current study. Under a fluorescence microscope, cells with large and irregular nuclei were assessed for chromosomal aberrations. The positive rate of p16 amplification in UC samples was 32.3% (21/65), which was significantly higher than that in benign urinary disease samples (16.7%, 2/12; P<0.05). Heterozygous and homozygous loss of p16 was identified in 12 (18.5%) and 23 (35.4%) patients with UC, respectively; p16 expression in the remainder of patients was normal. In addition, as tumor stage or grade advanced, the positive rate of p16 aberrations also increased significantly (P<0.05). In conclusion, p16 gene aberrations may serve important roles in the auxiliary diagnosis of UC by FISH and could be utilized to monitor UC progression.
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Affiliation(s)
- Xiaopeng Mao
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.,Department of Urology Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Baimou Li
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.,Department of Urology Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Ying Liang
- Department of Nephrology, General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong 510010, P.R. China
| | - Shuhua Li
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Jianwen Zhou
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Qiong He
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Neng Jiang
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Yangshan Chen
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Yu Sun
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Yongmei Cui
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Wenting Jiang
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Han Wang
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Liantang Wang
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Zunfu Ke
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
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Expression of proteins FGFR3, PI3K, AKT, p21Waf1/Cip1 and cyclins D1 and D3 in patients with T1 bladder tumours: clinical implications and prognostic significance. Actas Urol Esp 2017; 41:172-180. [PMID: 27726892 DOI: 10.1016/j.acuro.2016.09.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 09/04/2016] [Accepted: 09/05/2016] [Indexed: 11/21/2022]
Abstract
OBJECTIVE To determine the differential protein expression of biomarkers FGFR3, PI3K (subunits PI3Kp110α, PI3KClassIII, PI3Kp85), AKT, p21Waf1/Cip1 and cyclins D1 and D3 in T1 bladder cancer versus healthy tissue and to study their potential role as early recurrence markers. MATERIAL AND METHOD This is a prospective study that employed a total of 67 tissue samples (55 cases of T1 bladder tumours that underwent transurethral resection and 12 cases of adjacent healthy mucosa). The protein expression levels were assessed using Western blot, and the means and percentages were compared using Student's t-test and the chi-squared test. The survival analysis was conducted using the Kaplan-Meier method and the log-rank test. RESULTS Greater protein expression was detected for FGFR3, PI3Kp110α, PI3KClassIII, cyclins D1 and D3 and p21Waf1/Cip1 in the tumour tissue than in the healthy mucosa. However, these differences were not significant for PI3Kp85 and AKT. We observed statistically significant correlations between early recurrence and PI3Kp110α, PI3KClassIII, PI3Kp85 and AKT (P=.003, P=.045, P=.050 and P=.028, respectively), between the tumour type (primary vs. recurrence) and cyclin D3 (P=.001), between the tumour size and FGFR3 (P=.035) and between multifocality and cyclin D1 (P=.039). The survival analysis selected FGFR3 (P=.024), PI3Kp110α (P=.014), PI3KClassIII (P=.042) and AKT (P=.008) as markers of early-recurrence-free survival. CONCLUSIONS There is an increase in protein expression levels in bladder tumour tissue. The overexpression of FGFR3, PI3Kp110α, PI3KClassIII and AKT is associated with increased early-recurrence-free survival for patients with T1 bladder tumours.
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Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer 2015; 15:25-41. [PMID: 25533674 DOI: 10.1038/nrc3817] [Citation(s) in RCA: 878] [Impact Index Per Article: 87.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Urothelial carcinoma of the bladder comprises two long-recognized disease entities with distinct molecular features and clinical outcome. Low-grade non-muscle-invasive tumours recur frequently but rarely progress to muscle invasion, whereas muscle-invasive tumours are usually diagnosed de novo and frequently metastasize. Recent genome-wide expression and sequencing studies identify genes and pathways that are key drivers of urothelial cancer and reveal a more complex picture with multiple molecular subclasses that traverse conventional grade and stage groupings. This improved understanding of molecular features, disease pathogenesis and heterogeneity provides new opportunities for prognostic application, disease monitoring and personalized therapy.
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Affiliation(s)
- Margaret A Knowles
- Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK
| | - Carolyn D Hurst
- Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK
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Gebauer N, Schmidt-Werthern C, Bernard V, Feller AC, Keck T, Begum N, Rades D, Lehnert H, Brabant G, Thorns C. Genomic landscape of pancreatic neuroendocrine tumors. World J Gastroenterol 2014; 20:17498-17506. [PMID: 25516664 PMCID: PMC4265611 DOI: 10.3748/wjg.v20.i46.17498] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2014] [Revised: 05/03/2014] [Accepted: 07/25/2014] [Indexed: 02/07/2023] Open
Abstract
AIM: To investigate the prognostic role of genomic stability and copy number alterations (CNAs) pancreatic neuroendocrine tumors (PanNETs).
METHODS: A high-resolution array-based comparative genomic hybridization approach was utilized in order to investigate and quantify chromosomal aberrations in a panel of 37 primary PanNET and 11 metastatic samples. DNA samples were extracted from formalin-fixed and paraffin-embedded tumor specimen. Genomic findings were correlated with histopathological and immunohistochemical data. Moreover, the dataset was subjected to employing an unsupervised hierarchical clustering analysis approach utilizing Euclidean distance and average linkage and associations between genomically defined tumor groups and recurrent CNAs or clinicopathological features of the study group were assessed.
RESULTS: Numerous chromosomal aberrations were recurrently detected in both, primary tumor samples and metastases. Copy number gains were most frequently observed at 06p22.2-p22.1 (27.1%), 17p13.1 (20.8%), 07p21.3-p21.2 (18.8%), 09q34.11 (18.8%). Genomic losses were significantly less frequent and the only recurrent aberration affected 08q24.3 (6.3%). Moreover, we detected a high degree of genomic heterogeneity between primary tumors and metastatic lesions. Unsupervised hierarchical clustering of loci affected by CNAs in more than 3 primary tumor samples revealed two genetically distinct tumor groups as well as two chromosomal clusters of genomic imbalances indicating a small subset of tumors with common molecular features (13.5%). Aberrations affecting 6p22.2-22.1, 8q24.3, 9q34.11 and 17p13.1 (P = 0.011; 0.003; 0.003; 0.001), were significantly associated with a poorer survival prognosis.
CONCLUSION: This study suggests that several frequent CNAs in numerous candidate regions are involved in the pathogenesis and metastatic progression of PanNET.
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Dip N, Reis ST, Viana NI, Morais DR, Moura CM, Katz B, Abe DK, Iscaife A, Silva IA, Srougi M, Leite KRM. MiRNA in bladder carcinogenesis: A review. World J Clin Urol 2014; 3:238-248. [DOI: 10.5410/wjcu.v3.i3.238] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 06/30/2014] [Accepted: 08/31/2014] [Indexed: 02/06/2023] Open
Abstract
Bladder cancer (BC) is the second urological malignancy in incidence, currently being one of the most neoplasms studied with profile and biology poorly defined. In the world, BC is responsible by about 386000 new cases and 150000 deaths annually with considerable economic impact and high costs for health systems. After its discovery more than 20 years, micro RNAs (miRNAs) have been recognized as molecules that work specifically in post-transcriptional control in majority of eukaryote genomes. MiRNAs are a family of small non-coding RNAs of 19-25 nucleotides in length, expressed in a wide variety of organisms, comprising plants, worms and mammals, including humans. They have a fundamental role in physiological and pathological processes in organs and tissues in a context-dependent manner. This review brings new roles of protective and oncogenic miRNAs linked to carcinogenesis of urothelial carcinoma of the bladder, and associated with behavior of disease. Many studies have demonstrated promising roles of miRNAs working as diagnostic and prognostic biomarkers or involved in target therapies, consolidating miRNAs as crucial players in human cancer. This review allowed a reflection about the true functions of miRNAs in bladder carcinogenesis. Not only by their wide capacities of action, but also by abilities in define the cell date. The future of anti-tumor target therapies will be based not in one, but in groups of miRNAs working together in several steps of carcinogenic process, being able to identify the disease, predicting behavior and effectively treat bladder cancer.
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Pinto-Leite R, Carreira I, Melo J, Ferreira SI, Ribeiro I, Ferreira J, Filipe M, Bernardo C, Arantes-Rodrigues R, Oliveira P, Santos L. Genomic characterization of three urinary bladder cancer cell lines: understanding genomic types of urinary bladder cancer. Tumour Biol 2014; 35:4599-617. [PMID: 24459064 DOI: 10.1007/s13277-013-1604-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Accepted: 12/30/2013] [Indexed: 11/25/2022] Open
Abstract
Several genomic regions are frequently altered and associated with the type, stage and progression of urinary bladder cancer (UBC). We present the characterization of 5637, T24 and HT1376 UBC cell lines by karyotyping, fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH) and multiplex ligation-dependent probe amplification (MLPA) analysis. Some cytogenetic anomalies present in UBC were found in the three cell lines, such as chromosome 20 aneuploidy and the loss of 9p21. Some gene loci losses (e.g. CDKN2A) and gains (e.g. HRAS, BCL2L1 and PTPN1) were coincident across all cell lines. Although some significant heterogeneity and complexity were detected between them, their genomic profiles exhibited a similar pattern to UBC. We suggest that 5637 and HT1376 represent the E2F3/RB1 pathway due to amplification of 6p22.3, concomitant with loss of one copy of RB1 and mutation of the remaining copy. The HT1376 presented a 10q deletion involving PTEN region and no alteration of PIK3CA region which, in combination with the inactivation of TP53, bears more invasive and metastatic properties than 5637. The T24 belongs to the alternative pathway of FGFR3/CCND1 by presenting mutated HRAS and over-represented CCND1. These cell lines cover the more frequent subtypes of UBC and are reliable models that can be used, as a group, in preclinical studies.
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Affiliation(s)
- Rosário Pinto-Leite
- Cytogenetic Laboratory, Department of Human Genetics, Hospital Center of Trás-os-Montes and Alto Douro, Vila Real, Portugal
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11
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Wang YJ, Chen RJ. Pterostilbene Protection and Bladder Cancer Cells. Cancer 2014. [DOI: 10.1016/b978-0-12-405205-5.00027-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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12
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Immunohistochemistry as an adjunct in the differential diagnosis of radiation-induced atypia versus urothelial carcinoma in situ of the bladder: a study of 45 cases. Hum Pathol 2013. [DOI: 10.1016/j.humpath.2012.08.011] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Guancial EA, Chowdhury D, Rosenberg JE. Personalized therapy for urothelial cancer: review of the clinical evidence. CLINICAL INVESTIGATION 2011; 1:546-555. [PMID: 22754656 PMCID: PMC3384687 DOI: 10.4155/cli.11.26] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Despite a detailed understanding of the molecular aberrations driving the development of urothelial cancers, this knowledge has not translated into advances for the treatment of this disease. Urothelial cancers are chemosensitive, and platinum-based combination chemotherapy remains the standard of care for advanced disease, as well as neoadjuvant and adjuvant therapy for locally advanced disease. However, nearly half of patients who undergo resection of locally advanced urothelial cancer will relapse and eventually develop platinum-resistant disease. Clinical trials of targeted agents against angiogenesis and growth factors, as well as novel chemotheraputics, have generally been unsuccessful in urothelial cancers. Improvements in the theraputic arsenal for urothelial cancer depend upon identification of new targets and strategies to overcome platinum resistance.
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Affiliation(s)
- Elizabeth A. Guancial
- Clinical Fellow in Hematology and Oncology, Dana Farber Cancer Institute, 450 Brookline Avenue, Smith 353, Boston, MA 02115, 617-632-3779 (telephone), 617-632-5822 (fax),
| | - Dipanjan Chowdhury
- Assistant Professor, Dana Farber Cancer Institute, 450 Brookline Avenue, Jimmy Fund 5-517, Boston, MA 02115, 617-582-8639 (telephone), 617-582-8213 (fax),
| | - Jonathan E. Rosenberg
- Assistant Professor, Dana Farber Cancer Institute, 450 Brookline Avenue, Dana 1230, Boston, MA 02115, 617-632-4524 (telephone), 617-632-2165 (fax),
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14
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Detección de aneuploidías del cromosoma 17 y deleción del gen TP53 en una amplia variedad de tumores sólidos mediante hibridación in situ fluorescente bicolor. BIOMEDICA 2010. [DOI: 10.7705/biomedica.v30i3.273] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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15
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Liu HS, Hsu PY, Lai MD, Chang HY, Ho CL, Cheng HL, Chen HT, Lin YJ, Wu TJ, Tzai TS, Chow NH. An unusual function of RON receptor tyrosine kinase as a transcriptional regulator in cooperation with EGFR in human cancer cells. Carcinogenesis 2010; 31:1456-64. [PMID: 20498137 DOI: 10.1093/carcin/bgq100] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Homodimerization of RON (MST1R), a receptor tyrosine kinase, usually occurs in cells stimulated by a ligand and leads to the downstream activation of signaling pathways. Here we report that bladder cancer cells, in response to physiological stress, use an alternative mechanism for signaling activation. Time-course studies indicated that RON migrated directly from the membrane to the nucleus of bladder cancer cells in response to serum starvation. Biochemical and genetic studies implied that this nuclear internalization was complexed with epidermal growth factor receptor (EGFR) and required the docking of importins. In vivo analysis confirmed that nuclear RON was present in 38.4% (28/73) of primary bladder tumors. Chromatin immunoprecipitation (ChIP) on microarray analysis further revealed that this internalized complex bound to at least 134 target genes known to participate in three stress-responsive networks: p53, stress-activated protein kinase/c-jun N-terminal kinase and phosphatidylinositol 3-kinase/Akt. These findings suggest that RON, in a complex with EGFR, acts as a transcriptional regulator in response to acute disturbances (e.g. serum starvation) imposed on cancer cells. In an attempt to re-establish homeostasis, these cells bypass regular mechanisms required by ligand stimulation and trigger the RON-directed transcriptional response, which confers a survival advantage.
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Affiliation(s)
- Hsiao-Sheng Liu
- Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan
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Volanis D, Kadiyska T, Galanis A, Delakas D, Logotheti S, Zoumpourlis V. Environmental factors and genetic susceptibility promote urinary bladder cancer. Toxicol Lett 2010; 193:131-7. [PMID: 20051252 DOI: 10.1016/j.toxlet.2009.12.018] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2009] [Revised: 12/20/2009] [Accepted: 12/21/2009] [Indexed: 02/08/2023]
Abstract
Cancer of the urinary bladder is the second most common malignancy of the genitourinary tract, currently accounting for up to 5% of all newly diagnosed tumours in the western world. Urinary bladder carcinogenesis seems to develop from the interaction of environmental exposure and genetic susceptibility. Smoking, specific industrial chemicals, dietary nitrates and arsenic represent the most important exogenous risk factors. Chromosomal abnormalities, silencing of certain genes by abnormal methylation of their promoter region, alterations in tumour suppressor genes and proto-oncogenes that induce uncontrolled cell proliferation and reduced apoptosis, are molecular mechanisms that have been reported in bladder carcinogenesis. In this article, we discuss the environmental risk factors of bladder cancer and we review the genetic and epigenetic alterations, including aberrant DNA methylation and deregulation of microRNAs expression. We also discuss the role of p53 and retinoblastoma suppressor genes in disease progression. Finally, we present recent reports on the use of molecular profiling to predict disease stage and grade and direct targeted therapy.
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Affiliation(s)
- Dimitrios Volanis
- Department of Urology, Asklipieio General Hospital, Voula, Athens, Greece; Unit of Biomedical Applications, Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, 48 Vas. Constantinou Ave, 116 35 Athens, Greece
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17
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Martínez-Climent JA, Fontan L, Fresquet V, Robles E, Ortiz M, Rubio A. Integrative oncogenomic analysis of microarray data in hematologic malignancies. Methods Mol Biol 2010; 576:231-277. [PMID: 19882266 DOI: 10.1007/978-1-59745-545-9_13] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
During the last decade, gene expression microarrays and array-based comparative genomic hybridization (array-CGH) have unraveled the complexity of human tumor genomes more precisely and comprehensively than ever before. More recently, the simultaneous assessment of global changes in messenger RNA (mRNA) expression and in DNA copy number through "integrative oncogenomic" analyses has allowed researchers the access to results uncovered through the analysis of one-dimensional data sets, thus accelerating cancer gene discovery. In this chapter, we discuss the major contributions of DNA microarrays to the study of hematological malignancies, focusing on the integrative oncogenomic approaches that correlate genomic and transcriptomic data. We also present the basic aspects of these methodologies and their present and future application in clinical oncology.
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Affiliation(s)
- Jose A Martínez-Climent
- Division of Oncology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
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Establishment and characterization of human bladder cancer cell lines BexBra1, BexBra2, and BexBra4. In Vitro Cell Dev Biol Anim 2009; 46:131-9. [PMID: 19915932 DOI: 10.1007/s11626-009-9252-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2009] [Accepted: 10/06/2009] [Indexed: 01/13/2023]
Abstract
Bladder cancer (BC) is the fourth most common cancer in the USA. In Brazil, BC represents 3% of the total existing carcinomas in the population and represents the second highest incidence among urological tumors. The majority of bladder cancer cell lines available were derived from Caucasians and established in the seventies or eighties. Thus, neoplasia development in these cells likely occurred in environment conditions vastly different than today. In the present study, we report the establishment and characterization of three Brazilian bladder cancer cell lines (BexBra1, BexBra2, and BexBra4). These cell lines may be helpful for dissecting the genetic and epigenetic aspects that trigger the progression of BC. Moreover, the development of a Brazilian representative of the disease will allow us to investigate the potential inter-racial differences of malignancy-associated phenotypes in bladder cancer.
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Abstract
Detailed molecular insights into bladder cancer biology might allow more detailed prognostication and optimization of treatment with the objective of improving patient outcome and quality of life. However, in bladder cancer research the search for biomarkers has been called into question and has even obtained notoriety. It is unlikely that any single marker will be able to improve prognostication for patients with bladder cancer above and beyond grade and stage, but a combination of multiple independent markers might more precisely predict the outcome. From a previous review, we identified seven biomarkers to study within the setting of the Bladder Cancer Prognosis Programme (BCPP), a 5-year multicentre programme of research based at the University of Birmingham and funded by Cancer Research UK, investigating their effectiveness in predicting recurrence and progression. As part of the ongoing quality-assurance process for BCPP we present an updated review of our selected biomarkers, as well as highlighting other recent important developments in bladder cancer research.
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Affiliation(s)
- Richard T Bryan
- Department of Public Health Epidemiology and Biostatistics, School of Population Sciences, University of Birmingham, Birmingham, UK.
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20
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Riener MO, Nikolopoulos E, Herr A, Wild PJ, Hausmann M, Wiech T, Orlowska-Volk M, Lassmann S, Walch A, Werner M. Microarray comparative genomic hybridization analysis of tubular breast carcinoma shows recurrent loss of the CDH13 locus on 16q. Hum Pathol 2008; 39:1621-9. [PMID: 18656243 DOI: 10.1016/j.humpath.2008.02.021] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2007] [Revised: 02/15/2008] [Accepted: 02/28/2008] [Indexed: 11/18/2022]
Abstract
Tubular breast carcinoma is a highly differentiated carcinoma with an excellent prognosis. Distinct genetic alterations in tubular breast carcinoma cells have been described, especially broad genetic losses on the q-arm of chromosome 16. These are more common in lobular breast carcinoma and low-grade ductal carcinoma in situ than in ductal breast carcinoma and high-grade ductal carcinoma in situ. To further delineate the molecular changes involved in tubular breast carcinoma more precisely, we examined 23 formalin-fixed and paraffin wax-embedded tissue samples (21 of tubular breast carcinoma and 2 of nonneoplastic breast epithelium) by microarray-based comparative genomic hybridization focusing on 287 genomic target clones of oncogenes and tumor suppressor genes. The results obtained from all nonneoplastic tissue samples of breast epithelium indicate no DNA copy number changes. In the tubular breast carcinoma samples, the highest frequencies for DNA sequence copy number losses were detected for CDH13 (in 86% of the samples) and MSH2, KCNK12 (in 52% of the samples). The highest frequencies of DNA sequence copy number gains were detected for HRAS and D13S319XYZ (each in 62% of the samples). Using principal component analysis, 3 subgroups of tubular breast carcinomas showing relative genetic changes were identified. For validation, the most frequent DNA copy number loss for CDH13 (18/21) was confirmed using fluorescence in situ hybridization in 4 of 5 tubular breast carcinomas analyzed. The newly identified genes with considerable copy number changes may include so far unknown candidate genes for the development and progression of tubular breast carcinoma, such as CDH13. The study provides the starting point for further delineating their detailed influence on the pathogenesis of tubular breast carcinoma.
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Affiliation(s)
- Marc-Oliver Riener
- Institute of Pathology, University Hospital Freiburg, Freiburg i. Br., Germany
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21
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Caner V, Turk NS, Duzcan F, Tufan NLS, Kelten EC, Zencir S, Dodurga Y, Bagci H, Duzcan SE. No strong association between HER-2/neu protein overexpression and gene amplification in high-grade invasive urothelial carcinomas. Pathol Oncol Res 2008; 14:261-6. [PMID: 18415713 DOI: 10.1007/s12253-008-9027-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2008] [Accepted: 03/05/2008] [Indexed: 01/29/2023]
Abstract
The generation of urothelial carcinoma is caused by the accumulation of various molecular changes, as in most malignancies. There are conflicting data about the status of HER-2/neu oncogene in urothelial carcinomas. The aim of this study was to determine the status of HER-2/neu oncogene in high-grade invasive urothelial carcinoma of urinary bladder both in protein and DNA level. We evaluated HER-2/neu protein overexpression by immunohistochemistry (IHC) and gene amplification by fluorescent in situ hybridization (FISH) and real-time quantitative PCR in paraffin-embedded samples of high-grade invasive urothelial carcinoma obtained from 36 patients. Polysomy 17 was also assessed by FISH. Immunohistochemically, HER-2/neu protein overexpression was observed in 22 (61.1%) tumors (ten tumors with score 3+ and 12 with score 2+). Fourteen of 36 tumors (38.9%) were evaluated as negative (score 0 or 1+). Complete concordance between FISH and the PCR was seen in all of the samples scored as 0 and 1+ by IHC. HER-2/neu gene amplification was observed in three of 27 (11.1%) tumors by FISH (nine samples were non-informative) and in eight of 36 (22.2%) tumors by the PCR. The complete concordance between HER2-2/neu protein overexpression and gene amplification was seen only in three of 27 tumors. Polysomy 17 was seen in nine tumors (33.3%). The results indicated that, in contrast to breast cancer, there was no strong association between HER-2/neu overexpression and gene amplification in invasive urothelial carcinomas, and polysomy 17 was higher in tumors showing HER-2/neu overexpression.
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Affiliation(s)
- Vildan Caner
- Department of Medical Biology, School of Medicine, Pamukkale University, Denizli, Turkey
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Familial papillary renal carcinoma: cytogenetic characterization in normal and tumor tissues in two brothers. A case report. Urol Oncol 2008; 26:295-8. [PMID: 18452823 DOI: 10.1016/j.urolonc.2007.01.025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2007] [Accepted: 01/31/2007] [Indexed: 11/20/2022]
Abstract
BACKGROUND Renal tumor subtypes are associated with distinct, recurring cytogenetic abnormalities and hereditary cancer syndromes. In papillary renal carcinoma, trisomy 7 and 17 and loss of the Y chromosome are the most common chromosomal defects. CASE PRESENTATION The present paper analyzes the chromosomes 7, 17, and Y alterations found in familial papillary carcinoma and in the normal tissue of two brothers. The evaluation, performed by fluorescence in situ hybridization (FISH) and cytogenetic conventional methods, was carried out on blood samples, normal kidney tissue, and tumor samples of the two brothers. Patient 1 showed gains of chromosomes 7 and 17 both in normal and tumor tissue. Chromosome Y status was normal. Patient 2 showed chromosome 7 and 17 gains, chromosome Y loss in tumor and chromosome 17 and Y alterations in normal kidney tissue. The constitutional karyotype was normal in both brothers. CONCLUSIONS Of particular relevance were the chromosome aberrations found in normal kidney parenchyma. In fact, the progressive alterations of 7, 17, and Y chromosomes could provide evidence of early genetic instability of tissue and may even precede the development of macroscopically identifiable lesions.
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Gallucci M, Vico E, Merola R, Leonardo C, Sperduti I, Felici A, Sentinelli S, Cantiani R, Orlandi G, Cianciulli A. Adverse genetic prognostic profiles define a poor outcome for cystectomy in bladder cancer. Exp Mol Pathol 2007; 83:385-91. [DOI: 10.1016/j.yexmp.2007.08.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2007] [Revised: 08/31/2007] [Accepted: 08/31/2007] [Indexed: 11/25/2022]
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Fassan M, Trabulsi EJ, Gomella LG, Baffa R. Targeted therapies in the management of metastatic bladder cancer. Biologics 2007; 1:393-406. [PMID: 19707309 PMCID: PMC2721287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
The management of metastatic urothelial carcinoma (UC) of the bladder is a common and complex clinical challenge. Despite the fact that UC is one of the most frequent tumors in the population, long term survival for metastatic disease remains low, and chemotherapy is curative for only a small minority of patients. UC is genetically heterogeneous, and it is surrounded by a complex tissue microenvironment. The problems of clinical practice in the field of metastatic bladder cancer have begun to stimulate translational research. Advances in the understanding of the molecular biology of urothelial cancer continue to contribute to the identification of molecular pathways upon which new therapeutic approaches can be targeted. New agents and strategies have recently been developed which can direct the most appropriate choice of treatment for advanced disease. A review of literature published on the targeted therapy for metastatic bladder cancer is presented, focusing on the molecular pathways shut down by the new therapeutic agents.
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Affiliation(s)
| | | | | | - Raffaele Baffa
- Correspondence: Raffaele Baffa, Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, 233, South 10th Street, BLSB, Room 526A, Philadelphia, Pennsylvania 19107, USA, Tel +1 215 955 9072, Fax +1 215 503 2627, Email
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Mounawar M, Mukeria A, Le Calvez F, Hung RJ, Renard H, Cortot A, Bollart C, Zaridze D, Brennan P, Boffetta P, Brambilla E, Hainaut P. Patterns of EGFR, HER2, TP53, and KRAS mutations of p14arf expression in non-small cell lung cancers in relation to smoking history. Cancer Res 2007; 67:5667-72. [PMID: 17575133 DOI: 10.1158/0008-5472.can-06-4229] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Mutations in the tyrosine kinase domain of the epidermal growth factor receptor EGFR are common in non-small cell lung cancer (NSCLC) of never smokers, whereas HER2 mutations are rare. We have analyzed EGFR and HER2 mutations and the expression of the two products of the CDKN2A gene (p14(arf) and p16(INK4a)) in 116 NSCLC that have been previously analyzed for TP53 and KRAS mutations in relation to smoking history of patients. EGFR mutations were detected in 20 of 116 (17%) tumors, whereas five (4.3%) tumors contained HER2 mutations. No tumor contained both mutations. Of tumors with EGFR or HER2 mutation, 72% were adenocarcinomas, 68% were from never smokers, and 32% were from former smokers. EGFR but not HER2 mutations were mutually exclusive with KRAS mutation. Among never smokers, 11 of 16 tumors with EGFR mutation also had TP53 mutation, in contrast with two of 17 tumors without EGFR mutation (P = 0.0008). Expression of p14(arf), but not p16(ink4a), was more frequently down-regulated in never smokers (62.5%) than ever smokers (35%; P = 0.008). All tumors with EGFR or HER2 mutations and wild-type TP53 showed down-regulation of p14(arf) expression. These observations suggest that functional inactivation of the p14(arf)/p53 connection is required in tumors with EGFR or HER2 mutations, consistent with the notion that these proteins are part of a fail-safe mechanism protecting cells against untimely or excessive mitotic signals.
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Mian C, Lodde M, Comploj E, Lusuardi L, Palermo S, Mian M, Maier K, Pycha A. Multiprobe fluorescence in situ hybridisation: prognostic perspectives in superficial bladder cancer. J Clin Pathol 2006; 59:984-7. [PMID: 16935973 PMCID: PMC1860484 DOI: 10.1136/jcp.2005.035394] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
AIM To establish independent prognostic factors on a chromosomal basis in superficial bladder cancer, using a multicolour fluorescence in situ hybridisation (FISH) probe mix. PATIENTS AND METHODS In 2002, voided urine from 75 consecutive patients (mean age 71.7, range 52-93) years under follow-up for superficial urothelial cancer was studied prospectively. The patients were observed for a mean (standard deviation (SD)) period of 39.3 (6.8) months (range 27-58) until July 2005. A multicolour FISH on liquid-based voided urinary cytology was carried out on all patients. Univariate analysis, using a log rank test, was used to determine the prognostic relevance of a low-risk pattern and a high-risk pattern. Progression-free survival time was calculated from the date of first diagnosis to first recurrence or progression according to the Kaplan-Meier product-limit method. RESULTS One patient was lost to follow-up. 27 of the 74 remaining (36.8%) patients showed recurrent disease. In 9 (33.3%) patients with a low-risk pattern disease recurred after a mean (SD) observation time of 29.7 (1.9) months (range 8.3-52.3, median 30.8 (12.4)). 18 (66.7%) patients with a high-risk pattern developed recurrence within a mean (SD) of 17.6 (2.0) months (range 4-38.8, median 16.7 (11.6)). The Kaplan-Meier curve for progression-free survival showed marked differences between the low-risk and the high-risk groups. CONCLUSION Patients with a high-risk chromosomal pattern have a markedly shorter disease-free survival time and higher progression rate than patients with a low-risk pattern. High-risk patients can therefore be treated more aggressively to prevent tumour spreading.
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Affiliation(s)
- C Mian
- Department of Pathology, Central Hospital of Bolzano, Bolzano, Italy.
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Gallucci M, Merola R, Leonardo C, Ruggeri EM, Cianciulli AM. Analysis of HER2 expression in primary urinary bladder carcinoma and corresponding metastases. BJU Int 2005; 96:440; author reply 440-1. [PMID: 16042748 DOI: 10.1111/j.1464-410x.2005.05755_1.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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