Microsatellite abnormalities and somatic down‐regulation of mismatch repair characterize nodular‐trabecular muscle‐invasive urothelial carcinoma of the bladder

Rubio, Javier; Blanes, Alfredo; Sanchez-Carrillo, Juan J.; Díaz‐Cano, Salvador

doi:10.1111/j.1365-2559.2007.02795.x

Cited by 11 publications

(15 citation statements)

References 40 publications

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“…To date, a series of studies have attempted to determine the expression of MMR proteins, mainly MSH2 and MLH1, in bladder cancer, the majority using IHC methods (17)(18)(19)(20)(21)(22)(23)(24). Only two previous studies have determined MMR mRNA levels in bladder cancer by qPCR analysis and even in a few series of clinical specimens with different percentages from IHC analysis (25,26).…”

Section: Discussionmentioning

confidence: 99%

“…The dysfunction of MMR genes may present as an absence or reduction of MMR gene expression or microsatellite instability (MSI) phenotype (15)(16)(17). The protein expression levels of the hMSH2, hMLH1 and hMSH6 MMR genes have been detected in histopathological material of UCC specimens by immunohistochemistry (IHC) with controversial results (17)(18)(19)(20)(21)(22)(23)(24). There is little and insufficient literature concerning the expression of the mRNA of MMR genes in bladder cancer specimens (25,26).…”

Section: Introductionmentioning

confidence: 99%

“…Genomic instability analysis was performed for the following polymorphic regions of the hMSH2 and hMLH1 loci: D3S1234 (3p14), D3S1612 (3p21. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] and D3S1768 (3p21. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] distal to the hMLH1 locus on chromosome 3p and D2S1788 (2p22.3) proximal to the hMSH2 locus on chromosome 2p, to compare the possible loss of mRNA expression with allelic imbalance of the chromosomal regions that contain the genes (28).…”

Section: Introductionmentioning

confidence: 99%

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Mismatch repair hMSH2, hMLH1, hMSH6 and hPMS2 mRNA expression profiles in precancerous and cancerous urothelium

et al. 2012

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Abstract. Changes in the expression of the mismatch repair (MMR) genes hMSH2, hMLH1, hMSH6 and hPMS2 reflect dysfunction of the DNA repair system that may allow the malignant transformation of tissue cells. The aim of the present study was to address the mRNA expression profiles of the mismatch DNA repair system in cancerous and precancerous urothelium. This is the first study to quantify MMR mRNA expression by applying quantitative real-time PCR (qPCR) and translate the results to mRNA phenotypic profiles (r, reduced; R, regular or elevated) in bladder tumors [24 urothelial cell carcinomas (UCCs) and 1 papillary urothelial neoplasm of low malignant potential (PUNLMP)] paired with their adjacent normal tissues (ANTs). Genetic instability analysis was applied at polymorphic sites distal or close to the hMSH2 and hMLH1 locus. Presenting our data, reduced hMSH2, hMSH6 and hPMS2 mRNA expression profiles were observed in cancerous and precancerous urothelia. Significantly, the ANTs of UCCs revealed the highest percentages of reduced hMSH2 (r 2 ), hMSH6 (r 6 ) and hPMS2 (p 2 ) mRNA phenotypes relative to their tumors (P<0.03). In particular, combined r 2 r 6 (P<0.02) presented a greater difference between ANTs of low-grade UCCs vs. their tumors compared with ANTs of high-grade UCCs (P= 0.000). Reduced hMLH1 (r 1 ) phenotype was not expressed in precancerous or cancerous urothelia. The hMSH6 mRNA was the most changed in UCCs (47.8%), while hMSH2, hMLH1 and hPMS2 showed overexpression (47.8, 35 and 30%, respectively) that was associated with gender and histological tumor grading or staging. Genetic instability was rare in polymorphic regions distal to hMLH1. Our data reveal a previously unrecognized hMSH2 and hMSH6 mRNA combined phenotype (r 2 r 6 ) correlated with a precancerous urothelium and show that hMLH1 is transcriptionally activated in precancerous or cancerous urothelium. In the present study, it is demonstrated that reduction of hMSH6 mRNA is a frequent event in bladder tumorigenesis and reflects a common mechanism of suppression with hMSH2, while alterations of hMSH2 or hMLH1 mRNA expression in UCCs does not correlate with the allelic imbalance of polymorphic regions harboring the genes. IntroductionThe most common histological type of bladder cancer is urothelial cell carcinoma (UCC) or transitional cell carcinoma (TCC). Papillary urothelial neoplasm of low malignant potential (PUNLMP) may also arise from urothelium of bladder (1,2). The urothelium of a patient with a bladder cancer is at risk as the cancer often recurrs in the urinary bladder following treatment (1,3). Numerous genetic and epigenetic factors have been implicated in the carcinogenesis of the urinary bladder that involved in its mutator phenotype (4-7). The DNA repair mechanism is essential to prevent DNA mutations that may be lethal for cells (8). Mismatch repair (MMR) genes encode a number of DNA repair enzymes that cooperate to recognize and repair DNA mismatches (8,9). These enzymes act as complexes. A crucial complex that recognizes base...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mismatch repair hMSH2, hMLH1, hMSH6 and hPMS2 mRNA expression profiles in precancerous and cancerous urothelium

et al. 2012

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“…7 (b) Additional allele bands present in tumor samples but not in the corresponding controls were considered as evidence of somatic microsatellite abnormalities. 7,19,20,29 Immunohistochemical Detection of Ki-67, Cell Cycle Regulators, and TERT Sections were mounted on positively charged slides (Superfrost Plus, Fisher Scientific, Fair Lawn, NJ, USA), baked at 601C for 2 h, and processed as described. 22,24,30 After routine dewaxing and rehydration, endogenous peroxidase quenching, and antigen heat retrieval, the slides were transferred to a moist chamber.…”

Section: Tsg Microsatellite Analysismentioning

confidence: 99%

Heterogeneous topographic profiles of kinetic and cell cycle regulator microsatellites in atypical (dysplastic) melanocytic nevi

et al. 2011

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Atypical (dysplastic) melanocytic nevi are clinically heterogeneous malignant melanoma precursors, for which no topographic analysis of cell kinetic, cell cycle regulators and microsatellite profile is available. We selected low-grade atypical melanocytic nevi (92), high-grade atypical melanocytic nevi (41), melanocytic nevi (18 junctional, 25 compound) and malignant melanomas (16 radial growth phase and 27 vertical growth phase). TP53, CDKN2A, CDKN1A, and CDKN1B microsatellite patterns were topographically studied after microdissection; Ki-67, TP53, CDKN2A, CDKN1A, and CDKN1B expressions and DNA fragmentation by in situ end labeling for apoptosis were topographically scored. Results were statistically analyzed. A decreasing junctional-dermal marker expression gradient was observed, directly correlating with atypical melanocytic nevus grading. High-grade atypical melanocytic nevi revealed coexistent TP53-CDKN2A-CDKN1B microsatellite abnormalities, and significantly higher junctional Ki67-TP53 expression (inversely correlated with CDKN1A-CDKN1B expression and in situ end labeling). Malignant melanomas showed coexistent microsatellite abnormalities (CDKN2A-CDKN1B), no topographic gradient, and significantly decreased expression. Melanocytic nevi and low-grade atypical melanocytic nevi revealed sporadic junctional CDKN2A microsatellite abnormalities and no significant topographic kinetic differences. High-grade atypical melanocytic nevi accumulate junctional TP53-CDKN1A-CDKN1B microsatellite abnormalities, being progression TP53-independent and better assessed in the dermis. Melanocytic nevi and low-grade atypical melanocytic nevi show low incidence of microsatellite abnormalities, and kinetic features that make progression unlikely.

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“…The clonal relationships between LGUD and CIS associated with muscle-invasive UCC have not been addressed. Although bladder UCC infrequently reveals microsatellite instability [9][10][11], the reduced expression of mismatch repair (MMR) proteins contributes to the development of a subset of UCC [12,13].…”

Section: Introductionmentioning

confidence: 99%

Coexistent intraurothelial carcinoma and muscle-invasive urothelial carcinoma of the bladder: clonality and somatic down-regulation of DNA mismatch repair

et al. 2009

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Microsatellite abnormalities and somatic down‐regulation of mismatch repair characterize nodular‐trabecular muscle‐invasive urothelial carcinoma of the bladder

Abstract: Somatic down-regulation of MMR proteins in nodular-trabecular muscle-invasive UroC results in RB1/NF1 microsatellite abnormalities, correlating with higher cellular turnover and longer survival.

Cited by 11 publications

References 40 publications

Mismatch repair hMSH2, hMLH1, hMSH6 and hPMS2 mRNA expression profiles in precancerous and cancerous urothelium

Mismatch repair hMSH2, hMLH1, hMSH6 and hPMS2 mRNA expression profiles in precancerous and cancerous urothelium

Heterogeneous topographic profiles of kinetic and cell cycle regulator microsatellites in atypical (dysplastic) melanocytic nevi

Coexistent intraurothelial carcinoma and muscle-invasive urothelial carcinoma of the bladder: clonality and somatic down-regulation of DNA mismatch repair

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