Low frequency of defective mismatch repair in a population-based series of upper urothelial carcinoma

Ericson, Kajsa; Isinger, Anna; Isfoss, Björn L; Nilbert, Mef

doi:10.1186/1471-2407-5-23

Cited by 44 publications

(34 citation statements)

References 29 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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“…A total of 25 tumours (four MSI, two with variants at 1 locus and 19 MSS) have been further analysed using the original Bethesda panel leading to identical results. Whereas the four MSI tumours displayed MSI at all three dinucleotide loci (D2S123, D5S346, D17S250), no instability (Ericson et al, 2005), but is significantly lower than the majority of the others, reporting 21-31% MSI-H tumours Hartmann et al, 2002;Catto et al, 2003;Roupret et al, 2004). Although these studies had also been carried out on unselected UUC, the Bethesda panel used was significantly modified with the frequent inclusion of the BAT40 mononucleotide marker, as well as a number of additional dinucleotide markers.…”

Section: Introductionmentioning

confidence: 92%

“…These markers have been shown to establish tumour MSI status with clear interpretation of data and 100% specificity and sensitivity with no need for matched normal tissue (Suraweera et al, 2002;Buhard et al, 2004). Few studies addressed the MSI status of UUC; they were performed using the original or a modified Bethesda panel and reported dramatic variations in the incidence rate (4-31%) Hartmann et al, 2002Hartmann et al, , 2003Catto et al, 2003;Roupret et al, 2004;Ericson et al, 2005). Moreover, extensive analyses of mutational targets of MSI in UUC are not available to date.…”

Section: Introductionmentioning

confidence: 99%

Microsatellite instability and mutation analysis of candidate genes in urothelial cell carcinomas of upper urinary tract

Mongiat-Artus

Miquel²,

et al. 2005

Oncogene

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A subset of upper urinary tract urothelial cell carcinomas (UUC), arising sporadically or as a manifestation of hereditary non-polyposis colorectal cancer, displays microsatellite instability (MSI). MSI tumours are characterized by defective mismatch repair and accumulation of frameshift mutations in numerous genes harbouring repeats in their coding sequences. We have evaluated the incidence of MSI in UUC and the intratumoral distribution of mutations in 13 candidate target genes. A total of 58 unselected UUC were screened for MSI using the panel of five mononucleotide markers recently recommended by the National Cancer Institute for a precise MSI assessment. Four tumours displayed MSI (7%), among which at least three had alterations in the genes MSH3, BAX, MRE11, RAD50. Mutations in genes involved in key cellular pathways (ATR, DNA-PKcs, MBD4, TCF-4, MSH6, and BLM) were further detected. BAX and MRE11 mutations tend to present homogeneously within the three MSI UUC. Immunohistochemistry (MLH1, MSH2, MSH6) showed that loss of mismatch repair protein expression occurred in all MSI UUC defining the gene defect and that MRE11 and RAD50 mutations were associated with their concomitant loss expression. In conclusion, MSI UUC represent a small proportion of UUC in which BAX and MRE11 mutations are frequent and may play a role early in UUC tumorigenesis.

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Pathology of Renal Pelvis, Ureter, and Urethra

2012

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Low frequency of defective mismatch repair in a population-based series of upper urothelial carcinoma

Cited by 44 publications

References 29 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

Microsatellite instability and mutation analysis of candidate genes in urothelial cell carcinomas of upper urinary tract

Pathology of Renal Pelvis, Ureter, and Urethra

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