Distinct patterns of microsatellite instability are seen in tumours of the urinary tract

Abstract

To date, two forms of microsatellite instability (MSI) have been described in human cancer. MSI typical of hereditary nonpolyposis colon cancer (HNPCC), is due to deficient DNA mismatch repair (MMR) and is defined with mono-and dinucleotide repeat microsatellites. A second variety of instability is best seen at selective tetranucleotide repeats (EMAST; elevated microsatellite alterations at select tetranucleotides). While MSI occurs infrequently in bladder cancers, EMAST is common. Sporadic tumours with the largest proportion showing MSI are those found most frequently in HNPCC kindreds. While bladder cancer is not frequently seen in HNPCC, upper urinary tract tumours (UTTs) are. Having previously found a low frequency of MSI in bladder cancer, we sought to determine the relative levels of MSI and EMAST in transitional cell carcinoma (TCC) of the upper and lower urinary tracts. Microsatellite analysis was performed at 10 mono-and dinucleotide and eight tetranucleotide loci, in 89 bladder and 71 UTT TCC. Contrasting patterns of instability were seen in urinary tumours. In bladder cancer, MSI was rare and EMAST was common. The presence of EMAST was not related to tumour grade, stage, subsequent outcome or immunohistochemical expression of the MMR proteins. In UTT, while MSI occurred frequently, EMAST was seen less frequently than in bladder cancer. When TCC of the upper and lower urinary tracts are compared, MSI-H is more frequent in UTT and EMAST more frequent in bladder cancer. Our findings show that, as for colorectal cancer, the pattern of MSI varies with location in the urinary tract. In addition, we have confirmed that MSI and EMAST are discrete forms of MSI, and that the presence of EMAST does not affect tumour phenotype.

973 Relationship of EMAST and Microsatellite Instability Among Patients With Rectal Cancer

“…[3][4][5][6][7][25][26][27] Several studies could find no link between EMAST and DNA MMR deficiency, the cause of MSI. While the etiology of EMAST is still not clear, general clues point toward some epigenetic relaxation of DNA MMR as one possibility for its cause.…”

“…EMAST has been previously observed in non-small-cell lung, 3,4 skin, 5 ovarian, 6 and bladder cancers. 5,7 The etiology for EMAST is not known, but EMAST has been used as a biomarker for some of these tumors.…”

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

“…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.…”

“…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.…”

Colorectal Cancer: Sailing with a T-Cell EMAST

“…Since its initial discovery in non-small cell lung cancers [2,3], EMAST has subsequently been observed in several other human cancers, including skin [4], ovarian [5], endometrial [6], bladder [4,7], prostate [8,9] and colorectal [10][11][12][13]. Most microsatellite sequences (either mono-, di-or tetra-nucleotide repeats) are present in the non-coding regions of DNA; however, small minorities of these tandem repeats exist within the coding sequences of growth regulatory genes that play a critical role in driving CRC pathogenesis.…”