MMR deficiency in urothelial carcinoma of the bladder presents with temporal and spatial homogeneity throughout the tumor mass
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MMR deficiency in urothelial carcinoma of the bladder presents with temporal and spatial homogeneity throughout the tumor mass. / Fraune, Christoph; Simon, Ronald; Hube-Magg, Claudia; Makrypidi-Fraune, Georgia; Kähler, Christian; Kluth, Martina; Höflmayer, Doris; Büscheck, Franziska; Dum, David; Luebke, Andreas M; Burandt, Eike; Clauditz, Till Sebastian; Wilczak, Waldemar; Sauter, Guido; Steurer, Stefan.
In: UROL ONCOL-SEMIN ORI, Vol. 38, No. 5, 05.2020, p. 488-495.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - MMR deficiency in urothelial carcinoma of the bladder presents with temporal and spatial homogeneity throughout the tumor mass
AU - Fraune, Christoph
AU - Simon, Ronald
AU - Hube-Magg, Claudia
AU - Makrypidi-Fraune, Georgia
AU - Kähler, Christian
AU - Kluth, Martina
AU - Höflmayer, Doris
AU - Büscheck, Franziska
AU - Dum, David
AU - Luebke, Andreas M
AU - Burandt, Eike
AU - Clauditz, Till Sebastian
AU - Wilczak, Waldemar
AU - Sauter, Guido
AU - Steurer, Stefan
N1 - Copyright © 2019 Elsevier Inc. All rights reserved.
PY - 2020/5
Y1 - 2020/5
N2 - BACKGROUND: Microsatellite instability (MSI), a hypermutator phenotype described in many cancers, has emerged as a predictive biomarker for immune checkpoint inhibitor therapy. Cancer heterogeneity represents a potential obstacle for the analysis of predicitive biomarkers. MSI has been reported in bladder cancer, but data on the possible extent of intratumoral heterogeneity are lacking.METHODS: To study MSI heterogeneity in bladder cancer, a tissue microarray (TMA) comprising 598 muscle-invasive urothelial carcinomas of the bladder was utilized to screen for MSI by immunhistochemistry with antibodies for MLH1, PMS2, MSH2, and MSH6.RESULTS: In 9 cases suspicious for MSI, MMR status was further evaluated by large section examination and polymerase chain reaction (PCR)-based analysis of microsatellites ("Bethesda panel") resulting in the identification of 5 validated MSI cases from 448 interpretable cancers (prevalence 1.1%). MMR deficiency always involved PMS2 loss, in 3 cases with additional loss or reduction of MLH1 expression. Four cancers were MSI-high and 1 was MSI-low in the PCR analysis. Parallel sequencing revealed an inactivating MLH1 mutation in 1 tumor but no further known pathogenic MMR gene mutations were found. Immunostaining of all available 72 cancer-containing tissue blocks of the 5 confirmed bladder cancer with MSI including prior and subsequent biopsies showed complete homogeneity of the MMR protein defects and the status of the 4 MMR proteins did not markedly change in sequential resections. In all 4 cases with noninvasive precursor lesions, MSI was also detectable.CONCLUSION: These data suggest that MSI occurs early in invasive bladder cancer and immunohistochemical MMR analysis on limited biopsy material is sufficient to estimate MMR status of the entire cancer mass.
AB - BACKGROUND: Microsatellite instability (MSI), a hypermutator phenotype described in many cancers, has emerged as a predictive biomarker for immune checkpoint inhibitor therapy. Cancer heterogeneity represents a potential obstacle for the analysis of predicitive biomarkers. MSI has been reported in bladder cancer, but data on the possible extent of intratumoral heterogeneity are lacking.METHODS: To study MSI heterogeneity in bladder cancer, a tissue microarray (TMA) comprising 598 muscle-invasive urothelial carcinomas of the bladder was utilized to screen for MSI by immunhistochemistry with antibodies for MLH1, PMS2, MSH2, and MSH6.RESULTS: In 9 cases suspicious for MSI, MMR status was further evaluated by large section examination and polymerase chain reaction (PCR)-based analysis of microsatellites ("Bethesda panel") resulting in the identification of 5 validated MSI cases from 448 interpretable cancers (prevalence 1.1%). MMR deficiency always involved PMS2 loss, in 3 cases with additional loss or reduction of MLH1 expression. Four cancers were MSI-high and 1 was MSI-low in the PCR analysis. Parallel sequencing revealed an inactivating MLH1 mutation in 1 tumor but no further known pathogenic MMR gene mutations were found. Immunostaining of all available 72 cancer-containing tissue blocks of the 5 confirmed bladder cancer with MSI including prior and subsequent biopsies showed complete homogeneity of the MMR protein defects and the status of the 4 MMR proteins did not markedly change in sequential resections. In all 4 cases with noninvasive precursor lesions, MSI was also detectable.CONCLUSION: These data suggest that MSI occurs early in invasive bladder cancer and immunohistochemical MMR analysis on limited biopsy material is sufficient to estimate MMR status of the entire cancer mass.
U2 - 10.1016/j.urolonc.2019.12.012
DO - 10.1016/j.urolonc.2019.12.012
M3 - SCORING: Journal article
C2 - 32067846
VL - 38
SP - 488
EP - 495
JO - UROL ONCOL-SEMIN ORI
JF - UROL ONCOL-SEMIN ORI
SN - 1078-1439
IS - 5
ER -