Loss of MTAP expression is strongly linked to homozygous 9p21 deletion, unfavorable tumor phenotype, and noninflamed microenvironment in urothelial bladder cancer
Abstract Homozygous 9p21 deletions usually result in a complete loss of S‐methyl‐5′‐thioadenosine phosphorylase (MTAP) expression visualizable by immunohistochemistry (IHC). MTAP deficiency has been proposed as a marker for predicting targeted treatment response. A tissue microarray including 2,710...
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2025-01-01
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| Series: | The Journal of Pathology: Clinical Research |
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| Online Access: | https://doi.org/10.1002/2056-4538.70012 |
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| author | Natalia Gorbokon Niklas Wößner Viktoria Ahlburg Henning Plage Sebastian Hofbauer Kira Furlano Sarah Weinberger Paul Giacomo Bruch Simon Schallenberg Florian Roßner Sefer Elezkurtaj Maximilian Lennartz Niclas C Blessin Andreas H Marx Henrik Samtleben Margit Fisch Michael Rink Marcin Slojewski Krystian Kaczmarek Thorsten Ecke Tobias Klatte Stefan Koch Nico Adamini Sarah Minner Ronald Simon Guido Sauter Henrik Zecha David Horst Thorsten Schlomm Lukas Bubendorf Martina Kluth |
| author_facet | Natalia Gorbokon Niklas Wößner Viktoria Ahlburg Henning Plage Sebastian Hofbauer Kira Furlano Sarah Weinberger Paul Giacomo Bruch Simon Schallenberg Florian Roßner Sefer Elezkurtaj Maximilian Lennartz Niclas C Blessin Andreas H Marx Henrik Samtleben Margit Fisch Michael Rink Marcin Slojewski Krystian Kaczmarek Thorsten Ecke Tobias Klatte Stefan Koch Nico Adamini Sarah Minner Ronald Simon Guido Sauter Henrik Zecha David Horst Thorsten Schlomm Lukas Bubendorf Martina Kluth |
| author_sort | Natalia Gorbokon |
| collection | DOAJ |
| description | Abstract Homozygous 9p21 deletions usually result in a complete loss of S‐methyl‐5′‐thioadenosine phosphorylase (MTAP) expression visualizable by immunohistochemistry (IHC). MTAP deficiency has been proposed as a marker for predicting targeted treatment response. A tissue microarray including 2,710 urothelial bladder carcinomas were analyzed for 9p21 deletion by fluorescence in situ hybridization and MTAP expression by IHC. Data were compared with data on tumor phenotype, patient survival, intratumoral lymphocyte subsets, and PD‐L1 expression. The 9p21 deletion rate increased from pTaG2 low (9.2% homozygous, 25.8% heterozygous) to pTaG2 high (32.6%, 20.9%; p < 0.0001) but was slightly lower in pTaG3 (16.7%, 16.7%) tumors. In pT2–4 carcinomas, 23.3% homozygous and 17.9% heterozygous deletions were found, and deletions were tied to advanced pT (p = 0.0014) and poor overall survival (p = 0.0461). Complete MTAP loss was seen in 98.4% of homozygous deleted while only 1.6% of MTAP negative tumors had retained 9p21 copies (p < 0.0001). MTAP loss was linked to advanced stage and poor overall survival in pT2–4 carcinomas (p < 0.05 each). The relationship between 9p21 deletions/MTAP loss and poor patient prognosis was independent of pT and pN (p < 0.05 each). The 9p21 deletions were associated with a noninflamed microenvironment (p < 0.05). Complete MTAP loss is strongly tied to homozygous 9p21 deletion, aggressive disease, and noninflamed microenvironment. Drugs targeting MTAP‐deficiency may be useful in urothelial bladder carcinoma. MTAP IHC is a near perfect surrogate for MTAP deficiency in this tumor type. |
| format | Article |
| id | doaj-art-411506ea9d7b4c6393ff1601892c4ed2 |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
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| series | The Journal of Pathology: Clinical Research |
| spelling | doaj-art-411506ea9d7b4c6393ff1601892c4ed22025-01-28T03:40:31ZengWileyThe Journal of Pathology: Clinical Research2056-45382025-01-01111n/an/a10.1002/2056-4538.70012Loss of MTAP expression is strongly linked to homozygous 9p21 deletion, unfavorable tumor phenotype, and noninflamed microenvironment in urothelial bladder cancerNatalia Gorbokon0Niklas Wößner1Viktoria Ahlburg2Henning Plage3Sebastian Hofbauer4Kira Furlano5Sarah Weinberger6Paul Giacomo Bruch7Simon Schallenberg8Florian Roßner9Sefer Elezkurtaj10Maximilian Lennartz11Niclas C Blessin12Andreas H Marx13Henrik Samtleben14Margit Fisch15Michael Rink16Marcin Slojewski17Krystian Kaczmarek18Thorsten Ecke19Tobias Klatte20Stefan Koch21Nico Adamini22Sarah Minner23Ronald Simon24Guido Sauter25Henrik Zecha26David Horst27Thorsten Schlomm28Lukas Bubendorf29Martina Kluth30Institute of Pathology University Medical Center Hamburg‐Eppendorf Hamburg GermanyInstitute of Pathology University Medical Center Hamburg‐Eppendorf Hamburg GermanyInstitute of Pathology University Medical Center Hamburg‐Eppendorf Hamburg GermanyDepartment of Urology Charité Berlin Berlin GermanyDepartment of Urology Charité Berlin Berlin GermanyDepartment of Urology Charité Berlin Berlin GermanyDepartment of Urology Charité Berlin Berlin GermanyDepartment of Urology Charité Berlin Berlin GermanyInstitute of Pathology Charité Berlin Berlin GermanyInstitute of Pathology Charité Berlin Berlin GermanyInstitute of Pathology Charité Berlin Berlin GermanyInstitute of Pathology University Medical Center Hamburg‐Eppendorf Hamburg GermanyInstitute of Pathology University Medical Center Hamburg‐Eppendorf Hamburg GermanyDepartment of Pathology Academic Hospital Fuerth Fuerth GermanyDepartment of Pathology Academic Hospital Fuerth Fuerth GermanyDepartment of Urology University Medical Center Hamburg‐Eppendorf Hamburg GermanyDepartment of Urology Marienhospital Hamburg Hamburg GermanyDepartment of Urology and Urological Oncology Pomeranian Medical University Szczecin PolandDepartment of Urology and Urological Oncology Pomeranian Medical University Szczecin PolandDepartment of Urology Helios Hospital Bad Saarow Bad Saarow GermanyDepartment of Urology Helios Hospital Bad Saarow Bad Saarow GermanyDepartment of Pathology Helios Hospital Bad Saarow Bad Saarow GermanyDepartment of Urology Albertinen Hospital Hamburg GermanyInstitute of Pathology University Medical Center Hamburg‐Eppendorf Hamburg GermanyInstitute of Pathology University Medical Center Hamburg‐Eppendorf Hamburg GermanyInstitute of Pathology University Medical Center Hamburg‐Eppendorf Hamburg GermanyDepartment of Urology Charité Berlin Berlin GermanyInstitute of Pathology Charité Berlin Berlin GermanyDepartment of Urology Charité Berlin Berlin GermanyInstitute of Pathology University Hospital Basel Basel SwitzerlandInstitute of Pathology University Medical Center Hamburg‐Eppendorf Hamburg GermanyAbstract Homozygous 9p21 deletions usually result in a complete loss of S‐methyl‐5′‐thioadenosine phosphorylase (MTAP) expression visualizable by immunohistochemistry (IHC). MTAP deficiency has been proposed as a marker for predicting targeted treatment response. A tissue microarray including 2,710 urothelial bladder carcinomas were analyzed for 9p21 deletion by fluorescence in situ hybridization and MTAP expression by IHC. Data were compared with data on tumor phenotype, patient survival, intratumoral lymphocyte subsets, and PD‐L1 expression. The 9p21 deletion rate increased from pTaG2 low (9.2% homozygous, 25.8% heterozygous) to pTaG2 high (32.6%, 20.9%; p < 0.0001) but was slightly lower in pTaG3 (16.7%, 16.7%) tumors. In pT2–4 carcinomas, 23.3% homozygous and 17.9% heterozygous deletions were found, and deletions were tied to advanced pT (p = 0.0014) and poor overall survival (p = 0.0461). Complete MTAP loss was seen in 98.4% of homozygous deleted while only 1.6% of MTAP negative tumors had retained 9p21 copies (p < 0.0001). MTAP loss was linked to advanced stage and poor overall survival in pT2–4 carcinomas (p < 0.05 each). The relationship between 9p21 deletions/MTAP loss and poor patient prognosis was independent of pT and pN (p < 0.05 each). The 9p21 deletions were associated with a noninflamed microenvironment (p < 0.05). Complete MTAP loss is strongly tied to homozygous 9p21 deletion, aggressive disease, and noninflamed microenvironment. Drugs targeting MTAP‐deficiency may be useful in urothelial bladder carcinoma. MTAP IHC is a near perfect surrogate for MTAP deficiency in this tumor type.https://doi.org/10.1002/2056-4538.70012MTAP9p21 deletiontissue microarrayFISHimmunohistochemistryurothelial bladder carcinoma |
| spellingShingle | Natalia Gorbokon Niklas Wößner Viktoria Ahlburg Henning Plage Sebastian Hofbauer Kira Furlano Sarah Weinberger Paul Giacomo Bruch Simon Schallenberg Florian Roßner Sefer Elezkurtaj Maximilian Lennartz Niclas C Blessin Andreas H Marx Henrik Samtleben Margit Fisch Michael Rink Marcin Slojewski Krystian Kaczmarek Thorsten Ecke Tobias Klatte Stefan Koch Nico Adamini Sarah Minner Ronald Simon Guido Sauter Henrik Zecha David Horst Thorsten Schlomm Lukas Bubendorf Martina Kluth Loss of MTAP expression is strongly linked to homozygous 9p21 deletion, unfavorable tumor phenotype, and noninflamed microenvironment in urothelial bladder cancer The Journal of Pathology: Clinical Research MTAP 9p21 deletion tissue microarray FISH immunohistochemistry urothelial bladder carcinoma |
| title | Loss of MTAP expression is strongly linked to homozygous 9p21 deletion, unfavorable tumor phenotype, and noninflamed microenvironment in urothelial bladder cancer |
| title_full | Loss of MTAP expression is strongly linked to homozygous 9p21 deletion, unfavorable tumor phenotype, and noninflamed microenvironment in urothelial bladder cancer |
| title_fullStr | Loss of MTAP expression is strongly linked to homozygous 9p21 deletion, unfavorable tumor phenotype, and noninflamed microenvironment in urothelial bladder cancer |
| title_full_unstemmed | Loss of MTAP expression is strongly linked to homozygous 9p21 deletion, unfavorable tumor phenotype, and noninflamed microenvironment in urothelial bladder cancer |
| title_short | Loss of MTAP expression is strongly linked to homozygous 9p21 deletion, unfavorable tumor phenotype, and noninflamed microenvironment in urothelial bladder cancer |
| title_sort | loss of mtap expression is strongly linked to homozygous 9p21 deletion unfavorable tumor phenotype and noninflamed microenvironment in urothelial bladder cancer |
| topic | MTAP 9p21 deletion tissue microarray FISH immunohistochemistry urothelial bladder carcinoma |
| url | https://doi.org/10.1002/2056-4538.70012 |
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