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Mismatch repair def...
Mismatch repair deficiency testing in Lynch syndrome-associated urothelial tumors
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- Rasmussen, Maria (author)
- Copenhagen University Hospital
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- Sowter, Peter (author)
- University of Newcastle upon Tyne
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- Gallon, Richard (author)
- University of Newcastle upon Tyne
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- Durhuus, Jon Ambæk (author)
- Copenhagen University Hospital,University of Copenhagen
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- Hayes, Christine (author)
- University of Newcastle upon Tyne
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- Andersen, Ove (author)
- Copenhagen University Hospital
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- Nilbert, Mef (author)
- Lund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Schejbel, Lone (author)
- Gentofte Hospital
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- Høgdall, Estrid (author)
- Gentofte Hospital
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- Santibanez-Koref, Mauro (author)
- University of Newcastle upon Tyne
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- Jackson, Michael S. (author)
- University of Newcastle upon Tyne
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- Burn, John (author)
- University of Newcastle upon Tyne
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- Therkildsen, Christina (author)
- Copenhagen University Hospital
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(creator_code:org_t)
- 2023
- 2023
- English.
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In: Frontiers in Oncology. - 2234-943X. ; 13
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Abstract
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- Introduction: Lynch syndrome-associated cancer develops due to germline pathogenic variants in one of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 or PMS2. Somatic second hits in tumors cause MMR deficiency, testing for which is used to screen for Lynch syndrome in colorectal cancer and to guide selection for immunotherapy. Both MMR protein immunohistochemistry and microsatellite instability (MSI) analysis can be used. However, concordance between methods can vary for different tumor types. Therefore, we aimed to compare methods of MMR deficiency testing in Lynch syndrome-associated urothelial cancers. Methods: Ninety-seven urothelial (61 upper tract and 28 bladder) tumors diagnosed from 1980 to 2017 in carriers of Lynch syndrome-associated pathogenic MMR variants and their first-degree relatives (FDR) were analyzed by MMR protein immunohistochemistry, the MSI Analysis System v1.2 (Promega), and an amplicon sequencing-based MSI assay. Two sets of MSI markers were used in sequencing-based MSI analysis: a panel of 24 and 54 markers developed for colorectal cancer and blood MSI analysis, respectively. Results: Among the 97 urothelial tumors, 86 (88.7%) showed immunohistochemical MMR loss and 68 were successfully analyzed by the Promega MSI assay, of which 48 (70.6%) were MSI-high and 20 (29.4%) were MSI-low/microsatellite stable. Seventy-two samples had sufficient DNA for the sequencing-based MSI assay, of which 55 (76.4%) and 61 (84.7%) scored as MSI-high using the 24-marker and 54-marker panels, respectively. The concordance between the MSI assays and immunohistochemistry was 70.6% (p = 0.003), 87.5% (p = 0.039), and 90.3% (p = 1.00) for the Promega assay, the 24-marker assay, and the 54-marker assay, respectively. Of the 11 tumors with retained MMR protein expression, four were MSI-low/MSI-high or MSI-high by the Promega assay or one of the sequencing-based assays. Conclusion: Our results show that Lynch syndrome-associated urothelial cancers frequently had loss of MMR protein expression. The Promega MSI assay was significantly less sensitive, but the 54-marker sequencing-based MSI analysis showed no significant difference compared to immunohistochemistry. Data from this study alongside previous studies, suggest that universal MMR deficiency testing of newly diagnosed urothelial cancers, using immunohistochemistry and/or sequencing-based MSI analysis of sensitive markers, offer a potentially useful approach to identification of Lynch syndrome cases.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- immunohistochemistry
- Lynch syndrome
- microsatellite instability
- mismatch repair deficiency
- universal testing
- urothelial cancer
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Rasmussen, Maria
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Sowter, Peter
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Gallon, Richard
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Durhuus, Jon Amb ...
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Hayes, Christine
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Andersen, Ove
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show more...
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Nilbert, Mef
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Schejbel, Lone
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Høgdall, Estrid
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Santibanez-Koref ...
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Jackson, Michael ...
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Burn, John
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Therkildsen, Chr ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Cancer and Oncol ...
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Frontiers in Onc ...
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Lund University