Unexplained mismatch repair deficiency: Case closed
Summary: To identify Lynch syndrome (LS) carriers, DNA mismatch repair (MMR) immunohistochemistry (IHC) is performed on colorectal cancers (CRCs). Upon subsequent LS diagnostics, MMR deficiency (MMRd) sometimes remains unexplained (UMMRd). Recently, the importance of complete LS diagnostics to expla...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | HGG Advances |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666247722000847 |
| _version_ | 1797961025120632832 |
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| author | Ellis L. Eikenboom Sarah Moen Lotte van Leeuwen Willemina R.R. Geurts-Giele Carli M.J. Tops Tjakko J. van Ham Winand N.M. Dinjens Hendrikus J. Dubbink Manon C.W. Spaander Anja Wagner |
| author_facet | Ellis L. Eikenboom Sarah Moen Lotte van Leeuwen Willemina R.R. Geurts-Giele Carli M.J. Tops Tjakko J. van Ham Winand N.M. Dinjens Hendrikus J. Dubbink Manon C.W. Spaander Anja Wagner |
| author_sort | Ellis L. Eikenboom |
| collection | DOAJ |
| description | Summary: To identify Lynch syndrome (LS) carriers, DNA mismatch repair (MMR) immunohistochemistry (IHC) is performed on colorectal cancers (CRCs). Upon subsequent LS diagnostics, MMR deficiency (MMRd) sometimes remains unexplained (UMMRd). Recently, the importance of complete LS diagnostics to explain UMMRd, involving MMR methylation, germline, and somatic analyses, was stressed. To explore why some MMRd CRCs remain unsolved, we performed a systematic review of the literature and mapped patients with UMMRd diagnosed in our center. A systematic literature search was performed in Ovid Medline, Embase, Web of Science, Cochrane CENTRAL, and Google Scholar for articles on UMMRd CRCs after complete LS diagnostics published until December 15, 2021. Additionally, UMMRd CRCs diagnosed in our center since 1993 were mapped. Of 754 identified articles, 17 were included, covering 74 patients with UMMRd. Five CRCs were microsatellite stable. Upon complete diagnostics, 39 patients had single somatic MMR hits, and six an MMR germline variant of unknown significance (VUS). Ten had somatic pathogenic variants (PVs) in POLD1, MLH3, MSH3, and APC. The remaining 14 patients were the only identifiable cases in the literature without a plausible identified cause of the UMMRd. Of those, nine were suspected to have LS. In our center, complete LS diagnostics in approximately 5,000 CRCs left seven MMRd CRCs unexplained. All had a somatic MMR hit or MMR germline VUS, indicative of a missed second MMR hit. In vitually all patients with UMMRd, complete LS diagnostics suggest MMR gene involvement. Optimizing detection of currently undetectable PVs and VUS interpretation might explain all UMMRd CRCs, considering UMMRd a case closed. |
| first_indexed | 2024-04-11T00:52:55Z |
| format | Article |
| id | doaj.art-15f2f8c5450b4384b0c47c436fd10c78 |
| institution | Directory Open Access Journal |
| issn | 2666-2477 |
| language | English |
| last_indexed | 2024-04-11T00:52:55Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | HGG Advances |
| spelling | doaj.art-15f2f8c5450b4384b0c47c436fd10c782023-01-05T07:03:39ZengElsevierHGG Advances2666-24772023-01-0141100167Unexplained mismatch repair deficiency: Case closedEllis L. Eikenboom0Sarah Moen1Lotte van Leeuwen2Willemina R.R. Geurts-Giele3Carli M.J. Tops4Tjakko J. van Ham5Winand N.M. Dinjens6Hendrikus J. Dubbink7Manon C.W. Spaander8Anja Wagner9Department of Clinical Genetics, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3015 CE Rotterdam, the Netherlands; Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3015 CE Rotterdam, the NetherlandsDepartment of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3015 CE Rotterdam, the NetherlandsDepartment of Clinical Genetics, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3015 CE Rotterdam, the NetherlandsDepartment of Clinical Genetics, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3015 CE Rotterdam, the NetherlandsDepartment of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the NetherlandsDepartment of Clinical Genetics, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3015 CE Rotterdam, the NetherlandsDepartment of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3015 CE Rotterdam, the NetherlandsDepartment of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3015 CE Rotterdam, the NetherlandsDepartment of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3015 CE Rotterdam, the NetherlandsDepartment of Clinical Genetics, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3015 CE Rotterdam, the Netherlands; Corresponding authorSummary: To identify Lynch syndrome (LS) carriers, DNA mismatch repair (MMR) immunohistochemistry (IHC) is performed on colorectal cancers (CRCs). Upon subsequent LS diagnostics, MMR deficiency (MMRd) sometimes remains unexplained (UMMRd). Recently, the importance of complete LS diagnostics to explain UMMRd, involving MMR methylation, germline, and somatic analyses, was stressed. To explore why some MMRd CRCs remain unsolved, we performed a systematic review of the literature and mapped patients with UMMRd diagnosed in our center. A systematic literature search was performed in Ovid Medline, Embase, Web of Science, Cochrane CENTRAL, and Google Scholar for articles on UMMRd CRCs after complete LS diagnostics published until December 15, 2021. Additionally, UMMRd CRCs diagnosed in our center since 1993 were mapped. Of 754 identified articles, 17 were included, covering 74 patients with UMMRd. Five CRCs were microsatellite stable. Upon complete diagnostics, 39 patients had single somatic MMR hits, and six an MMR germline variant of unknown significance (VUS). Ten had somatic pathogenic variants (PVs) in POLD1, MLH3, MSH3, and APC. The remaining 14 patients were the only identifiable cases in the literature without a plausible identified cause of the UMMRd. Of those, nine were suspected to have LS. In our center, complete LS diagnostics in approximately 5,000 CRCs left seven MMRd CRCs unexplained. All had a somatic MMR hit or MMR germline VUS, indicative of a missed second MMR hit. In vitually all patients with UMMRd, complete LS diagnostics suggest MMR gene involvement. Optimizing detection of currently undetectable PVs and VUS interpretation might explain all UMMRd CRCs, considering UMMRd a case closed.http://www.sciencedirect.com/science/article/pii/S2666247722000847Lynch syndromecolorectal cancerunexplained mismatch repair deficiencyUMMRdgenetic testing |
| spellingShingle | Ellis L. Eikenboom Sarah Moen Lotte van Leeuwen Willemina R.R. Geurts-Giele Carli M.J. Tops Tjakko J. van Ham Winand N.M. Dinjens Hendrikus J. Dubbink Manon C.W. Spaander Anja Wagner Unexplained mismatch repair deficiency: Case closed HGG Advances Lynch syndrome colorectal cancer unexplained mismatch repair deficiency UMMRd genetic testing |
| title | Unexplained mismatch repair deficiency: Case closed |
| title_full | Unexplained mismatch repair deficiency: Case closed |
| title_fullStr | Unexplained mismatch repair deficiency: Case closed |
| title_full_unstemmed | Unexplained mismatch repair deficiency: Case closed |
| title_short | Unexplained mismatch repair deficiency: Case closed |
| title_sort | unexplained mismatch repair deficiency case closed |
| topic | Lynch syndrome colorectal cancer unexplained mismatch repair deficiency UMMRd genetic testing |
| url | http://www.sciencedirect.com/science/article/pii/S2666247722000847 |
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