Current guidelines for Lynch syndrome detection in endometrial cancer (EC) patients rely either on risk evaluation, based on personal/family history, or detection of mismatch repair (MMR) deficiency on tumor tissue. We present a combined screening algorithm for Lynch syndrome.
In this study, 213 consecutive patients treated for EC at Kliniken Essen-Mitte between 2014 and 2018 were included. Personal/family history was evaluated by the Amsterdam II, revised Bethesda/German-DKG criteria and prediction model PREMM5. MMR testing was performed by immunohistochemistry (IHC) and/or polymerase chain reaction (PCR) based microsatellite analysis on tumor tissue. MLH1 promoter methylation analysis was performed in case of MLH1 loss or microsatellite instability.
Based on personal/family history 2/213 (Amsterdam II), 31/213 (revised Bethesda/German-DKG) and 149/213 (PREMM5) patients were identified as at risk for Lynch syndrome. MMR analysis was performed by IHC in 51.2%, by PCR in 32.4%, and in 16.4% of patients both methods were used. MMR deficiency was detected in 20.6% (44/213). Methylation analysis was performed in 27 patients of whom, 22 (81.4%) showed MLH1 promoter hypermethylation. Only 9% of MMR deficient patients were identified as at risk for Lynch syndrome by the revised Bethesda/German-DKG criteria. A pathogenic germline mutation was discovered in 3 out of 20 patients that underwent genetic testing. None of these patients were younger than 50 years or had a family history of Lynch syndrome-associated malignancies.
General MMR assessment is a feasible strategy to improve the detection of Lynch Syndrome in patients with EC.
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Conflict of interest
NP: none. AdB: reports personal fees from Roche, Astra Zeneca, Tesaro, Clovis, Pfizer, Genmab, Pharmar, Biocad, and MSD, outside the submitted work. PH: reports grants and personal fees from Astra Zeneca, Roche, Tesaro, and Public funding (ASCO, DKH, DFG), personal fees from Sotio, Stryker, Zai Lab, MSD, Clovis, and Immunogen, grants from GSK, Boehringer Ingelheim, Medac, and Genmab, outside the submitted work. SP: reports non-financial support from Tesaro, outside the submitted work. RS: reports personal fees from Astra Zeneca, Tesaro, Clovis, outside the submitted work. KR: reports personal fees from Astra Zeneca, Tesaro, Roche, non-financial support from Tesaro, outside the submitted work. BSM: none. JS: none. SH: none.FH: reports personal fees from Roche, AstraZeneca, and Clovis, personal fees and non-financial support from PharmaMar and Tesaro, outside the submitted work. StS: reports personal fees from Astra Zeneca, Tesaro outside the submitted work. TB: reports personal fees from GSK/Tesaro, grants from Amgen and non-financial support from Roche and Amgen outside of the submitted work. AT: reports no financial support outside the submitted work. SE: reports non-financial support from Tesaro, outside the submitted work. BA: reports personal fees and non-financial support from Roche and Tesaro, personal fees from Amgen, AstraZeneca, Clovis and Celgene, non-financial support from PharmaMar, outside the submitted work.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors. The Ethikkommission Ärztekammer Nordrhein stated that retrospective analyses and the publication of fully anonymised data are coverd by their statute (approval 51-2017).Independently, all analyses were carried out in accordance with the provisions of the German Genetic Diagnostics Act after extensive counsleling and written consent of the affected person.
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Supplementary file1 Figure 1: Molecular characteristic / mismatch repair result based on test method; MMR mismatch repair status; N number of patients; IHC immunohistochemistry; MS microsatellite; PCR polymerase chain reaction (PPTX 41 KB) (PPTX 41 KB)
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Pauly, N., Baert, T., Schmutzler, R. et al. Modern day screening for Lynch syndrome in endometrial cancer: the KEM experience. Arch Gynecol Obstet 304, 975–984 (2021). https://doi.org/10.1007/s00404-021-06006-w
- Endometrial cancer
- DNA mismatch repair
- MLH1 hypermethylation
- Lynch syndrome