Nina Pauly1, Thaïs Baert2,3, Rita Schmutzler4, Andreas du Bois2, Stephanie Schneider2, Kerstin Rhiem4, Birgid Schömig-Markiefka5, Janna Siemanowski5, Sebastian Heikaus6, Alexander Traut2, Florian Heitz2,7, Sonia Prader8, Sarah Ehmann2, Philipp Harter2, Beyhan Ataseven2,9. 1. Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte (KEM), Henricistrasse 92, 45136, Essen, Germany. n.pauly@kem-med.com. 2. Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte (KEM), Henricistrasse 92, 45136, Essen, Germany. 3. Department of Oncology, Laboratory of Tumour Immunology and Immunotherapy, ImmunOvar Research Group, KU Leuven, Leuven, Belgium. 4. Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany. 5. Institute of Pathology, University Hospital Cologne, Cologne, Germany. 6. Center for Pathology, Kliniken Essen-Mitte, Essen, Germany. 7. Department for Gynecology With the Center for Oncologic Surgery, Charité Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Berlin, Germany. 8. Department of Gynecology, Hospital Brixen, Brixen, Südtirol, Italy. 9. Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: General MMR assessment is a feasible strategy to improve the detection of Lynch Syndrome in patients with EC.
PURPOSE: 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. METHODS: 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. RESULTS: 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 deficientpatients 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. CONCLUSION: General MMR assessment is a feasible strategy to improve the detection of Lynch Syndrome in patients with EC.
Entities:
Keywords:
DNA mismatch repair; Endometrial cancer; Lynch syndrome; MLH1 hypermethylation
Authors: Heather Hampel; Wendy Frankel; Jenny Panescu; Janet Lockman; Kaisa Sotamaa; Daniel Fix; Ilene Comeras; Jennifer La Jeunesse; Hidewaki Nakagawa; Judith A Westman; Thomas W Prior; Mark Clendenning; Pamela Penzone; Janet Lombardi; Patti Dunn; David E Cohn; Larry Copeland; Lynne Eaton; Jeffrey Fowler; George Lewandowski; Luis Vaccarello; Jeffrey Bell; Gary Reid; Albert de la Chapelle Journal: Cancer Res Date: 2006-08-01 Impact factor: 12.701
Authors: M Aarnio; R Sankila; E Pukkala; R Salovaara; L A Aaltonen; A de la Chapelle; P Peltomäki; J P Mecklin; H J Järvinen Journal: Int J Cancer Date: 1999-04-12 Impact factor: 7.396
Authors: Karen H Lu; Mai Dinh; Wendy Kohlmann; Patrice Watson; Jane Green; Sapna Syngal; Prathap Bandipalliam; Lee-May Chen; Brian Allen; Peggy Conrad; Jonathan Terdiman; Charlotte Sun; Molly Daniels; Thomas Burke; David M Gershenson; Henry Lynch; Patrick Lynch; Russell R Broaddus Journal: Obstet Gynecol Date: 2005-03 Impact factor: 7.661
Authors: Daniel D Buchanan; Yen Y Tan; Michael D Walsh; Mark Clendenning; Alexander M Metcalf; Kaltin Ferguson; Sven T Arnold; Bryony A Thompson; Felicity A Lose; Michael T Parsons; Rhiannon J Walters; Sally-Ann Pearson; Margaret Cummings; Martin K Oehler; Penelope B Blomfield; Michael A Quinn; Judy A Kirk; Colin J Stewart; Andreas Obermair; Joanne P Young; Penelope M Webb; Amanda B Spurdle Journal: J Clin Oncol Date: 2013-12-09 Impact factor: 44.544
Authors: H F Vasen; G J Offerhaus; F C den Hartog Jager; F H Menko; F M Nagengast; G Griffioen; R B van Hogezand; A P Heintz Journal: Int J Cancer Date: 1990-07-15 Impact factor: 7.396
Authors: Karen H Lu; John O Schorge; Kerry J Rodabaugh; Molly S Daniels; Charlotte C Sun; Pamela T Soliman; Kristin G White; Rajyalakshmi Luthra; David M Gershenson; Russell R Broaddus Journal: J Clin Oncol Date: 2007-10-09 Impact factor: 44.544
Authors: Maran J W Berends; Ying Wu; Rolf H Sijmons; Tineke van der Sluis; Wietske Boersmavan Ek; Marjolijn J L Ligtenberg; Neeltje J W Arts; Klaske A ten Hoor; Jan H Kleibeuker; Elisabeth G E de Vries; Marian J E Mourits; Harry Hollema; Charles H C M Buys; Robert M W Hofstra; Ate G J van der Zee Journal: J Clin Oncol Date: 2003-12-01 Impact factor: 44.544