OBJECTIVE: Lynch syndrome (LS) is a hereditary syndrome that predisposes to multiple malignancies including endometrial cancer (EC). We aimed to evaluate a diagnostic strategy for LS based on routine analysis of microsatellite instability (MSI) and immunohistochemical (IHC) staining for mismatch repair (MMR) proteins in tumour tissue of all newly diagnosed EC patients ≤ 70 years. METHODS: Consecutive EC patients ≤ 70 years were included prospectively in eight Dutch centres. EC specimens were analysed for MSI, IHC of four MMR proteins, MMR gene methylation status and BRAF-mutations. tumours were classified as; 1) likely to be caused by LS, 2) sporadic MSI-H, or 3) microsatellite stable (MSS). RESULTS: Tumour specimens of 179 patients (median age 61 years, IQR 57-66) were analysed. In our study 92% of included patients were over 50 years of age. Eleven EC patients were found likely to have LS (6%; 95% CI 3-11%), including 1 patient suspected of an MLH1, 2 of an MSH2, 6 of an MSH6 and 2 of a PMS2 gene defect. Germline mutation analyses revealed 7 MMR gene germline mutations. Ten patients likely to have LS (92%) were older than 50 years. In addition, 31 sporadic MSI-H tumours with MLH1 promoter hypermethylation (17%; 95% CI 13-24%) were identified. CONCLUSIONS: Molecular screening for LS in patients with EC diagnosed ≤ 70 years, leads to identification of a profile likely to have LS in 6% of cases. New screening guidelines for LS are needed, including recommendations for EC patients older than 50 years of age.
OBJECTIVE:Lynch syndrome (LS) is a hereditary syndrome that predisposes to multiple malignancies including endometrial cancer (EC). We aimed to evaluate a diagnostic strategy for LS based on routine analysis of microsatellite instability (MSI) and immunohistochemical (IHC) staining for mismatch repair (MMR) proteins in tumour tissue of all newly diagnosed EC patients ≤ 70 years. METHODS: Consecutive EC patients ≤ 70 years were included prospectively in eight Dutch centres. EC specimens were analysed for MSI, IHC of four MMR proteins, MMR gene methylation status and BRAF-mutations. tumours were classified as; 1) likely to be caused by LS, 2) sporadic MSI-H, or 3) microsatellite stable (MSS). RESULTS:Tumour specimens of 179 patients (median age 61 years, IQR 57-66) were analysed. In our study 92% of included patients were over 50 years of age. Eleven EC patients were found likely to have LS (6%; 95% CI 3-11%), including 1 patient suspected of an MLH1, 2 of an MSH2, 6 of an MSH6 and 2 of a PMS2 gene defect. Germline mutation analyses revealed 7 MMR gene germline mutations. Ten patients likely to have LS (92%) were older than 50 years. In addition, 31 sporadic MSI-H tumours with MLH1 promoter hypermethylation (17%; 95% CI 13-24%) were identified. CONCLUSIONS: Molecular screening for LS in patients with EC diagnosed ≤ 70 years, leads to identification of a profile likely to have LS in 6% of cases. New screening guidelines for LS are needed, including recommendations for EC patients older than 50 years of age.
Authors: Aung Ko Win; Noralane M Lindor; Ingrid Winship; Katherine M Tucker; Daniel D Buchanan; Joanne P Young; Christophe Rosty; Barbara Leggett; Graham G Giles; Jack Goldblatt; Finlay A Macrae; Susan Parry; Matthew F Kalady; John A Baron; Dennis J Ahnen; Loic Le Marchand; Steven Gallinger; Robert W Haile; Polly A Newcomb; John L Hopper; Mark A Jenkins Journal: J Natl Cancer Inst Date: 2013-02-05 Impact factor: 13.506
Authors: Amanda S Bruegl; Bojana Djordjevic; Brittany Batte; Molly Daniels; Bryan Fellman; Diana Urbauer; Rajyalakshmi Luthra; Charlotte Sun; Karen H Lu; Russell R Broaddus Journal: Cancer Prev Res (Phila) Date: 2014-04-25
Authors: Amanda S Bruegl; Kari L Ring; Molly Daniels; Bryan M Fellman; Diana L Urbauer; Russell R Broaddus Journal: Cancer Prev Res (Phila) Date: 2016-12-13
Authors: Kari L Ring; Amanda S Bruegl; Brian A Allen; Eric P Elkin; Nanda Singh; Anne-Renee Hartman; Molly S Daniels; Russell R Broaddus Journal: Mod Pathol Date: 2016-07-22 Impact factor: 7.842