Prospective evaluation of molecular screening for Lynch syndrome in patients with endometrial cancer ≤ 70 years.
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.
Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. c.leenen@erasmusmc.nl
Celine H M
CH
Leenen
Margot G F
MG
van Lier
Helena C
HC
van Doorn
Monique E
ME
van Leerdam
Sjarlot G
SG
Kooi
Judith
J
de Waard
Robert F
RF
Hoedemaeker
Ans M W
AM
van den Ouweland
Sanne M
SM
Hulspas
Hendrikus J
HJ
Dubbink
Ernst J
EJ
Kuipers
Anja
A
Wagner
Winand N M
WN
Dinjens
Ewout W
EW
Steyerberg
D000251:Adenosine Triphosphatases / Q000235:genetics; D000368:Aged; D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000378:metabolism; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D053842:Microsatellite Instability; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics
D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes