MMR deficiency is common in high-grade endometrioid carcinomas and is associated with an unfavorable outcome.
OBJECTIVE
To assess the prevalence of MMR deficiency (dMMR) in contemporary reclassified high-grade endometrial carcinomas and correlate dMMR with molecular alterations and patient outcome.


METHODS
In this study we evaluated the expression of MLH1, MSH2, PMS2 and MSH6 assessed by two different methods in a series of 102 high-grade endometrial carcinomas. The series was comprised of 64 high-grade endometrioid carcinomas (HGEC), 27 serous (ESC), and 11 clear cell (CCC) carcinomas. Absence of expression in any of the proteins was considered dMMR. dMMR was correlated with clinicopathological parameters using a Chi-square test. Univariate and multivariate survival analysis was performed using Kaplan-Meier and Cox regression analyses.


RESULTS
The overall prevalence of dMMR was 28% (29/102) and was seen in 29/64 (45%) HGEC but not detected in any of the ESC and CCC. Within HGEC, dMMR was associated with loss of ARID1A (p=0.0099), loss of PTEN (p=0.044) and wild-type TP53 (p=0.024) expression. dMMR was associated with increased risk for disease specific death by univariate analysis (p=0.013) among stage III/IV HGEC but not in multivariate analysis (p=0.12).


CONCLUSIONS
Among high-grade endometrial carcinomas, dMMR is restricted to HGEC and could be used as an adjunct diagnostic tool to refute a diagnosis of ESC. The association with dMMR in HGEC with ARID1A/PTEN alterations, TP53 wild type expression pattern and unfavorable outcome suggests that different oncogenetic pathways within HGEC are present.
Department of Gynecologic Oncology, Tom Baker Cancer Centre, Calgary, Alberta, Canada; University of Calgary, Calgary, Alberta, Canada. Electronic address: gsnelson@ucalgary.ca.
Gregg S
GS
Nelson
Aaron
A
Pink
Sandra
S
Lee
Guangming
G
Han
Don
D
Morris
Travis
T
Ogilvie
Máire A
MA
Duggan
Martin
M
Köbel
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D018262:Adenocarcinoma, Clear Cell / Q000235:genetics / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018269:Carcinoma, Endometrioid / Q000235:genetics* / Q000378:metabolism; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000378:metabolism; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D060787:Neoplasm Grading; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D046888:Tissue Array Analysis
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes
High grade endometrioid carcinoma; Microsatellite instability; Mismatch repair deficiency; Outcome