Mismatch Repair (MMR) Protein Deficiency in Endometrioid Endometrial Carcinoma: Is There a Survival Impact?

Abstract

Aim: This study aimed to investigate the prognostic significance of mismatch repair (MMR) protein deficiency in patients with endometrioid endometrial carcinoma (EEC).
Material and Methods: A total of 201 EEC cases diagnosed between 2011 and 2025 were retrospectively analyzed. Immunohistochemistry was performed to assess the expression of MMR proteins (MLH1, PMS2, MSH2, MSH6), classifying tumors as deficient (dMMR) or proficient (pMMR). Survival outcomes were assessed, and the associations of MMR status with overall survival (OS), progression-free survival (PFS), and clinicopathological parameters were investigated, while the impact of specific histopathological features such as histological grade and serosal involvement on OS and PFS was evaluated.
Results: Among the cases, 32.3% (n=65) were classified as dMMR. Although dMMR cases had slightly shorter OS and PFS than pMMR cases, the differences were not statistically significant (p=0.514 and p=0.309, respectively). In multivariate analysis, serosal involvement, high-grade histology, age ≥60 years, and tumor invasion depth ≥2 cm independently predicted poorer OS, while serosal involvement and high-grade histology independently predicted shorter PFS. dMMR showed significant associations with higher histological grade, cervical stromal invasion, serosal involvement, high Ki-67 index, and advanced stage.
Conclusion: While MMR deficiency did not show a significant impact on survival, it was associated with adverse pathological features, suggesting a more aggressive tumor phenotype. These findings support further investigation into the role of MMR status in risk stratification and therapeutic decision-making in EEC.

Keywords

• Endometrioid endometrial carcinoma
• mismatch repair deficiency
• microsatellite instability
• prognosis

References

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-49. doi:10.3322/caac.21660.
2. Cancer Genome Atlas Research Network, Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73. doi:10.1038/nature12113.
3. Wadee R, Grayson W. A potpourri of pathogenetic pathways in endometrial carcinoma with a focus on Lynch syndrome. Ann Diagn Pathol. 2019;39:92-104. doi:10.1016/j.anndiagpath.2019.02.003.
4. Ryan NAJ, Glaire MA, Blake D, Cabrera-Dandy M, Evans DG, Crosbie EJ. The proportion of endometrial cancers associated with Lynch syndrome: a systematic review of the literature and meta-analysis. Genet Med. 2019;21(10):2167-80. doi:10.1038/s41436-019-0536-8.
5. Mills AM, Liou S, Ford JM, Berek JS, Pai RK, Longacre TA. Lynch syndrome screening should be considered for all patients with newly diagnosed endometrial cancer. Am J Surg Pathol. 2014;38(11):1501-9. doi:10.1097/PAS.0000000000000321.
6. Zhao P, Li L, Jiang X, Li Q. Mismatch repair deficiency/microsatellite instability-high as a predictor for anti-PD-1/PD-L1 immunotherapy efficacy. J Hematol Oncol. 2019;12(1):54. doi:10.1186/s13045-019-0738-1.
7. Reijnen C, Küsters-Vandevelde HVN, Prinsen CF, Massuger LFAG, Snijders MPML, Kommoss S, et al. Mismatch repair deficiency as a predictive marker for response to adjuvant radiotherapy in endometrial cancer. Gynecol Oncol. 2019;154(1):124-30. doi:10.1016/j.ygyno.2019.03.097.
8. Ruiz I, Martín-Arruti M, Lopez-Lopez E, Garcia-Orad A. Lack of association between deficient mismatch repair expression and outcome in endometrial carcinomas of the endometrioid type. Gynecol Oncol. 2014;134(1):20-3. doi:10.1016/j.ygyno.2014.04.053.

9. Chaowiwatkun K, Trongwongsa T, Rodpenpear N, Nutthachote P. Comparison of tissue mismatch repair protein deficiency between early- and advanced-stage endometrial cancer. Asian Pac J Cancer Prev. 2023;24(1):345-51. doi:10.31557/APJCP.2023.24.1.345.
10. Angelina YA, Tjokroprawiro BA, Sandhika W. Mismatch repair protein deficiency does not affect disease free survival in type I endometrial carcinoma. Asian Pac J Cancer Prev. 2023;24(9):3229-34. doi:10.31557/APJCP.2023.24.9.3229.
11. Kim SR, Pina A, Albert A, McAlpine JN, Wolber R, Gilks B, et al. Mismatch repair deficiency and prognostic significance in patients with low-risk endometrioid endometrial cancers. Int J Gynecol Cancer. 2020;30(6):783-8. doi:10.1136/ijgc-2019-000910.
12. Kato M, Takano M, Miyamoto M, Sasaki N, Goto T, Tsuda H, et al. DNA mismatch repair-related protein loss as a prognostic factor in endometrial cancers. J Gynecol Oncol. 2015;26(1):40-5. doi:10.3802/jgo.2015.26.1.40.
13. Conlon N, Leitao MM Jr, Abu-Rustum NR, Soslow RA. Grading uterine endometrioid carcinoma: a proposal that binary is best. Am J Surg Pathol. 2014;38(12):1583-7. doi:10.1097/PAS.0000000000000327.
14. Paleari L, Rutigliani M, D’Ecclesiis O, Gandini S, Briata IM, Webber TB, et al. Exploring the prognostic and predictive roles of Ki-67 in endometrial cancer. Int J Transl Med. 2023;3(4):479-86. doi:10.3390/ijtm3040033.
15. Jiang P, Jia M, Hu J, Huang Z, Deng Y, Lai L, et al. Prognostic value of Ki67 in patients with stage 1-2 endometrial cancer: validation of the cut-off value of Ki67 as a predictive factor. Onco Targets Ther. 2020;13:10841-50. doi:10.2147/OTT.S274420.
16. Tangjitgamol S, Kittisiam T, Tanvanich S. Prevalence and prognostic role of mismatch repair gene defect in endometrial cancer patients. Tumour Biol. 2017;39(9):1010428317725834. doi:10.1177/1010428317725834.
17. Hashmi AA, Mudassir G, Hashmi RN, Irfan M, Asif H, Khan EY, et al. Microsatellite instability in endometrial carcinoma by immunohistochemistry, association with clinical and histopathologic parameters. Asian Pac J Cancer Prev. 2019;20(9):2601-6. doi:10.31557/APJCP.2019.20.9.2601.
18. Cohn DE, Frankel WL, Resnick KE, Zanagnolo VL, Copeland LJ, Hampel H, et al. Improved survival with an intact DNA mismatch repair system in endometrial cancer. Obstet Gynecol. 2006;108(5):1208-15. doi:10.1097/01.AOG.0000239097.42987.0c.
19. Fountzilas E, Kotoula V, Pentheroudakis G, Manousou K, Polychronidou G, Vrettou E, et al. Prognostic implications of mismatch repair deficiency in patients with nonmetastatic colorectal and endometrial cancer. ESMO Open. 2019;4(2):e000474. doi:10.1136/esmoopen-2018-000474.
20. Woo YL, Cheah PL, Shahruddin SI, Omar SZ, Arends M. The immunohistochemistry signature of mismatch repair (MMR) proteins in a multiethnic Asian cohort with endometrial carcinoma. Int J Gynecol Pathol. 2014;33(6):554-9. doi:10.1097/PGP.0000000000000099.
21. McMeekin DS, Tritchler DL, Cohn DE, Mutch DG, Lankes HA, Geller MA, et al. Clinicopathologic significance of mismatch repair defects in endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study. J Clin Oncol. 2016;34(25):3062-8. doi:10.1200/JCO.2016.67.8722.
22. Tang Y, Chen Y, Zeng T, Huang K, Zhao J, Zhang P, et al. Immune checkpoint inhibitors or targeted therapy by mismatch repair status in endometrial cancer: a meta-analysis. Future Sci OA. 2025;11(1):2541517. doi:10.1080/20565623.2025.2541517.
23. Picheta N, Piekarz J, Kułak K, Tarkowski R. The efficacy of pembrolizumab immunotherapy in the treatment of endometrial cancer: a systematic review. Int J Mol Sci. 2025;26(18):8789. doi:10.3390/ijms26188789.