Prognostic Importance of PTEN, p53, and MDM2 Expressions in Endometrioid and Serous-Type Endometrial Carcinomas

Abstract

Aim: Endometrial carcinomas (ECs) are neoplasms with the highest rate of change in the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. In this study, the relationship among PTEN, MDM2, and p53 protein expression in the PI3K/AKT/mTOR pathway with clinicopathological data in endometrioid endometrial carcinomas (EECs) and serous-type endometrial carcinomas (SECs) was evaluated. Material and Method: A hundred and twenty cases of patients who underwent hysterectomy for EC between 2009 and 2021 were included in the study. Thirty cases of SEC and 90 cases of EEC were evaluated. EEC cases consist of grades 1-3 tumors, and each group includes 30 patients. p53 was examined in two groups as normal/wild type and abnormal/mutant type. PTEN and MDM2 were examined in two groups: positive and negative. The relationship among p53, PTEN, and MDM2 immunohistochemical expression status with histological grade, myometrial invasion, cervical invasion, lymphovascular invasion (LVI), metastatic lymph nodes, presence of tumor in peritoneal fluid, tumor stage, and overall and progression-free survival was evaluated. Results: Loss of PTEN was associated with EEC compared to SEC (p<0.001). PTEN loss is mostly associated with p53 normal/wild type (p=0.038). MDM2 expression was associated with a lower histological grade (p<0.001) and stage (p=0.002). MDM2 expression was inversely associated with lymphovascular invasion (p=0.017), cervical invasion (p=0.040), and peritoneal fluid retention (p=0.018). In most cases showing MDM2 expression, p53 was found to be normal/wild type (p=0.011). p53 mutation was found to be associated with advanced age (p=0.002), SEC (p<0.001), high grade (p<0.001), high risk (p<0.001), advanced stage (p=0.002), adjuvant therapy (p=0.002), and peritoneal fluid involvement (p=0.002) and low overall (p=0.014) and progression-free survival (p=0.050). Conclusion: MDM2 expression was found to be associated with positive prognostic parameters. PTEN loss can be used to distinguish between EEC and SEC. p53 remains a critical determinant of prognosis in ECs.

Keywords

• Endometrial carcinomas
• PTEN
• MDM2
• p53
• immunohistochemistry

Kaynakça

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7-30.
2. Clarke BA, Gilks CB. Endometrial carcinoma: controversies in histopathological assessment of grade and tumour cell type. J Clin Pathol. 2010;63:410-5.
3. Hanley KZ, Birdsong GG, Mosunjac MB. Recent developments in surgical pathology of the uterine corpus. Arch Path Lab. 2017;141:528-41.
4. Santoro A, Angelico G, Travaglino A, et al. New pathological and clinical insights in endometrial cancer in view of the updated ESGO/ESTRO/ESP guidelines. Cancers. 2021;13:2623.
5. Barra F, Evangelisti G, Ferro Desideri L, et al. Investigational PI3K/AKT/mTOR inhibitors in development for endometrial cancer. Expert Opin Investig Drugs. 2019;28:131-42.
6. Xie Y, Naizabekov S, Chen Z, Tokay T. Power of PTEN/AKT: molecular switch between tumor suppressors and oncogenes. Oncol Lett. 2016;12:375-8.
7. Chang CJ, Freeman DJ, Wu H. PTEN regulates Mdm2 expression through the P1 promoter. J Biol Chem. 2004;279:29841-8.
8. Nakanishi A, Kitagishi Y, Ogura Y, Matsuda S. The tumor suppressor PTEN interacts with p53 in hereditary cancer. Int J Oncol. 2014;44:1813-9.

9. Mayo LD, Donner DB. The PTEN, Mdm2, p53 tumor suppressor–oncoprotein network. Trends Biochem Sci. 2002;27:462-7.
10. Mayo LD, Dixon JE, Durden DL, et al. PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. J Biol Chem. 2002;277:5484-9.
11. Jeczen R, Skomra D, Cybulski M, et al. P53/MDM2 Overexpression in metastatic endometrial cancer: correlation with clinicopathological features and patient outcome. Clin Exp Metastasis. 2007;24:503-11.
12. Wang L, Piskorz A, Bosse T, et al. Immunohistochemistry and next-generation sequencing are complementary tests in identifying PTEN abnormality in endometrial carcinoma biopsies. Int J Gynecol Pathol. 2022;41:12-9.
13. Liu L, Yang L, Chang H, et al. CP31398 attenuates endometrial cancer cell invasion, metastasis and resistance to apoptosis by downregulating MDM2 expression. Int J Oncol. 2019;54:942-54.
14. Köbel M, Kang EY. The many uses of p53 immunohistochemistry in gynecological pathology: proceedings of the ISGyP companion society session at the 2020 USCAP annual meeting. Int J Gynecol Pathol. 2021;40:32-40.
15. Djordjevic B, Hennessy BT, Li J, et al. Clinical assessment of PTEN loss in endometrial carcinoma: immunohistochemistry outperforms gene sequencing. Mod Pathol. 2012;25:699-708.
16. Sal V, Demirkiran F, Erenel H, et al. Expression of PTEN and β-catenin and their relationship with clinicopathological and prognostic factors in endometrioid type endometrial cancer. Int J Gynecol Cancer. 2016;26:512-20.
17. Tao Y, Liang B. PTEN mutation: a potential prognostic factor associated with immune infiltration in endometrial carcinoma. Pathol Res Pract. 2020;216:152943.
18. Akiyama-Abe A, Minaguchi T, Nakamura Y, et al. Loss of PTEN expression is an independent predictor of favourable survival in endometrial carcinomas. Br J Cancer. 2013;109:1703-10.
19. Li W, Wang Y, Fang X, et al. Differential expression and clinical significance of DNA methyltransferase 3B (DNMT3B), phosphatase and tensin homolog (PTEN) and human MutL homologs 1 (hMLH1) in endometrial carcinomas. Med Sci Monit. 2017;23:938-47.
20. Stavropoulos A, Varras M, Vasilakaki T, et al. Expression of p53 and PTEN in human primary endometrial carcinomas: Clinicopathological and immunohistochemical analysis and study of their concomitant expression. Oncol Lett. 2019;17:4575-89.
21. Daniilidou K, Frangou-Plemenou M, Grammatikakis J, et al. Prognostic significance and diagnostic value of PTEN and p53 expression in endometrial carcinoma. a retrospective clinicopathological and immunohistochemical study. J BUON. 2013;18:195-201.
22. Soslow RA, Peter U, Shen F, Chung MH. Distinctive p53 and mdm2 immunohistochemical expression profiles suggest different pathogenetic pathways in poorly differentiated endometrial carcinoma. Int J Gynecol Pathol. 1998;17:129-34.
23. Buchynska LG, Nesina IP, Kashuba EV. Different trends of p53, MDM2 and p14 ARF expression patterns in endometrial adenocarcinomas versus hyperplasia. Exp Oncol. 2007;29:287-94.
24. Lax SF, Kendall B, Tashiro H, et al. The frequency of p53, K-ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma: evidence of distinct molecular genetic pathways. Cancer. 2000;88:814-24.
25. Zheng W, Cao P, Zheng, et al. p53 overexpression and bcl-2 persistence in endometrial carcinoma: comparison of papillary serous and endometrioid subtypes. Gynecol Oncol. 1996;61:167-74.
26. Ambros RA, Sheehan CE, Kallakury BV, et al. MDM2 and p53 protein expression in the histologic subtypes of endometrial carcinoma. Mod Pathol. 1996;9:1165-9.
27. Khalifa MA, Mannel RS, Haraway SD, et al. Expression of EGFR, HER-2/neu, P53, and PCNA in endometrioid, serous papillary, and clear cell endometrial adenocarcinomas. Gynecol Oncol. 1994;53:84-92.
28. Lukes AS, Kohler MF, Pieper CF, et al. Multivariable analysis of DNA ploidy, p53, and HER-2/neu as prognostic factors in endometrial cancer. Cancer. 1994;73:2380-5.
29. Hamel NW, Sebo TJ, Wilson TO, et al. Prognostic value of p53 and proliferating cell nuclear antigen expression in endometrial carcinoma. Gynecol Oncol. 1996;62:192-8.
30. Kohlberger P, Gitsch G, Loeschet A, et al. p53 protein overexpression in early stage endometrial cancer. Gynecol Oncol. 1996;62:213-7.
31. Ozalp S, Yalcin OT, Tanir HM, et al. p53 overexpression as a prognostic indicator in endometrial carcinoma. Eur J Gynaecol Oncol. 2003;24:275-8.
32. Osmanağaoğlu MA, Kadioğlu S, Osmanağaoğlu S, et al. The relationship between mutant p53 gene, DNA contents and conventional clinicopathological prognostic variables in cases with endometrial carcinoma. Eur J Gynaecol Oncol. 2005;26:64-70.
33. Athanassiadou P, Athanassiades P, Grapsaet D, et al. The prognostic value of PTEN, p53, and beta-catenin in endometrial carcinoma: a prospective immunocytochemical study. Int J Gynecol Cancer. 2007;17:697-704.
34. Kohler MF, Carney P, Dodge R, et al. p53 overexpression in advanced-stage endometrial adenocarcinoma. Am J Obstet Gynecol. 1996;175:1246-52.
35. Jeon YT, Kang S, Kang DH, et al. Cyclooxygenase-2 and p53 expressions in endometrial cancer. Cancer Epidemiol Biomarkers Prev. 2004;13:1538-42.