Expression of p53 and PTEN in human primary endometrial carcinomas: Clinicopathological and immunohistochemical analysis and study of their concomitant expression

Stavropoulos,Aggelis; Varras,Michail; Vasilakaki,Thivi; Varra,Viktoria‑Konstantina; Tsavari,Aikaterini; Varra,Fani‑Niki; Nonni,Aphrodite; Kavantzas,Nikolaos; Lazaris,Andreas  C.

doi:10.3892/ol.2019.10093

Expression of p53 and PTEN in human primary endometrial carcinomas: Clinicopathological and immunohistochemical analysis and study of their concomitant expression

Authors:
- Aggelis Stavropoulos
- Michail Varras
- Thivi Vasilakaki
- Viktoria‑Konstantina Varra
- Aikaterini Tsavari
- Fani‑Niki Varra
- Aphrodite Nonni
- Nikolaos Kavantzas
- Andreas C. Lazaris
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Affiliations: Fourth Obstetrics and Gynecology Department, ‘Elena Venizelou’ General Hospital, Athens 11521, Greece, Fifth Obstetrics and Gynecology Department, ‘Elena Venizelou’ General Hospital, Athens 11521, Greece, Pathology Department, ‘Tzaneio’ General Hospital, Piraeus 18536, Greece, Pharmacy Department, University of Patras, Patra 26504, Greece, Pharmacy Department, Frederick University, Nicosia 1036, Republic of Cyprus, First Pathology Department, Medical School, National Kapodistrian University, Athens 11527, Greece
Published online on: March 1, 2019 https://doi.org/10.3892/ol.2019.10093
Pages: 4575-4589
Copyright: © Stavropoulos et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Endometrial carcinoma is a common malignancy of the female genital tract. Alterations in the expression levels of various oncogenes and tumor suppressor genes serve important roles in the carcinogenesis and biological behavior of endometrial carcinoma. The aim of the present study was to evaluate the combination and individual expression of p53 and phosphatase and tensin homolog (PTEN) protein in human endometrial carcinoma. In addition, the correlation of these proteins with clinicopathological parameters was also assessed. Retrospective immunohistochemical analysis of the expression of p53 and PTEN tumor suppressor proteins was conducted in 99 women with endometrial carcinoma. The overall rate of p53 and PTEN positivity was 89 and 77%, respectively, according to the sum of stain intensity and scores of immunopositive cells. The sum of p53 positivity correlated strongly with PTEN expression (ρ=0.256; P=0.044). The concomitant sum of p53 and PTEN expression was identified in 45% of patients with endometrial adenocarcinoma. Notably, the sum of the immunohistochemical expression of p53 was significantly correlated with patient age (P=0.037), histologic type (P=0.008), histologic grade (P=0.002) and fallopian and/or ovarian invasion (P=0.014). Furthermore, PTEN expression was associated with myometrial invasion (ρ=‑0.377; P=0.002) and clinical stage (P=0.019). In addition, concomitant p53 and PTEN expression was correlated with patient age (P=0.008) and histologic differentiation (P=0.028). The findings indicated a correlation between the expression of p53 and PTEN in endometrial adenocarcinoma, which suggested an intrinsic association between expression levels of these tumor suppressor genes. The study also suggested that concomitant p53 and PTEN expression contributed in characterizing the tumor behavior of endometrial carcinoma. Taken together, the present study suggested the combined expression of p53 and PTEN in the development of high‑grade endometrial carcinoma in older patients. In addition, the findings indicated activation of different molecular pathways in the tumor progression between low‑grade and high‑grade endometrial carcinomas.

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1	Liu FS: Molecular carcinogenesis of endometrial cancer. Taiwan J Obstet Gynecol. 46:26–32. 2007. View Article : Google Scholar : PubMed/NCBI
2	Sasnauskienė A, Jonušienė V, Krikštaponienė A, Butkytė S, Dabkevičienė D, Kanopienė D, Kazbarienė B and Didžiapetrienė J: NOTCH1, NOTCH3, NOTCH4, and JAG2 protein levels in human endometrial cancer. Medicina (Kaunas). 50:14–18. 2014. View Article : Google Scholar : PubMed/NCBI
3	Elbasateeny SS, Salem AA, Abdelsalam WA and Salem R: Immunohistochemical expression of cancer stem cell related markers CD44 and CD133 in endometrial cancer. Pathol Res Pract. 212:10–16. 2016. View Article : Google Scholar : PubMed/NCBI
4	Li Y, Zhang X, Ge J, Liu X, Xu S, Zhu Z, Fang G, Liu J, Zhang H and Sun X: Can Nup88 expression be associated with atypical endometrial hyperplasia and endometrial cancer? A preliminary study. Pathol Res Pract. 212:274–278. 2016. View Article : Google Scholar : PubMed/NCBI
5	Agopianz M, Forgez P, Casse JM, Lacomme S, Charra-Brunaud C, Clerc-Urmès I, Morel O, Bonnet C, Guéant JL, Vignaud JM, et al: Expression of neurotensin receptor 1 in endometrial adenocarcinoma is correlated with histological grade and clinical outcome. Virchows Arch. 471:521–530. 2017. View Article : Google Scholar : PubMed/NCBI
6	Khabaz MN, Abdelrahman AS, Butt NS, Al-Maghrabi B and Al-Maghrabi J: Cyclin D1 is significantly associated with stage of tumor and predicts poor survival in endometrial carcinoma patients. Ann Diagn Pathol. 30:47–51. 2017. View Article : Google Scholar : PubMed/NCBI
7	Mittal P, Klingler-Hoffmann M, Arentz G, Winderbaum L, Kaur G, Anderson L, Scurry J, Leung Y, Stewart CJ, Carter J, et al: Annexin A2 and alpha actinin 4 expression correlates with metastatic potential of primary endometrial cancer. Biochim Biophys Acta Proteins Proteom. 1865:846–857. 2017. View Article : Google Scholar : PubMed/NCBI
8	Qiu M, Bao W, Wang J, Yang T, He X, Liao Y and Wan X: FOXA1 promotes tumor cell proliferation through AR involving the Notch pathway in endometrial cancer. BMC Cancer. 14:782014. View Article : Google Scholar : PubMed/NCBI
9	Gu X, Liu Q, Yang N, Shen JF, Zhang XG, Cao F and Ding HZ: Clinicopathological significance of increased ZIC1 expression in human endometrial cancer. J Huazhong Univ Sci Technolog Med Sci. 35:898–903. 2015. View Article : Google Scholar : PubMed/NCBI
10	Bansal N, Yendluri V and Wenham RM: The molecular biology of endometrial cancers and the implications for pathogenesis, classification, and targeted therapies. Cancer Control. 16:8–13. 2009. View Article : Google Scholar : PubMed/NCBI
11	Dohi S, Ohno S, Ohno Y, Kyo S, Soma G, Sugiyama H and Inoue M: WT1 expression correlates with angiogenesis in endometrial cancer tissue. Anticancer Res. 30:3187–3192. 2010.PubMed/NCBI
12	Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP and Mak TW: Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 95:29–39. 1998. View Article : Google Scholar : PubMed/NCBI
13	Scully MM, Palacios-Helgeson LK, Wah LS and Jackson TA: Rapid estrogen signaling negatively regulates PTEN activity through phosphorylation in endometrial cancer cells. Horm Cancer. 5:218–231. 2014. View Article : Google Scholar : PubMed/NCBI
14	Erkanli S, Kayaselcuk F, Kuscu E, Bagis T, Bolat F, Haberal A and Demirhan B: Expression of survivin, PTEN and p27 in normal, hyperplastic, and carcinomatous endometrium. Int J Gynecol Cancer. 16:1412–1418. 2006. View Article : Google Scholar : PubMed/NCBI
15	Konopka B, Paszko Z, Janiec-Jankowska A and Goluda M: Assessment of the quality and frequency of mutations occurrence in PTEN gene in endometrial carcinomas and hyperplasias. Cancer Lett. 178:43–51. 2002. View Article : Google Scholar : PubMed/NCBI
16	Kimura F, Watanabe J, Hata H, Fujisawa T, Kamata Y, Nishimura Y, Jobo T and Kuramoto H: PTEN immunohistochemical expression is suppressed in G1 endometrioid adenocarcinoma of the uterine corpus. J Cancer Res Clin Oncol. 130:161–168. 2004. View Article : Google Scholar : PubMed/NCBI
17	Machwinnie N and Monaghan H: The use of P53, PTEN, and C-erbB-2 to differentiate uterine serous papillary carcinoma from endometrioid endometrial carcinoma. Int J Gynecol Cancer. 14:938–946. 2004. View Article : Google Scholar : PubMed/NCBI
18	Kapucuoglu N, Aktepe F, Kaya H, Bircan S, Karahan N and Ciriş M: Immunohistochemical expression of PTEN in normal, hyperplastic and malignant endometrium and its correlation with hormone receptors, bcl-2, bax, and apoptotic index. Pathol Res Pract. 203:153–162. 2007. View Article : Google Scholar : PubMed/NCBI
19	Kanamori Y, Kigawa J, Itamochi H, Sultana H, Suzuki M, Ohwada M, Kamura T, Sugiyama T, Kikuchi Y, Kita T, et al: PTEN expression is associated with prognosis for patients with advanced endometrial carcinoma undergoing postoperative chemotherapy. Int J Cancer. 100:686–689. 2002. View Article : Google Scholar : PubMed/NCBI
20	Mayo LD, Dixon JE, Durden DL, Tonks NK and Donner DB: PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. J Biol Chem. 277:5484–5489. 2002. View Article : Google Scholar : PubMed/NCBI
21	Garg K, Broaddus RR, Soslow RA, Urbauer DL, Levine DA and Djordjevic B: Pathologic scoring of PTEN immunohistochemistry in endometrial carcinoma is highly reproducible. Int J Gynecol Pathol. 31:48–56. 2012. View Article : Google Scholar : PubMed/NCBI
22	Jeczen R, Skomra D, Cybulski M, Scheider-Stock R, Szewczuk W, Roessner A, Rechberger T and Semczuk A: P53/MDM2 overexpression in metastatic endometrial cancer: correlation with clinicopathological features and patient outcome. Clin Exp Metastasis. 24:503–511. 2007. View Article : Google Scholar : PubMed/NCBI
23	Pallares J, Bussaglia E, Martínez-Guitarte JL, Dolcet X, Llobet D, Rue M, Sanchez-Verde L, Palacios J, Prat J and Matias-Guiu X: Immunohistochemical analysis of PTEN in endometrial carcinoma: A tissue microarray study with a comparison of four commercial antibodies in correlation with molecular abnormalities. Mod Pathol. 18:719–727. 2005. View Article : Google Scholar : PubMed/NCBI
24	Westin SN, Ju Z, Broaddus RR, Krakstad C, Li J, Pal N, Lu KH, Coleman RL, Hennessy BT, Klempner SJ, et al: PTEN loss is a context-dependent outcome determinant in obese and non-obese endometrioid endometrial cancer patients. Mol Oncol. 9:1694–1703. 2015. View Article : Google Scholar : PubMed/NCBI
25	Chen J, Li S, Yang Z, Lu G and Hu H: Correlation between NDRG1 and PTEN expression in endometrial carcinoma. Cancer Sci. 99:706–710. 2008. View Article : Google Scholar : PubMed/NCBI
26	Lacey JV Jr, Mutter GL, Ronnett BM, Ioffe OB, Duggan MA, Rush BB, Glass AG, Richesson DA, Chatterjee N, Langholz B and Sherman ME: PTEN expression in endometrial biopsies as a marker of progression to endometrial carcinoma. Cancer Res. 68:6014–6020. 2008. View Article : Google Scholar : PubMed/NCBI
27	Merritt MA and Cramer DW: Molecular pathogenesis of endometrial and ovarian cancer. Cancer Biomark. 9:287–305. 2010. View Article : Google Scholar : PubMed/NCBI
28	Fadare O and Parksh V: p53 aberrations in low grade endometrioid carcinoma of the endometrium with nodal metastases: Possible insights on pathogenesis discerned from immunohistochemistry. Diagn Pathol. 12:812017. View Article : Google Scholar : PubMed/NCBI
29	Jiang Z, Xu W, Dan G, Liu Y and Xiong J: P53 and murine double minute 2 (MDM2) expression changes and significance in different types of endometrial lesions. Med Sci Monit. 22:4786–4793. 2016. View Article : Google Scholar : PubMed/NCBI
30	Kounelis S, Kapranos N, Kouri E, Coppola D, Papadaki H and Jones MW: Immunohistochemical profile of endometrial adenocarcinoma: A study of 61 cases and review of the literature. Mod Pathol. 13:379–388. 2000. View Article : Google Scholar : PubMed/NCBI
31	Mazurek A, Kuć P, Mazurek-Wadołkowska E and Laudański T: A role of thymidine phosphorylase and P53 tissue protein expression in biology of endometrial cancer. Neoplasma. 55:261–265. 2008.PubMed/NCBI
32	Oda K, Okada J, Timmerman L, Rodriguez-Viciana P, Stokoe D, Shoji K, Taketani Y, Kuramoto H, Knight ZA, Shokat KM and McCormick F: PIK3CA cooperates with other phosphatidylinositol 3′-kinase pathway mutations to effect oncogenic transformation. Cancer Res. 68:8127–8136. 2008. View Article : Google Scholar : PubMed/NCBI
33	Li SF, Shiozawa T, Nakayama K, Nikaido T and Fujii S: Stepwise abnormality of sex steroid hormone receptors, tumor suppressor gene products (p53 and Rb), and cyclin E in uterine endometrioid carcinoma. Cancer. 77:321–329. 1996. View Article : Google Scholar : PubMed/NCBI
34	Ozkara SK and Corakci A: Significantly decreased P27 expression in endometrial carcinoma compared to complex hyperplasia with atypia (correlation with p53 expression). Pathol Oncol Res. 10:89–97. 2004. View Article : Google Scholar : PubMed/NCBI
35	Edmondson RJ, Crosbie EJ, Nickkho-Amiry M, Kaufmann A, Stelloo E, Nijman HW, Leary A, Auguste A, Mileshkin L, Pollock P, et al: Markers of the p53 pathway further refine molecular profiling in high-risk endometrial cancer: A TransPORTEC initiative. Gynecol Oncol. 146:327–333. 2017. View Article : Google Scholar : PubMed/NCBI
36	Suzuki C, Matsumoto T, Sonoue H, Arakawa A, Furugen Y and Kinoshita K: Prognostic significance of the infiltrative pattern invasion in endometrioid adenocarcinoma of the endometrium. Pathol Int. 53:495–500. 2003. View Article : Google Scholar : PubMed/NCBI
37	Ambros RA, Ross JS, Kallakury BV, Malfetano J, Kim Y, Hwang J, Breese K and Figge J: p53 gene status in endometrial carcinomas showing diffuse positivity for p53 protein by immunohistochemical analysis. Mod Pathol. 8:441–445. 1995.PubMed/NCBI
38	Ambros RA, Sheehan CE, Kallakury BV, Ross JS, Malfetano J, Paunovich E and Figge J: MDM2 and p53 protein expression in the histologic subtypes of endometrial carcinoma. Mod Pathol. 9:1165–1169. 1996.PubMed/NCBI
39	Tashiro H, Blazes MS, Wu R, Cho KR, Bose S, Wang SI, Li J, Parsons R and Ellenson LH: Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res. 57:3935–3940. 1997.PubMed/NCBI
40	Sakuragi N, Hirai A, Tada M, Yamada H, Yamamoto R, Fujimoto S and Moriuchi T: Dominant-negative mutation of p53 tumor suppressor gene in endometrial carcinoma. Gynecol Oncol. 83:485–490. 2001. View Article : Google Scholar : PubMed/NCBI
41	Appel ML, Edelweiss MI, Fleck J, Rivero LF, Rivoire WA, Mônego HI and Dos Reis R: P53 and BCL-2 as prognostic markers in endometrial carcinoma. Pathol Oncol Res. 14:23–30. 2008. View Article : Google Scholar : PubMed/NCBI
42	Athanassiadou P, Athanassiades P, Grapsa D, Gonidi M, Athanassiadou AM, Stamati PN and Patsouris E: The prognostic value of PTEN, p53, and beta-catenin in endometrial carcinoma: A prospective immunocytochemical study. Int J Gynecol Cancer. 17:697–704. 2007. View Article : Google Scholar : PubMed/NCBI
43	Ellenson LH: Early molecular changes in endometrial cancer. Int J Gynecol Cancer. 15:399–400. 2005. View Article : Google Scholar
44	Lax SF: Molecular genetic pathways in various types of endometrial carcinoma: From a phenotypical to a molecular-based classification. Virchows Arch. 444:213–223. 2004. View Article : Google Scholar : PubMed/NCBI
45	Darvishian F, Hummer AJ, Thaler HT, Bhargava R, Linkov I, Asher M and Soslow RA: Serous endometrial cancers that mimic endometrioid adenocarcinomas: A clinicopathologic and immunohistochemical study of a group of problematic cases. Am J Surg Pathol. 28:1568–1578. 2004. View Article : Google Scholar : PubMed/NCBI
46	Cancer Genome Atlas Research Network, ; Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, Robertson AG, Pashtan I, Shen R, et al: Integrated genomic characterization of endometrial carcinoma. Nature. 497:67–73. 2013. View Article : Google Scholar : PubMed/NCBI
47	Fadare O and Zheng W: Insights into endometrial serous carcinogenesis and progression. Int J Clin Exp Pathol. 2:411–432. 2009.PubMed/NCBI
48	Fadare O, Gwin K, Desouki MM, Crispens MA, Jones HW III, Khabele D, Liang SX, Zheng W, Mohammed K, Hecht JL and Parkash V: The clinicopathologic significance of p53 and BAF-250a (ARID1A) expression in clear cell carcinoma of the endometrium. Mod Pathol. 26:1101–1110. 2013. View Article : Google Scholar : PubMed/NCBI
49	Ramalingam P, Masand RP, Eucher ED and Malpica A: Undifferentiated carcinoma of the endometrium: An expanded immunohistochemical analysis including PAX-8 and basal-like carcinoma surrogate markers. Int J Gynecol Pathol. 35:410–418. 2016. View Article : Google Scholar : PubMed/NCBI
50	Hoang LN, Lee YS, Karnezis AN, Tessier-Cloutier B, Almandani N, Coatham M, Gilks CB, Soslow RA, Stewart CJ, Köbel M and Lee CH: Immunophenotypic features of dedifferentiated endometrial carcinoma-insights from BRG1/INI1-deficient tumours. Histopathology. 69:560–569. 2016. View Article : Google Scholar : PubMed/NCBI
51	Lopez-Garcia MA and Palacios J: Pathologic and molecular features of uterine carcinosarcomas. Semin Diagn Pathol. 27:274–286. 2010. View Article : Google Scholar : PubMed/NCBI
52	Cherniack AD, Shen H, Walter V, Stewart C, Murray BA, Bowlby R, Hu X, Ling S, Soslow RA, Broaddus RR, et al: Integrated molecular characterization of uterine carcinosarcoma. Cancer Cell. 31:411–423. 2017. View Article : Google Scholar : PubMed/NCBI
53	Alvarez T, Miller E, Duska L and Oliva E: Molecular profile of grade 3 endometrioid endometrial carcinoma: Is it a type I or type II endometrial carcinoma? Am J Surg Pathol. 36:753–761. 2012. View Article : Google Scholar : PubMed/NCBI
54	Sherman ME, Bur ME and Kurman RJ: p53 in endometrial cancer and its putative precursors: Evidence for diverse pathways of tumorigenesis. Hum Pathol. 26:1268–1274. 1995. View Article : Google Scholar : PubMed/NCBI
55	Moll MU, Chalas E, Auguste M, Meaney D and Chumas J: Uterine papillary serous carcinoma evolves via a p53-driven pathway. Hum Pathol. 27:1295–1300. 1996. View Article : Google Scholar : PubMed/NCBI
56	Zheng W, Cao P, Zheng M, Kramer EE and Godwin TA: p53 overexpression and bcl-2 persistence in endometrial carcinoma: Comparison of papillary serous and endometrioid subtypes. Gynecol Oncol. 61:167–174. 1996. View Article : Google Scholar : PubMed/NCBI
57	Bur ME, Perlman C, Edelmann BS, Fey E and Rose PG: p53 expression in neoplasms of the uterine corpus. Am J Clin Pathol. 98:81–87. 1992. View Article : Google Scholar : PubMed/NCBI
58	Inoue M, Fujita M, Enomoto T, Morimoto H, Monden T, Shinano T and Tanizawa O: Immunohistochemical analysis of p53 in gynecologic tumors. Am J Clin Pathol. 102:665–670. 1994. View Article : Google Scholar : PubMed/NCBI
59	Prat J, Oliva E, Lerma E, Vaquero M and Matías-Guiu X: Uterine papillary serous adenocarcinoma. A 10-case study of p53 and c-erbB-2 expression and DNA content. Cancer. 74:1778–1783. 1994. View Article : Google Scholar : PubMed/NCBI
60	Reinartz JS, George E, Lindgren BR and Niehans GA: Expression of p53, transforming growth factor alpha, epidermal growth factor receptor, and c-erbB-2 in endometrial carcinoma and correlation with survival and known predictors of survival. Hum Pathol. 25:1075–1083. 1994. View Article : Google Scholar : PubMed/NCBI
61	Khalifa MA, Mannel RS, Haraway SD, Walker J and Min KW: Expression of EGFR, HER-2/neu, P53, and PCNA in endometrioid, serous papillary, and clear cell endometrial adenocarcinomas. Gynecol Oncol. 53:84–92. 1994. View Article : Google Scholar : PubMed/NCBI
62	King SA, Adas AA, LiVolsi VA, Takahashi H, Behbakht K, McGovern P, Benjamin I, Rubin SC and Boyd J: Expression and mutation analysis of the p53 gene in uterine papillary serous carcinoma. Cancer. 75:2700–2705. 1995. View Article : Google Scholar : PubMed/NCBI
63	Tashiro H, Isacson C, Levine R, Kurman RJ, Cho KR and Hedrick L: p53 gene mutations are common in uterine serous carcinoma and occur early in their pathogenesis. Am J Pathol. 150:177–185. 1997.PubMed/NCBI
64	Soslow RA, Shen PU, Chung MH and Isacson C: Distinctive p53 and mdm2 immunohistochemical expression profiles suggest different pathogenetic pathways in poorly differentiated endometrial carcinoma. Int J Gynecol Pathol. 17:129–134. 1998. View Article : Google Scholar : PubMed/NCBI
65	Garcia-Dios DA, Lambrechts D, Coenegrachts L, Vandenput I, Capoen A, Webb PM, Ferguson K; ANECS, Akslen LA, Claes B, et al: High-throughput interrogation of PIK3CA, PTEN, KRAS, FBXW7 and TP53 mutations in primary endometrial carcinoma. Gynecol Oncol. 128:327–334. 2013. View Article : Google Scholar : PubMed/NCBI
66	Seeger A, Kölbl H, Petry IB, Gebhard S, Battista MJ, Böhm D and Steiner E: p53 is correlated with low BMI negative progesterone receptor status and recurring disease in patients with endometrial cancer. Gynecol Oncol. 125:200–207. 2012. View Article : Google Scholar : PubMed/NCBI
67	Urabe R, Hachisuga T, Kurita T, Kagami S, Kawagoe T, Matsuura Y and Shimajiri S: Prognostic significance of overexpression of p53 in uterine endometrioid adenocarcinomas with an analysis of nuclear grade. J Obstet Gynaecol Res. 40:812–819. 2014. View Article : Google Scholar : PubMed/NCBI
68	Lee EJ, Kim TJ, Kim DS, Choi CH, Lee JW, Lee JH, Bae DS and Kim BG: p53 alteration independently predicts poor outcomes in patients with endometrial cancer: A clinicopathologic study of 131 cases and literature review. Gynecol Oncol. 116:533–538. 2010. View Article : Google Scholar : PubMed/NCBI
69	Kurnit KC, Kim GN, Fellman BM, Urbauer DL, Mills GB, Zhang W and Broaddus RR: CTNNB1 (beta-catenin) mutation identifies low grade, early stage endometrial cancer patients at increased risk of recurrence. Mod Pathol. 30:1032–1041. 2017. View Article : Google Scholar : PubMed/NCBI
70	Daniilidou K, Frangou-Plemenou M, Grammatikakis J, Grigoriou O, Vitoratos N and Kondi-Pafiti A: Prognostic significance and diagnostic value of PTEN and p53 expression in endometrial carcinoma. A retrospective clinicopathological and immunohistochemical study. J BUON. 18:195–201. 2013.PubMed/NCBI
71	Ohkouchi T, Sakuragi N, Watari H, Nomura E, Todo Y, Yamada H and Fujimoto S: Prognostic significance of Bcl-2, p53 overexpression, and lymph node metastasis in surgically staged endometrial carcinoma. Am J Obstet Gynecol. 187:353–359. 2002. View Article : Google Scholar : PubMed/NCBI
72	Erdem O, Erdem M, Dursun A, Akyol G and Erdem A: Angiogenesis, p53, and bcl-2 expression as prognostic indicators in endometrial cancer: comparison with traditional clinicopathologic variables. Int J Gynecol Pathol. 22:254–260. 2003. View Article : Google Scholar : PubMed/NCBI
73	Hirschowitz L, Ganesan R and McCluggage WG: WT1, p53 and hormone receptor expression in uterine serous carcinoma. Histopathology. 55:478–482. 2009. View Article : Google Scholar : PubMed/NCBI
74	Mariani A, Sebo TJ, Webb MJ, Riehle D, Katzmann JA, Keeney GL, Roche PC, Lesnick TG and Podratz KC: Molecular and histopathologic predictors of distant failure in endometrial cancer. Cancer Detect Prev. 27:434–441. 2003. View Article : Google Scholar : PubMed/NCBI
75	Ito K, Watanabe K, Nasim S, Sasano H, Sato S, Yajima A, Silverberg SG and Garrett CT: Prognostic significance of p53 overexpression in endometrial cancer. Cancer Res. 54:4667–4670. 1994.PubMed/NCBI
76	Alkushi A, Lim P, Coldman A, Huntsman D, Miller D and Gilks CB: Interpretation of p53 immunoreactivity in endometrial carcinoma: Establishing a clinically relevant cut-off level. Int J Gynecol Pathol. 23:129–137. 2004. View Article : Google Scholar : PubMed/NCBI
77	Hamel NW, Sebo TJ, Wilson TO, Keeney GL, Roche PC, Suman VJ, Hu TC and Podratz KC: Prognostic value of p53 and proliferating cell nuclear antigen expression in endometrial carcinoma. Gynecol Oncol. 62:192–198. 1996. View Article : Google Scholar : PubMed/NCBI
78	Bancher-Todesca D, Gitsch G, Williams KE, Kohlberger P, Neunteufel W, Obermair A, Heinze G, Breitenecker G and Hacker NF: p53 protein overexpression: A strong prognostic factor in uterine papillary serous carcinoma. Gynecol Oncol. 71:59–63. 1998. View Article : Google Scholar : PubMed/NCBI
79	Geisler JP, Geisler HE, Wiemann MC, Zhou Z, Miller GA and Crabtree W: p53 expression as a prognostic indicator of 5-year survival in endometrial cancer. Gynecol Oncol. 74:468–471. 1999. View Article : Google Scholar : PubMed/NCBI
80	Oreskovic S, Babic D, Kalafatic D, Barisic D and Beketic-Oreskovic L: A significance of immunohistochemical determination of steroid receptors, cell proliferation factor Ki-67 and protein p53 in endometrial carcinoma. Gynecol Oncol. 93:34–40. 2004. View Article : Google Scholar : PubMed/NCBI
81	Osmanağaoğlu MA, Kadioğlu S, Osmanağaoğlu S, Bozkaya H, Reis A and Tekelioğlu Y: The relationship between mutant p53 gene, DNA contents and conventional clinicopathological prognostic variables in cases with endometrial carcinoma. Eur J Gynaecol Oncol. 26:64–70. 2005.PubMed/NCBI
82	Soong R, Knowles S, Williams KE, Hammond IG, Wysocki SJ and Iacopetta BJ: Overexpression of p53 protein is an independent prognostic indicator in human endometrial carcinoma. Br J Cancer. 74:562–567. 1996. View Article : Google Scholar : PubMed/NCBI
83	Jeon YT, Kang S, Kang DH, Yoo KY, Park IA, Bang YJ, Kim JW, Park NH, Kang SB, Lee HP and Song YS: Cyclooxygenase-2 and p53 expression in endometrial cancer. Cancer Epidemiol Biomarkers Prev. 13:1538–1542. 2004.PubMed/NCBI
84	Risinger JI, Hayes K, Maxwell GL, Carney ME, Dodge RK, Barrett JC and Berchuck A: PTEN Mutation in endometrial cancers is associated with favorable clinical and pathologic characteristics. Clin Cancer Res. 4:3005–3010. 1998.PubMed/NCBI
85	Maxwell GL, Risinger JI, Hayes KA, Alvarez AA, Dodge RK, Barrett JC and Berchuck A: Racial disparity in the frequency of PTEN mutations, but not microsatellite instability, in advanced endometrial cancers. Clin Cancer Res. 6:2999–3005. 2000.PubMed/NCBI
86	Levine RL, Cargile CB, Blazes MS, van Rees B, Kurman RJ and Ellenson LH: PTEN mutations and microsatellite instability in complex atypical hyperplasia, a precursor lesion to uterine endometrioid carcinoma. Cancer Res. 58:3254–3258. 1998.PubMed/NCBI
87	Yoshinaga K, Sasano H, Furukawa T, Yamakawa H, Yuki M, Sato S, Yajima A and Horii A: The PTEN, BAX, and IGFIIR genes are mutated in endometrial atypical hyperplasia. Jpn J Cancer Res. 89:985–990. 1998. View Article : Google Scholar : PubMed/NCBI
88	Mutter GL, Lin MC, Fitzgerald JT, Kum JB, Baak JP, Lees JA, Weng LP and Eng C: Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst. 92:924–930. 2000. View Article : Google Scholar : PubMed/NCBI
89	Peiffer SL, Herzog TJ, Tribune DJ, Mutch DG, Gersell DJ and Goodfellow PJ: Allelic loss of sequences from the long arm of chromosome 10 and replication errors in endometrial cancers. Cancer Res. 55:1922–1926. 1995.PubMed/NCBI
90	Nagase S, Sato S, Tezuka F, Wada Y, Yajima A and Horii A: Deletion mapping on chromosome 10q25-q26 in human endometrial cancer. Br J Cancer. 74:1979–1983. 1996. View Article : Google Scholar : PubMed/NCBI
91	Akiyama-Abe A, Minaguchi T, Nakamura Y, Michikami H, Shikama A, Nakao S, Sakurai M, Ochi H, Onuki M, Matsumoto K, et al: Loss of PTEN expression is an independent predictor of favourable survival in endometrial carcinomas. Br J Cancer. 109:1703–1710. 2013. View Article : Google Scholar : PubMed/NCBI
92	Bussaglia E, del Rio E, Matias-Guiu X and Prat J: PTEN mutations in endometrial carcinomas: A molecular and clinicopathologic analysis of 38 cases. Hum Pathol. 31:312–317. 2000. View Article : Google Scholar : PubMed/NCBI
93	Kanamori Y, Kigawa J, Itamochi H, Shimada M, Takahashi M, Kamazawa S, Sato S, Akeshima R and Terakawa N: Correlation between loss of PTEN expression and Akt phosphorylation in endometrial carcinoma. Clin Cancer Res. 7:892–895. 2001.PubMed/NCBI
94	Minaguchi T, Yoshikawa H, Oda K, Ishino T, Yasugi T, Onda T, Nakagawa S, Matsumoto K, Kawana K and Taketani Y: PTEN mutation located only outside exons 5, 6, and 7 is an independent predictor of favorable survival in endometrial carcinomas. Clin Cancer Res. 7:2636–2642. 2001.PubMed/NCBI
95	Dellas A, Jundt G, Sartorius G, Schneider M and Moch H: Combined PTEN and p27kip1 protein expression patterns are associated with obesity and prognosis in endometrial carcinomas. Clin Cancer Res. 15:2456–2462. 2009. View Article : Google Scholar : PubMed/NCBI
96	Mackay HJ, Gallinger S, Tsao MS, McLachlin CM, Tu D, Keiser K, Eisenhauer EA and Oza AM: Prognostic value of microsatellite instability (MSI) and PTEN expression in women with endometrial cancer: Results from studies of the NCIC Clinical Trials Group (NCIC CTG). Eur J Cancer. 46:1365–1373. 2010. View Article : Google Scholar : PubMed/NCBI
97	Terakawa N, Kanomori Y and Yoshida S: Loss of PTEN expression followed by Akt phosphorylation is poor prognostic factor for patients with endometrial cancer. Endocr Relat Cancer. 10:203–208. 2003. View Article : Google Scholar : PubMed/NCBI
98	Salvesen HB, Stefansson I, Kalvenes MB, Das S and Akslen LA: Loss of PTEN expression is associated with metastatic disease in patients with endometrial carcinoma. Cancer. 94:2185–2191. 2002. View Article : Google Scholar : PubMed/NCBI
99	Catasus L, Gallardo A, Cuatrecasas M and Prat J: Concomitant PI3K-AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis. Mod Pathol. 22:522–529. 2009. View Article : Google Scholar : PubMed/NCBI
100	Nout RA, Bosse T, Creutzberg CL, Jürgenliemk-Schulz IM, Jobsen JJ, Lutgens LC, van der Steen-Banasik EM, van Eijk R, Ter Haar NT and Smit VT: Improved risk assessment of endometrial cancer by combined analysis of MSI, PI3K-AKT, Wnt/β-catenin and P53 pathway activation. Gynecol Oncol. 126:466–473. 2012. View Article : Google Scholar : PubMed/NCBI
101	Uegaki K, Kanamori Y, Kigawa J, Kawaguchi W, Kaneko R, Naniwa J, Takahashi M, Shimada M, Oishi T, Itamochi H and Terakawa N: PTEN-positive and phosphorylated-Akt-negative expression is a predictor of survival for patients with advanced endometrial carcinoma. Oncol Rep. 14:389–392. 2005.PubMed/NCBI