Abstract
To further elucidate the significance of p53 mutation in endometrial carcinoma, we investigated it in endometrioid-type endometrial carcinomas showing intratumoral heterogeneous p53 expression. In addition, we also examined the correlation of p53 mutation and cyclin A expression, because we previously reported a topological correlation between the expression of p53 and cyclin A. The p53 mutation in exons 5–8 in 54 cases of endometrial carcinoma showing immunohistochemical expression of p53 was examined using microdissected tissue DNAs. Of the 54 p53-positive endometrial carcinomas, 23 (43%) had p53 mutation with a tendency in histologically higher grade tumors. Ten of the 54 showed a heterogeneous p53 expression, and in 9 of the 10 cases, p53 mutation was present only in p53-positive sites, which were often found in histologically less differentiated areas with elevated Ki-67 in the same tumor. Cyclin A expression was topologically observed in p53-positive areas; however, it was noted in both tumors with (12/23, 52%) and without (18/31, 58%) p53 mutation. These results suggest that p53 mutation is a late event and plays an important role in the acquisition of malignant potentials in endometrioid-type endometrial adenocarcinomas. Unexpectedly, accumulation of the p53 protein itself may be important in cyclin A overexpression.
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Ambros RA, Ross JS, Kallakury BV, Malfetano J, Kim Y, Hwang J, Breese K, Figge J (1995) p53 gene status in endometrial carcinomas showing diffuse positivity for p53 protein by immunohistochemical analysis. Mod Path 8:441–445
Barakat RR, Grisby PW, Sabbatini P (2000) Corpus: epithelial tumors. In: Hoskins WJ, Perez CA, Young RC (eds) Principles and practice of gynecologic oncology, 3rd edn. Lippincott Williams & Wilkins, Philadelphia, pp 919–959
Berchuck A, Boyd J (1995) Molecular basis of endometrial cancer. Cancer 76:2034–2040
Crompton NE, Saydan N (1999) Control of the cell cycle. J Neuro-Oncol 22:255–259
Dictor M, Ehinger M, Mertens F, Akervall J, Wennerberg J (1999) Abnormal cell cycle regulation in malignancy. Am J Clin Pathol 112:40–52
Hartwell LH, Kasten MB (1994) Cell cycle control and cancer. Science 266:1821–1828
Haupt Y, Maya R, Kazaz A, Oren M (1997) Mdm2 promotes the rapid degradation of p53. Nature 387:296–299
Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253:49–53
Ito K, Sasano H, Matsunaga G, Sato S, Yajima A, Nasim S, Garret CT (1997) Correlations between p21 expression and clinicopathological findings, p53 gene and protein alterations, and survival in patients with endometrial carcinoma. J Pathol 183:318–324
Kihana T, Hamada K, Inoue Y, Yano N, Iketani H, Murao S, Ukita M, Matsuura S (1995) Mutation and allelic loss of the p53 gene in endometrial carcinoma. Incidence and outcome in 92 surgical patients. Cancer 76:72–78
Koga T, Hashimoto S, Sugio K, Yoshino I, Nakagawa K, Yonemitsu Y, Sugimachi K, Sueishi K (2001) Heterogeneous distribution of P53 immunoreactivity in human lung adenocarcinoma correlates with MDM2 protein expression, rather than with P53 gene mutation. Int J Cancer 95:232–239
Kohler MF, Berchuck A, Davidoff AM, Humphrey PA, Dodge RK, Iglehart JD, Soper JT, Clarke-Pearson DL, Bast RC Jr, Marks JR (1992) Overexpression and mutation of p53 in endometrial carcinoma. Cancer Res 52:1622–1627
Koshiyama M, Konishi I, Fujii S (1998) Pathology, hormonal aspects, and molecular genetics of the two types of endometrial cancer. Cancer J 11:277–283
Kubbutat MH, Jones SN, Vousden KH (1997) Regulation of p53 stability by Mdm2. Nature 387:299–303
Ronnett BM, Zaino RJ, Ellenson H, Kurman RJ (2002) Endometrial carcinoma. In: Kurmann RJ (ed) Blaustein's pathology of the female genital tract, 5th edn. Springer, Berlin Heidelberg New York, pp 501–559
Lax SF (2004) Molecular genetic pathways in various types of endometrial carcinoma: from a phenotypical to a molecular-based classification. Virchows Arch 444:213–223
Li SF, Shiozawa T, Nakayama K, Nikaido T, Fujii S (1996) 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
Luciani MG, Hutchins JR, Zheleva D, Hupp TR (2000) The C-terminal regulatory domain of p53 contains a functional docking site for cyclin A. J Mol Biol 300:503–518
Oda T, Tsuda H, Scarpa A, Sakamoto M, Hirohashi S (1992) Mutation pattern of the p53 gene as a diagnostic marker for multiple hepatocellular carcinoma. Cancer Res 52:3674–3678
Schneider J, Rubio MP, Rodriguez-Escudero FJ, Seizinger BR, Castresana JS (1994) Identification of p53 mutations by means of single strand conformation polymorphism analysis in gynaecological tumours: comparison with the results of immunohistochemistry. Eur J Cancer 30:504–508
Sherr CJ (1994) G1 phase progression: cyclin on cue. Cell 79:551–555
Sherr CJ, Roberts JM (1995) Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 9:1149–1163
Shih HC, Shiozawa T, Kato K, Imai T, Miyamoto T, Uchikawa J, Nikaido T, Konishi I (2003) Immunohistochemical expression of cyclins, cyclin-dependent kinases, tumor suppressor gene products, Ki-67 and sex steroid receptors in endometrial carcinoma: positive staining for cyclin A as poor prognostic indicator. Human Pathol 34:471–478
Shiozawa T, Xin L, Nikaido T, Fujii S (1997) Immunohistochemical detection of cyclin A with reference to p53 expression in human endometrial endometrioid carcinoma. Int J Gynecol Pathol 16:348–353
Shiozawa T, Nikaido T, Shimizu M, Zhai Y, Fujii S (1997) Immunohistochemical analysis of the expression of cdk4 and p16INK4 in human endometrioid-type endometrial carcinoma. Cancer 80:2250–2256
Soong R, Knowles S, Williams KE, Hammond IG, Wysocki SJ, Iacopetta BJ (1996) Overexpression of p53 protein is an independent prognostic indicator in human endometrial carcinoma. Br J Cancer 74:562–567
Soong R, Robbins PD, Dix BR, Grieu F, Lim B, Knowles S, Williams KE, Turbett GR, House AK, Iacopetta BJ (1996) Concordance between p53 protein overexpression and gene mutation in a large series of common human carcinomas. Human Pathol 27:1050–1055
Soslow RA, Shen PU, Chung MH, Isacson C (1998) Distinctive p53 and mdm2 immunohistochemical expression profiles suggest different pathogenetic pathways in poorly differentiated endometrial carcinoma. Int J Gynecol Pathol 17:129–134
Yamamoto M, Yoshida M, Ono K, Fujita T, Ohtani-Fujita N, Sakai T, Nikaido T (1994) Effect of tumor suppressors on cell cycle-regulatory genes: RB suppresses p34cdc2 expression and normal p53 suppresses cyclin A expression. Exp Cell Res 210:94–101
Zhai YL, Nikaido T, Orii A, Horiuchi A, Toki T, Fujii S (1999) Frequent occurrence of loss of heterozygosity among tumor suppressor genes in uterine leiomyosarcoma. Gynecol Oncol 75:453–459
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This work was supported in part by a Grant-in-aid for Scientific Research from the Ministry of Education and Culture (No. 06454468 and No. 09671670), Japan.
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Feng, YZ., Shiozawa, T., Horiuchi, A. et al. Intratumoral heterogeneous expression of p53 correlates with p53 mutation, Ki-67, and cyclin A expression in endometrioid-type endometrial adenocarcinomas. Virchows Arch 447, 816–822 (2005). https://doi.org/10.1007/s00428-005-0029-9
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DOI: https://doi.org/10.1007/s00428-005-0029-9