Prognostic significance of apoptotic index and bcl-2 and p53 expression in epithelial ovarian carcinoma

Purpose of the study: To determine if bcl-2 and p53 expression, and apoptotic index (AI) were associated with patient outcome in epithelial carcinomas of the ovary (EOC) and therefore useful as prognostic factors to predict survival.

Methods: A total of 50 women with epithelial carcinomas of the ovary were retrospectively analyzed. The archival paraffin-embedded material of of these cases were evaluated for expression of p53 and bcl-2 by immunohistochemical techniques. Apoptotic cells were detected with an in situ hybridisation method.

Results: A total of 33 (66%) of 50 cases showed positive immunoreactivity for the p53 antibody. Twenty-four of the 50 cases showed positive bcl-2 protein expression. Median value for AI was found to be 2.48. No statistically significant association was found between bcl-2 and p53 expression and clinicopathologic features. Univariate survival analysis of AI failed to reveal any effect on prognosis in the study population.

Conclusion: We found neither p53 nor bcl-2 immunoreactivity to be of prognostic significance in patients with EOC. In addition, AI was not found to be an independent prognostic factor.

Apoptosis; Protein p53; Protein bcl-2; Apoptotic index; Ovarian cancer

[1] Kristensen G., Trope C.: "Epithelial ovarian carcinoma". Lancet, 1997, 349, 113.

[2] Stanley J. Korsmeyer.: "Bcl-2 initiates a new category of oncogenes: regulators of cell death". Blood, 1992, 80 (4), 879.

[3] Kerr J. F. R., Winterford C. M., Harmon B. Y.: "Apoptosis: its s1gmficance in cancer and cancer therapy". Cancer, 1994, 73, 2013.

[4] Bellamy C. O. C.: "P53 and apoptosis". Brit. Med. Bull., 1996, 53(3), 522.

[5] White E.: "Life, death, and pursuit of apoptosis". Genes. Dev., 1996, 10, 1.

[6] Herod J. J.,E liopoulos A. G.,W arwick J.,N iedobitek G.,Y oung L. S., Kerr D. J.: "T he prognostic significance of Bcl-2 and p53 expression in ovarian carcinoma". Cancer Res., 1996, 56 (9), 2178.

[7] Livingstone L. R., White A., Sprouse J.: "Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53". Cell, 1992, 70, 923.

[8] Hollstein M., Sidransky D., Vogelstein B., Harris C. C.: "p53 mutations in human cancers". Science, 1991, 253, 49.

[9] Cleary M. L., Smith S. D., Sklar J.: "Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(l4; 18) translocation". Cell, 1986, 47, 19.

[10] Vaux D. L., Cory 5, Adams J. M.: "Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize preB cells". Nature, 1988, 335, 440.

[11] Pezzella F., Tse A. G. D.: "Expression of the bcl-2 oncogene protein is not specific for the 14; 18 chromosomal translocation". Am. J. Pathol., 1990, 137, 225.

[12] Tsujimoto Y.,F inger L. R.,Yu nis J.: "Cloning oft he chromosome brake point of neoplastic B cells with the (14, 18) chromosome translocation". Science, 1989, 226, 1097.

[13] Jiang M. C., Yang-Yen H.F., Lin J. K.: "Differential regulation of p53, c-myc, bcl-2 and bax protein expression during apoptosis induced by widly divergent stimuli in human hepatoblastoma cells". Human Cell,1996, 9 (3), 223.

[14] Hockenbery D., Nunez G., Milliman C., Schreiber R. D., Korsmeyer S. J.: "Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death". Nature, 1990, 348, 334.

[15] Marx D., Binder C., Meden H., Len the T., Ziemek T., Hiddemann T. et al.: "Differential expression of apoptosis associated genes bax and bcl-2 in ovarian cancer". Anticancer Res., 1997, 17, 2233.

[16] Henriksen R., Wilander E., Oberg K.: "Expression and prognostic significance ofBcl-2 in ovarian tumours". Br. J. Cancer, 1995, 72(5), 1324.

[17] Diebold J.,B aretton G.,F elchner M.,M eier W.,D opfer K.,S chmidt M. et al.: "bcl-2 expression, p53 accumulation, and apoptosis in ovarian carcinomas". Am. J. Clin. Pathol., 1996, 105 (3), 341.

[18] Cancer Committee of the International Federation of Gynecology and Obstetrics: Staging Announcement: FIGO Cancer Committee. Gynecol. Oncol., 1986, 25, 383.

[19] Serov S. F., Scully R. E., Sobin L. H.: International Histologic Classification and Staging of Tumors (vol 9) Histologic Typing of Ovarian Tumors. Geneva, Switzerland, World Health Organizalion, 1973.

[20] Henriksen R., Strang P., Wilander E., Backstrom T., Tribukait B., Oberg K.: "p53 expression in epithelial ovarian neoplasms: Relationship to clinical and pathological parameters, Ki-67 expression and flow cytometry". Gynecol. Oncol., 1994, 53, 301.

[21] Soini Y., Paakko P.: "Extent of apoptosis in relation to p53 and bcl-2 expression in germ cell tumors". Hum. Pathol., 1996, 27, 1221.

[22] Anttila M.A., Ji H., Juhola M. T., Saarikoski S. V., Syrjanen K. J.: "The prognostic significance of p53 expression quantitated by computerized image analysis in epithelial ovarian cancer". Int. J. Gynecol. Pathol., 1999, 18 (1), 42.

[23] Wen W. H., Reles A., Runnebaum I. B., Sullivan-Halley J., Bernstein L., Jones L.A. et al.: "p53 mutations and expression in ovarian cancers: correlation with overall survival". Int. J. Gynecol. Pathol., 1999, 18 (1), 29.

[24] Cummings M. C., Winterford C. M., Walker N. I.: "Apoptosis". Am. J. Surgical Pathol., 1997, 21 (1), 88.

[25] Sato S., Kigawa J., Minagawa Y., Okada M., Shimada M., Takahashi M.: "Chemosensitivity and p53-dependent apoptosis in epithelial ovarian carcinoma". Cancer, 1999, 86, 1307.

[26] Reed I. C.: "Bcl-2 and the regulation of programmed cell death". J. Cell. Biol., 1994, 124, 1.

[27] Stewart B. W.: "Mechanisms of apoptosis: integration of genetic, biochemical, and cellular indicators". J. Natl. Cancer Inst., 1994, 86, 1286.

[28] Vogl F. D., Stickeler E., Weyermann M., Kohler T., Grill H. J., Negri G. et al.: "p53 autoantibodies in patients with primary ovarian cancer are associated with higher age, advanced stage and a higher proportion of p53-positive tumor cells". Oncology, 1999, 57 (4), 324.

[29] Milner B. J.,A llan L.A., Eccles D. M.,K itchener H. C.,L eonard R. C., Kelly K. F. et al.: "p53 mutation is a common genetic event in ovarian carcinoma". Cancer Res., 1993, 53 (9), 2128.

[30] OkamotoA .,S ameshima Y.,Y okoyama S.: "Frequent allelic losses and mutations of the p53 gene in human ovarian cancer". Cancer, Res., 1991, 51, 5171.

[31] Kihana T., Tsuda H., Teshima S., Okada S., Matsuura S., Hirohashi S.: "High incidence of p53 gene mutation in human ovarian cancer and its association with nuclear accumulation of p53 protein and tumor DNA aneuploidy". Jpn. J. Cancer Res., 1992, 83 (9), 978.

[32] Marks J. R., Davidoff A. M., Kerns B. J., Humphrey P.A., Pence J. C., Dodge R. K. et al.: "Overexpression and mutation of p53 in epithelial ovarian cancer". Cancer Res., 1991, 51 (11), 2979.

[33] Eccles D. M., Brett L., Lessells A., Gruber L., Lane D., Steel C. M. et al.: "Overexpression of the p53 protein and allele loss at 17pl3 in ovarian carcinoma". Br. J. Cancer, 1992, 65 (1), 40.

[34] Kohler M. F., Kerns B. J., Humphrey P. A., Marks J. R., Bast R. C. Jr., Berchuck A.: "Mutation and overexpression of p53 in earlystage epithelial ovarian cancer". Obstet. Gynecol., 1993, 81, 643.

[35] Kupryjanczyk J., Bell D. A., Yandell D. W., Scully R. E., Thor A. D.: "p53 expression in ovarian borderline tumors and stage I carcinomas". Am. J. Clin. Pathol., 1994, 102 (5), 671.

[36] Bosari S., Viale G., Radaelli U., Bossi P., Bonoldi E., Coggi G.: "p53 accumulation in ovarian carcinomas and its prognostic implications". Hum. Pathol., 1993, 24 (11), 1175.

[37] Livingstone L. R., White A., Sprouse J.: "Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53". Cell, 1992, 70, 923.

[38] Yamaguchi A., Kurosaka Y., F ushida S.: "Expression of p53 protein in colorectal cancer and its relationship to short-term prognosis". Cancer, 1992, 70, 2778.

[39] Chang F., Syrjanen S., Syrjanen K.: "Implications of the p53 tumor suppressor gene in clinical oncology". J. Clin. Oneal., 1995, 13, 1009.

[40] Dowell S. P., Hall P.A.: "The clinical relevance of the p53 tumour suppressor gene". Cytopathology, 1994, 5 (3), 133.

[41] Hartmann L. C., Podratz K. C., Keeney G. L., Kamel N. A., Edmonson J. H., Grill J.P. et al.: "Prognostic significance of p53 immunostaining in epithelial ovarian cancer". J. Clin. Oneal., 1994, 12 (1), 64.

[42] Levesque M. A., Katsaros D., Yu H., Zola P., Sismondi P., Giardina G. et al.: "Mutant p53 protein overexpression is associated with poor outcome in patients with well or moderately differentiated ovarian carcinoma". Cancer, 1995, 75 (6), 1327.

[43] Klemi P. J., Pylkkanen L., Kiilholma P., Kurvinen K., Joensuu H.: "p53 protein detected by immunohistochemistry as a prognostic factor in patients with epithelial ovarian carcinoma". Cancer, 1995, 76 (7), 1201.

[44] Niwa K., ltoh M., Murase T., Itoh N., Mori H., Tamaya T.: "Alteration of p53 gene in ovarian carcinoma: clinicopathological correlation and prognostic significance". Br. J. Cancer, 1994, 70, 1191.

[45] Sheridan E., Silcocks P., Smith J., Hancock B. W., Goyns M. H.: "P53 mutation in a series of epithelial ovarian cancers from the U.K., and its prognostic significance". Eur. J. Cancer, 1994, 30 A (11), 1701.

[46] Reles A., Schmider A., Press M. F., Schonbom I., Friedmann W., Huber-Schumacher S. et al.: "Immunostaining of p53 protein in ovarian carcinoma: correlation with histopathological data and clinical outcome". J. Cancer Res. Clin. Oneal., 1996, 122 (8), 489.

[47] Kiberu S. W., Pringle J. H., Murphy P., Lauder I.: "Correlation between apoptosis,p roliferation and bcl-2 expression in malignant non-Hodgkin's lymphoma". J. Clin. Pathol. Mo/. Pathol., 1996, 49, 268.

[48] Hickman J.: "Apoptosis and chemotherapy resistance". Eur. J. Cancer, 1996, 32, 921.

[49] Reed J.: "Bcl-2 family proteins: Regulators of apoptosis and chemoresistance in hematologic malignancies". Semin. Hematol., 1997, 34, 9.

[50] Brady H. J., Gil-Gomez G., Kirberg J., Berns A. J.: "Bax alpha perturbs T cell development and affects cell cycle entry of T cells". EMBO J., 1996, 15 (24), 6991.

[51] Thompson C. B.: "Apoptosis in the pathogenesis and treatment of disease". Science, 1995, 267, 1456.

[52] Leoncini L., Del vecchio M. T., Kraft R., Cottier H.: "Correlations between apoptotic and proliferative indices in malignant nonHodgkin's lymphomas". Am. J. Pathol., 1993, 142, 755.

[53] Chyle V., Pollack A., Terry N. H., Meyn R. E.: "Apoptosis and downstaging after preoperative radiotherapy for muscle-invasive bladder cancer". Int. J. Radiat. Oncol. Biol. Phys., 1996, 35, 281.

[54] Yamasaki F., Tokunaga O., Sugimori H.: "Apoptotic index in ovarian carcinoma: correlation with clinicopathologic factors and prognosis". Gynecol. Oncol., 1997, 66 (3), 439.

[55] Baretton G. B., Diebold J., Christoforis G., Dopfer K.: "Apoptosis and immunohistochemical bcl-2 expression in colorectal adenomas and carcinomas". Cancer, 1996, 77, 255.