Prognostic significance of Bcl-2, p53 overexpression, and lymph node metastasis in surgically staged endometrial carcinoma

Ohkouchi, Toshihiro; Sakuragi, Noriaki; Watari, Hidemichi; Nomura, Eiji; Todo, Yukiharu; Yamada, Hideto; Fujimoto, Seiichiro

doi:10.1067/mob.2002.123203

Cited by 50 publications

(47 citation statements)

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“…Cancers also often involve loss of the regulation of apoptosis. In endometrial cancer, the expression of Bax, an apoptosis-promoting gene, may be lost due to mutation (39), while Bcl-2, an anti-apoptosis factor, has an enhanced expression in endometrial hyperplasia and a reduced expression in endometrial cancer (40).…”

Section: Other Biomarkersmentioning

confidence: 99%

Biomarkers in endometrial cancer: Possible clinical applications (Review)

et al. 2012

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Abstract. The number of cases of endometrial cancer has shown a tendency to increase in recent years. Endometrial cancer originates from the endometrium and is classified, based on the development mechanism, into types 1 and 2, which are responsive and non-responsive to estrogen, respectively, and have significantly different gene expression profiles. Studies of genes with abnormal expression in endometrial cancer have identified multiple oncogenes, tumor suppressors, mismatch repair genes, apoptosis-associated genes, levels of hormone receptors and DNA ploidy and aneuploidy as biomarkers of endometrial cancer. The use of these molecules and genes may facilitate accurate diagnosis and prognostic prediction and contribute to individualized treatment. Trials of drugs which target these biomarkers and searches for new biomarkers using cDNA microarrays and RT-qPCR are ongoing and it is likely that these findings can be translated to clinical use. Contents1. Introduction 2. Differences in biomarkers in subtypes of endometrial cancer 3. Oncogenes 4. Tumor suppressors 5. Mismatch repair genes and microsatellite instability 6. Other biomarkers 7. Biomarkers for prognosis and treatment 8. Conclusion IntroductionEndometrial cancer is the seventh most common cancer worldwide in women (1). The incidence differs depending on the region: in developed countries, 10-20 in 100,000 women have endometrial cancer, whereas the incidence is approximately one-tenth this level in developing countries. The number of cases is rapidly increasing in Japan. Obesity, nulliparity and the administration of tamoxifen have been identified as risk factors for endometrial cancer (2).In the last 10 years, numerous studies have aimed to identify tumor biomarkers. The US National Cancer Institute (NCI) defines a biomarker as ʻa biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or diseaseʼ. According to this definition, a biomarker includes not only the proteins normally used as tumor markers, such as CA-125, but also genes and chromosomes. Biomarkers of endometrial cancer that have been identified include the K-ras, HER2/neu, epithelial growth factor receptor (EGFR), phosphatidylinositol 3-kinase catalytic subunit (PI3KCA) and fibroblast growth factor receptor 2 (FGFR2) oncogenes; the phosphatase and tensin homolog (PTEN), p53, p21 and cyclin-dependent kinase inhibitor 2A (CDKN2A) cancer suppressor genes; the hMLH1, hMSH2, hMSH6, PMS1 and PMS2 mismatch repair genes; Ki-67, an index of cell proliferation; BCL2-associated X protein (Bax), an apoptosis promotor gene; Bcl-2, an apoptosis suppressor; expression levels of estrogen and progesterone receptors; microvascular density (MVD); and vascular endothelial growth factor A (VEGF-A), which are all indices of angiogenesis; expression changes in E/P-cadherin and β-catenin, which are associated with infiltration and metastatic capacity; and ploidy and aneuploidy of DNA. The characteristics and functions of each of these bioma...

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Section: Other Biomarkersmentioning

confidence: 99%

Biomarkers in endometrial cancer: Possible clinical applications (Review)

et al. 2012

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“…p53 overexpression has been shown to predict patient survival in endometrial cancer. [5][6][7] p53 overexpression, as determined by immunohistochemistry (IHC), is a surrogate marker of missense mutation of p53 protein. Because MDM2 is a transcriptional target of p53, loss of p53 function reduces the production of MDM2.…”

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confidence: 99%

Functional analysis of p53 gene and the prognostic impact of dominant‐negative p53 mutation in endometrial cancer

Sakuragi

Watari

Ebina

et al. 2005

Intl Journal of Cancer

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In addition to the loss of function, mutant p53 can possess a dominant-negative effect on wild-type p53 and may also exert gain-offunction activity. It is not clear whether the functional status of p53 mutation contributes to differences in outcome in endometrial cancer. We collected a total of 92 RNA samples of high quality from endometrial cancer tissues, and the samples were subjected to yeast functional assay and sequencing for p53 mutations. The detected mutant p53 genes were further investigated for their dominant-negative activity using a yeast-based transdominance assay. p53 mutation was found in 24 out of 92 (26.1%) tumors, of which 10 exhibited no dominant-negative activity (recessive mutation) and 14 showed dominant-negative activity. Dominant-negative p53 mutation was related to advanced stages (p 5 0.01), nonendometrioid type tumors (p 5 0.01) and grade 3 tumors (p 5 0.04). The patients with dominant-negative mutation had significantly shorter survival than patients with no mutation (p < 0.0001) and those with a recessive mutation (p 5 0.01) in the p53 gene. No difference in survival was found between the patients with tumors harboring a recessive p53 mutation and those with tumors harboring a wild-type p53. Multivariate analysis revealed that dominantnegative p53 mutation (p 5 0.019), FIGO stage (p 5 0.0037) and histologic subtype (p 5 0.014) were independently related to patient survival. Dominant-negative p53 mutation was the most important prognostic factor for stage III/IV endometrial cancer (p 5 0.0023). In conclusion, dominant-negative p53 mutation is often found in advanced stages and aggressive histologic subtypes of endometrial cancer and it is a strong predictor of survival of patients with advanced endometrial cancer. To elucidate further the role of p53 mutation in endometrial cancer, it is necessary to investigate gain-of-function activity involving dominant-negative p53 mutant proteins. ' 2005 Wiley-Liss, Inc.Key words: endometrial cancer; p53; mutation; dominant negative; survival; serous adenocarcinoma The p53 tumor suppressor gene is mutated in about 50% of all tumors, 1-3 and more than 19,000 different somatic mutations have been identified. 4 Mutation of the p53 gene plays a key role in the carcinogenesis and progression of many different malignancies, including endometrial cancer. p53 overexpression has been shown to predict patient survival in endometrial cancer. 5-7 p53 overexpression, as determined by immunohistochemistry (IHC), is a surrogate marker of missense mutation of p53 protein. Because MDM2 is a transcriptional target of p53, loss of p53 function reduces the production of MDM2. MDM2 degrades p53 protein through ubiquitination of the protein, and reduced MDM2 production will lead to an accumulation of p53 protein in the nucleus, which is detected as overexpression by IHC. 8 IHC is a convenient method for the investigation of p53 status. However, it can be affected by many factors, such as antibody used, antigen retrieval technique and subjectivity of criteria for p53 ...

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“…It is therefore probable that the increased expression of this oncogene may be one of the frequent events in endometrial carcinogenesis (Chen et al, 1999). Frequent studies demonstrate the loss of the bcl-2 expression correlates with poor prognosis, deeper invasion, advanced clinical stage and aggressive histological types (Erdem et al, 2003, Ohkouchi et al, 2002. The inversion relationship between the loss of expression and biological aggressiveness of the tumour seems to be an obvious paradox.…”

Section: Bcl-2mentioning

confidence: 99%