Mutation and allelic loss of the p53 gene in endometrial carcinoma. Incidence and outcome in 92 surgical patients

Kihana, Toshimasa; Hamada, Katsuyuki; Inoue, Yasuhiro; Yano, Naoki; Iketani, Haruhiko; Murao, Shinichi; Ukita, Masahiko; Matsuura, Sumio

doi:10.1002/1097-0142(19950701)76:1<72::aid-cncr2820760110>3.0.co;2-3

Cited by 59 publications

(38 citation statements)

References 29 publications

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“…It has been documented that genetic alterations, such as p53 gene mutation and loss of heterozygosity at certain chromosomal loci, are significantly associated with a poor prognosis of endometrial cancer. 20,28) It is conceivable that accumulation of such genetic changes enhances tumor aggressiveness during the multistep progression of human cancer. Even if tumors with MI truly have MMRdeficient phenotype, which induces the alteration of repetitive sequences in multiple genomic regions, MI might not have much influence on the activation of proto-oncogenes or the inactivation of tumor suppressor genes, which influence tumor aggressiveness.…”

Section: Discussionmentioning

confidence: 99%

Association of Replication Error Positive Phenotype with Lymphocyte Infiltration in Endometrial Cancers

Kihana

Fujioka²,

Hamada³

et al. 1998

Japanese Journal of Cancer Research

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Microsatellite instability (MI) has been detected in certain sporadic cancers as well as in hereditary non-polyposis colorectal cancer (HNPCC).It is now generally understood that accumulation of genetic changes, both in proto-oncogenes and tumor suppressor genes, plays a critical role in the development of human cancer.1) In addition to the oncogene and suppressor pathway of carcinogenesis, a novel mechanism has recently been discovered in hereditary non-polyposis colorectal cancer (HNPCC) syndrome.2) A defect in the mismatch repair (MMR) system of aberrant genetic sequences during DNA replication causes development of this disease. Disruption of one of the MMR genes, such as hMSH2, hMLH1, hPMS1, hPMS2 and/or GTBP, results in loss of the ability to repair or correct aberrant DNA segments.2, 3) Thus, a mutated MMR gene causes replication errors (RER) in repeated genetic sequences at several regions, including critical genes responsible for human tumorigenesis.4) These findings support the notion that alteration in either of the MMR pathways is likely to be associated with the development of human cancer. 3,5) Microsatellites are short repetitive DNA sequences located throughout the genome. When MMR is defective, expansion or contraction of repetitive sequences at microsatellite regions frequently occurs during DNA replication, and this is called microsatellite instability (MI) or a replication error positive (RER+) phenotype. This alteration has been found in sporadic colorectal cancer, endometrial cancer, and many other cancers as well as HNPCC.Since endometrial cancer is the second most common tumor in women with HNPCC syndrome, 2) it is important to verify the effect of MI on the clinicopathological features of this cancer. Although previous reports on MI in endometrial cancer have shown that its incidence was almost the same (17-23%) [6][7][8][9][10] as that in sporadic colon cancer (17%), 11) the association of MI with specific clinicopathological features of the tumor, which was analyzed well in colon cancer, is still not clear in endometrial cancer. Accordingly, we used polymerase chain reaction (PCR) microsatellite analysis to investigate MI in 90

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Section: Discussionmentioning

confidence: 99%

Association of Replication Error Positive Phenotype with Lymphocyte Infiltration in Endometrial Cancers

Kihana

Fujioka²,

Hamada³

et al. 1998

Japanese Journal of Cancer Research

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“…Normal p53 undergoes rapid degradation, but non-functional mutated p53 is resistant to degradation and the mutation and overexpression of p53 are simultaneously reported in 76% of cases with a p53 mutation (22). In endometrial cancer, the overexpression of p53 occurs in 15-30% of cases and the mutation of p53 is found in 10-20% of cases (23)(24)(25)(26). It has been proposed that the overexpression of p53 is observed more frequently in serous adenocarcinoma than in endometrioid cancer, with the mutation of p53 occurring in the early development of serous adenocarcinoma and in the later development of endometrioid adenocarcinoma (27).…”

Section: Tumor Suppressorsmentioning

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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“…Although the frequency of p53 mutation we observed was quite low (13%) in comparison with most other major cancer types, survey of the literature revealed an overall frequency of just 18% (54/298) for this cancer type (Okamoto et al, 1991;Risinger et al, 1992;Enomoto et al, 1993Enomoto et al, , 1995Honda et al, 1993;Kohler et al, 1993;Schneider et al, 1994;Kihana et al, 1995). Our results show a trend towards worse prognosis for tumours with a p53 gene mutation (Figure 3d), however this did not reach significance (P=0.11).…”

Section: Frequency Of P53 Alterations In Endometrial Carcinomamentioning

confidence: 99%

“…Our results show a trend towards worse prognosis for tumours with a p53 gene mutation (Figure 3d), however this did not reach significance (P=0.11). With the exception of a recent report of poorer outcome for endometrial cancers with both p53 mutation and loss of heterozygosity (Kihana et al, 1995), patient numbers in previous studies have been too small to assess the prognostic significance of p53 mutations.…”

Section: Frequency Of P53 Alterations In Endometrial Carcinomamentioning

confidence: 99%

Overexpression of p53 protein is an independent prognostic indicator in human endometrial carcinoma

Soong

Knowles²,

Williams³

et al. 1996

Br J Cancer

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Summary The important role of the p53 gene in tumour progression and cellular response to DNA damage has prompted investigation of the clinical significance of alterations to this gene. We examined both p53 overexpression and mutation of the gene in endometrial carcinoma in order to evaluate the prognostic significance of these changes. Of 122 endometrial carcinomas, 33 (27%) showed overexpression of p53 in the nucleus and 66 (54%) in the cytoplasm. Mutation in the p53 gene was found in 16 (13%) cases but showed no significant association with patient survival. Nuclear p53 overexpression was associated with poor survival (48% vs 80% alive in negative tumours 5 years post operatively, P<0.001). In contrast, cytoplasmic p53 overexpression was associated with better survival (85% vs 55%, P<0.001). When patients were separated into prognostic subgroups according to established clinical markers, these associations remained significant within most subgroups examined. In multivariate analysis adjusted for surgical stage, histological grade and type and vascular invasion, both nuclear p53 overexpression [hazard ratio 4.9 (95% CI 1.3-17.6), P=0.016] and cytoplasmic overexpression [0.25 (0.06-0.98), P=0.047] were independent prognostic factors. Immunohistochemical assessment of p53 overexpression in the nucleus and cytoplasm could provide useful prognostic information for the management of patients with endometrial cancer.

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Mutation and allelic loss of the p53 gene in endometrial carcinoma. Incidence and outcome in 92 surgical patients

Cited by 59 publications

References 29 publications

Association of Replication Error Positive Phenotype with Lymphocyte Infiltration in Endometrial Cancers

Association of Replication Error Positive Phenotype with Lymphocyte Infiltration in Endometrial Cancers

Biomarkers in endometrial cancer: Possible clinical applications (Review)

Overexpression of p53 protein is an independent prognostic indicator in human endometrial carcinoma

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