Frequent Occurrence of Loss of Heterozygosity among Tumor Suppressor Genes in Uterine Leiomyosarcoma

Zhai, Ya Li; Nikaido, Toshio; Orii, Ayaka; Horiuchi, Akiko; Toki, Toshihiko; Fujii, Shingo

doi:10.1006/gyno.1999.5629

Cited by 51 publications

(40 citation statements)

References 22 publications

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“…DNA was extracted as previously described (12). In brief, four or five 8-Am-thick sections of endometrial tissue were prepared from the paraffin-embedded blocks.…”

Section: Methodsmentioning

confidence: 99%

BRAF Mutation in Endometrial Carcinoma and Hyperplasia: Correlation with KRAS and p53 Mutations and Mismatch Repair Protein Expression

Feng

Shiozawa

Miyamoto

et al. 2005

Clinical Cancer Research

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Purpose: Although several gene abnormalities have been reported in endometrial carcinoma, the genetic alterations have not fully been elucidated. Recent studies have revealed frequent activating mutations of the gene for BRAF, an effector of Ras protein in the mitogen-activated protein kinase pathway, in several malignancies. However, the prevalence and significance of BRAF mutations in endometrial carcinoma remain unclear. Experimental Design:We examined BRAF mutations in exons11and15 in 97 cases of endometrial carcinoma (endometrioid type, 78; nonendometrioid type,19), 9 cases of atypical endometrial hyperplasia, and 20 cases of normal endometrium by direct sequencing. In addition, mutations of KRAS and p53 and the immunohistochemical expression of hMLH1 and hMSH2 were also examined. Results: Of the 97 carcinomas and 9 hyperplasias, 20 (21%) and 1 (11%) had BRAF mutations, most of them at previously unreported sites. Twenty samples of normal endometrium and 21 samples of normal endometrium obtained from sites adjacent to neoplastic lesions had no BRAF mutations. There was no apparent difference in the prevalence of BRAF mutation among stages, histologic subtypes, or grades. Mutations of KRAS and p53 were found in 18 (19%) and 22 (23%) cases, and 65 (67%) and 92 (95%) cases showed positive immunostaining for hMLH1 and hMSH2, respectively. BRAF mutation was more frequently found in hMLH1-negative cases (12 of 32, 41%) than in hMLH1-positive cases (7 of 65, 11%; P = 0.008), suggesting that it is associated with an abnormal mismatch repair function. Conclusions: These findings suggest that mutations of the BRAF gene are partly involved in the malignant transformation of the endometrium.Endometrial carcinomas are now classified into two histologic subtypes: endometrioid type and nonendometrioid type (1); and the molecular genetic changes involved differ between the two (2 -4). In endometrioid-type carcinomas, mutations of PTEN, KRAS, b-catenin, and p53 genes and microsatellite instability have been reported in f5% to 50% of cases. By contrast, in nonendometrioid-type carcinomas, as exemplified by serous papillary adenocarcinoma, the p53 gene is reportedly mutated in f90% of cases. However, the genetic changes in endometrial carcinoma have not fully been elucidated.Raf proteins are cytoplasmic serine-threonine kinases and play central roles in the conserved Ras/Raf/mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathway, acting to relay signals from activated Ras proteins via mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 to p42/ 44 mitogen-activated protein kinase or extracellular signalregulated kinase 1/2, the key effector of the pathway (5, 6). A recent report has shown the presence of an activating mutation in one of three Raf protein subtypes, B-Raf, in human melanomas and colon cancers, and that the mutation of BRAF transforms NIH 3T3 cells independent of KRAS gene mutation (7). In addition, mutual exclusi...

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“…DNA was extracted as previously described (12). In brief, four or five 8-Am-thick sections of endometrial tissue were prepared from the paraffin-embedded blocks.…”

Section: Methodsmentioning

confidence: 99%

BRAF Mutation in Endometrial Carcinoma and Hyperplasia: Correlation with KRAS and p53 Mutations and Mismatch Repair Protein Expression

Feng

Shiozawa

Miyamoto

et al. 2005

Clinical Cancer Research

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“…LOH and point mutations at TP53 have been reported in 35% (when the homozygous cases were excluded) and in 45% of uterine leiomyosarcomas, respectively, whereas both alterations have been reported in only 3 tumors [63]. There was no significant difference in patient survival between those cases with and those cases without LOH.…”

Section: Loh Tp53 and Clinicopathological Features Of Ecmentioning

confidence: 74%

“…There was no significant difference in patient survival between those cases with and those cases without LOH. As a final conclusion, the authors cannot exclude the possibility that TP53 alterations may be implicated in the progression of human uterine leiomyosarcomas [63]. …”

Section: Loh Tp53 and Clinicopathological Features Of Ecmentioning

confidence: 99%

Prevalence of Allelic Loss at <i>TP53</i> in Endometrial Carcinomas

Semczuk

Schneider‐Stock²,

Szewczuk³

2010

Oncology

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Alterations within the TP53 tumor suppressor belong to the most common genetic features reported in various human neoplasms, including endometrial cancer. In this article, the prevalence of allelic loss at the TP53 locus in primary human endometrial carcinomas (ECs) is discussed. Furthermore, we reviewed the role of allelic imbalance at 17p13.1 in metastatic human ECs on the basis of a literature review and on recently published data ascertained by our laboratory staff.

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“…Protooncogene c-kit is expressed only in the former tumour which opens perspective for treatment of myosarcomas using tyrosine kinase inhibitors. Zhai et al [27] also noted in myosarcoma loss of heterozygosity in nine loci (p53, RBI, DCC, NNM23, WTI, D14S67, p16, DPC4, PTCH) within or close to tumour suppressor genes in 20 patients. The conclusion follows that not an individual observation but only multidirectional studies, particularly immunocytochemical ones, provide the most accurate diagnostic and predictive criteria.…”

Section: Myoma and Leiomyoma -Presence Of Dis-oric Zonementioning

confidence: 96%

Pathomorphosis of Uterine Myomas in Women

Madej¹,

Madej²

2008

TOPATJ

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Taking stroma (ECM-extracellular matrix) and not tumour parenchyma as a criterion of categorization, the tumours can be divided into two groups, i.e. those which produce stroma (non-epithelial malignant tumours) or sarcomas and the tumours which take advantage of the local tissue stroma (malignant epithelial tumours) or carcinomas. Involvement of stroma is noted also within the reciprocal relationship between stroma and tumour cells, which has been described in detail on the example of uterine myoma. ECM also "collaborates" with CAM (cell adhesion molecules), particularly in development of neoplastic metastases.Pathomorphosis of myomas, myosarcomas and of "stromal" uterine tumours was described with particular attention given to differential diagnosis and the resulting clinic predictive and prognostic implications. A probable mechanism of neoplasia based on dissipative structures of cells was presented and introduction of a disoric zone of a tumour, i.e. of a marginal zone between the tumour and the morphologically normal tissue was suggested. The zone seems extremely important in prediction and prognosis related to relapse and/or tumour metastases.

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Frequent Occurrence of Loss of Heterozygosity among Tumor Suppressor Genes in Uterine Leiomyosarcoma

Cited by 51 publications

References 22 publications

BRAF Mutation in Endometrial Carcinoma and Hyperplasia: Correlation with KRAS and p53 Mutations and Mismatch Repair Protein Expression

BRAF Mutation in Endometrial Carcinoma and Hyperplasia: Correlation with KRAS and p53 Mutations and Mismatch Repair Protein Expression

Prevalence of Allelic Loss at <i>TP53</i> in Endometrial Carcinomas

Pathomorphosis of Uterine Myomas in Women

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