Studies on Ras Oncogene Activation in Endometrial Carcinoma

The aim of this study was to detect activated c-K-ras by gene point mutation and to find c-erbB-2 gene amplification with p185 expression in association with the c-K-ras gene product p21 in the human endometrium. Specimens obtained from 25 normal, 31 hyperplastic and 72 malignant samples of the human endometrium were examined for point mutation in codons 12, 13 and 61 of the c-K-ras by direct sequencing and c-erbB-2 gene amplification with p185 and p21 expression by differential polymerase chain reaction (DPCR) and immunohistochemistry. Neither the normal endometrium nor endometrial hyperplasias were found to have mutations in the c-K-ras gene, although a double mutation of codons 12 and 13 as a single-point mutation was observed in one case of endometrioid carcinoma (2.8%). In each of two other cases of endometrioid carcinoma (2/72), two single-point mutations of codon 13 (5.6%) were shown. Using DPCR, we found c-erbB-2 to be amplified in 15 premalignant (48%) and 45 malignant (63%) samples. We noticed that nonamplification of the c-erbB-2 gene was associated with the absence of immunoreactivity. Our data indicate that, while c-erbB-2 plays a role in the early development of endometrioid carcinomas, c-K-ras gene activation by point mutation does not.

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“…Our findings were supported by Fujimoto et al [23], who observed a trend towards metastases in patients whose tumors contained mutant c-K-ras.…”

Section: Discussionsupporting

confidence: 82%

Oncogenic Potential of c-erbB-2 and Its Association with c-K-ras in Premalignant and Malignant Lesions of the Human Uterine Endometrium

Manavi¹,

Bauer²,

Baghestanian³

et al. 2001

Tumor Biol

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“…Mutations in gene products such as the tumor suppressor gene p53, transforming growth factor-a, Ki-ras, HER-2/neu oncogenes, and others have been correlated with the transfor- mation of normal endometrium into endome trial hyperplasia, atypical hyperplasia, and eventually frank carcinoma [25][26][27]. A pro gressive accumulation of mutations with these genes appears to push individual cell clones into neoplastic growth, with increas ingly aggressive behavior.…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic Localization of Endothelial Constitutive Nitric Oxide Synthase in Endometrial Carcinomas

Bentz¹,

Barnes²,

Haines³

et al. 1997

Tumor Biol

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Background: Production of nitric oxide by nitric oxide synthase (NOS) has been implicated in numerous physiologic and pathophysiologic processes including mutagenesis. This study was designed to examine the expression of the endothelial constitutive isoform of NOS (ecNOS) in endometrial carcinomas. Methods: Fifty endometrial carcinomas (42 endometrioid, 4 serous papillary, 2 clear cell, and 2 adenosquamous carcinomas) and 21 normal endometrial gland tissue specimens (5 cases of proliferative, 5 early secretory, 5 mid-secretory, and 5 late secretory and 1 menstrual phase endometrium), previously formalin fixed and paraffin embedded, were immunostained using a commercially available anti-ecNOS monoclonal antibody. Localization of ecNOS staining to the plasma membrane, cytoplasm and nuclei was graded with respect to overall staining intensity (0–3+ scale) and frequency (percentage of immunoreactive cells). Results: Relatively little staining for ecNOS was localized to the plasma membrane in either normal or neoplastic tissues. Normal and hyperplastic endometrial glands demonstrated moderate cytoplasmic and weak nuclear staining in a small percentage of cells. While ecNOS expression was most prominent in epithelial cells, weak expression was also rarely noted in endometrial stroma, blood vessel walls, and endothelium. We found a broad range of ecNOS expression in endometrial carcinomas, predominantly localized to the cytoplasm and nuclei. No statistically significant difference in ecNOS staining frequency or intensity was found between different histologic subtypes of endometrial carcinomas. No apparent correlation was found between ecNOS expression and tumor stage, grade, extension to the lower uterine segment or cervix, nodal or distant metastases, recurrence, or final patient status among patients with endometrioid adenocarcinomas. Endometrioid tumors invading more than 1/2 of myometrial thickness (n = 18) had significantly higher cytoplasmic staining intensity than those tumors limited to the inner 1/2 of myometrium (n = 27;2.0 vs. 1.3, p < 0.04). Furthermore, a trend toward shorter disease-free survival was noted with increased staining intensity and decreased staining frequency. Conclusions: Cytoplasmic and nuclear expression of ecNOS, which is primarily limited to the glandular elements of normal endometrium, is also found to be expressed in endometrial carcinoma. Increased ecNOS staining intensity and decreased frequency tends to correlate with decreased disease-free survival. Lastly, increased cytoplasmic ecNOS staining intensity correlates with increased myometrial invasion.

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“…KRAS mutation is 0% to 5% in non-endometrioid endometrial cancers. [46][47][48][49][50][51][52][53][54][55][56] The frequency of KRAS mutations in cervical cancer ranges between 5% and 14%. In the United States, the frequency of KRAS mutation is 8.8% in patients with cervical cancer.…”

Section: Frequency Of Ras Mutation In Genitourinary Cancermentioning

confidence: 99%

Frequency of RAS Mutations (KRAS, NRAS, HRAS) in Human Solid Cancer

Kodaz

2017

EJMO

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T he RAS oncogene affects numerous cellular functions, including growth, proliferation, apoptosis, migration, division, and differentiation of the cells. It has 3 known isoforms: Harvey-RAS (HRAS), Kirsten-RAS (KRAS), and neuroblastoma-RAS (NRAS). RAS has an intrinsic GTPase activity; it encodes proteins binding the guanine nucleotides. KRAS and HRAS were discovered in studies conducted on cancer-causing viruses. Retroviral oncogenes related to murine sarcoma virus genes (Kristen rat sarcoma virus and Harvey rat sarcoma virus) were discovered in 1982. These 2 oncogenes are similar to human KRAS. Approximately 30% of all human cancers have RAS gene involvement. Mutations in KRAS account for about 85% of all RAS mutations in human tumors, NRAS for about 11% to 15%, and HRAS for about 1%. Frequency of RAS mutation in intracranial tumorsGliomas constitute 80% of malignant brain tumors. RAS mutations are very rare in malignant gliomas; no RAS mutation was found in a study in which 30 glioblastoma multiforme (GBM) patients were evaluated. The frequency of NRAS mutation was 2.1% in another study, although KRAS and HRAS mutations were not detected. It was reported that RAS mutation frequency was 12% in a study of isocitrate-dehydrogenase 1-mutant malignant glioma. RAS genes were studied in 21 cases of glioblastoma multiforme, 4 cases of fibrillary astrocytoma, 4 cases of anaplastic astrocytoma, and 15 normal specimens. RAS mutation was de-RAS oncogene affects numerous cellular functions including growth, proliferation, apoptosis, migration, division and differentiation of the cells. It has 3 known isoforms as Harvey-RAS (HRAS), Kirsten -RAS (KRAS) and Neuroblastoma-RAS (NRAS). RAS has an intrinsic GTPase activity. It encodes proteins binding the guanine nucleotides. KRAS and HRAS were discovered in studies carried out on viruses leading to cancer. Retroviral oncogenes related to murine sarcoma virus genes (Kristen Rat Sarcoma Virus and Murine Sarcoma Virus) were discovered in 1982. These two oncogenes are similar to human KRAS. Approximately 30% of all human cancers have ras genes. Mutations in KRAS account for about 85% for all RAS mutations in human tumors, NRAS is about 11-15%, and HRAS is about 1%.

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Studies on Ras Oncogene Activation in Endometrial Carcinoma

Cited by 49 publications

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Oncogenic Potential of <i>c-erbB-2</i> and Its Association with <i>c-K-ras</i> in Premalignant and Malignant Lesions of the Human Uterine Endometrium

Oncogenic Potential of <i>c-erbB-2</i> and Its Association with <i>c-K-ras</i> in Premalignant and Malignant Lesions of the Human Uterine Endometrium

Cytoplasmic Localization of Endothelial Constitutive Nitric Oxide Synthase in Endometrial Carcinomas

Frequency of RAS Mutations (KRAS, NRAS, HRAS) in Human Solid Cancer

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