UMLS:C0476089 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0476089 (endometrial cancer)
11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The long-term treatment of tamoxifen (TAM), widely used for adjuvant chemotherapy and chemoprevention for breast cancer, increases a risk of developing endometrial cancer. A high frequency of K-ras mutations has been observed in the endometrium of women treated with TAM. Human DNA polymerase (pol) eta and pol kappa are highly expressed in the reproductive organs and are associated with translesion synthesis past bulky DNA adducts. To explore the miscoding properties of alpha-(N2-deoxyguanosinyl)tamoxifen (dG-N2-TAM), a major TAM-DNA adduct, site-specifically modified oligodeoxynucleotides containing a single diastereoisomer of trans or cis forms of dG-N2-TAM were prepared by phosphoramidite chemical procedure and used as templates. The primer extension reaction catalyzed by pol kappa deltaC, a truncated form of pol kappa, extended more efficiently past the adduct than that of pol eta by incorporating dCMP, a correct base, opposite the adduct. With pol eta, all diastereoisomers of dG-N2-TAM promoted small amounts of direct incorporation of dAMP and deletions. With pol kappa deltaC, dG-N2-TAM promoted small amounts of dTMP and/or dAMP incorporations and deletions. The miscoding properties varied depending on the diastereoisomer of dG-N2-TAM adducts and the DNA pol used. Steady-state kinetic studies were also performed using either the nonspecific sequence or the K-ras gene sequence containing a single dG-N2-TAM at the second base of codon 12. With pol eta, the bypass frequency past the dA x dG-N2-TAM pair positioned in the K-ras sequence was only 2.3 times lower than that for the dC x dG-N2-TAM pair, indicating that dG-N2-TAM in the K-ras sequence has higher miscoding potential than that in the nonspecific sequence. However, with pol kappa deltaC, the bypass frequency past the dC x dG-N2-TAM pair was higher than that of the dT x dG-N2-TAM pair in both sequences. The properties of pol eta and pol kappa are consistent with the mutagenic events attributed to TAM-DNA adducts.
...
PMID:Translesion synthesis past tamoxifen-derived DNA adducts by human DNA polymerases eta and kappa. 1700 16

Endometrial cancer is the most common gynecological malignancy, with 41,000 new cases projected in the United States for 2006. Two different clinicopathologic subtypes are recognized: the estrogen-related (type I, endometrioid) and the non-estrogen-related types (type II, nonendometrioid such as papillary serous and clear cell). The morphologic differences in these cancers are mirrored in their molecular genetic profile with type I showing defects in DNA-mismatch repair and mutations in PTEN, K-ras, and beta-catenin, and type II showing aneuploidy and p53 mutations. This article reviews the genetic aspects of endometrial carcinogenesis and progression. We will define the precursor lesion of type I endometrioid cancer and the role of genetics and estrogen in its progression.
...
PMID:Molecular and pathologic aspects of endometrial carcinogenesis. 1702 94

Tumor markers play an important role in the diagnosis of cancer. Cervical carcinoma and endometrial cancer are the most frequent diseases of the reproductive organs and their morbidity rates are constantly increasing. Many tumor markers may be used in the diagnosis and monitoring of endometrial and cervical carcinoma, for example CA 125, SCC-Ag, TPA, TPS, and CYFRA 21-1. New tumor markers useful in the early diagnosis and in monitoring the treatment and recurrence of the uterine cancer are still being sought. Investigations are underway on such substances as cytokines (e.g. M-CSF) and molecular markers of carcinogenesis (e.g. K-ras and p53).
...
PMID:[Tumor markers useful in the diagnostics and monitoring of endometrial and cervical cancer]. 1736 80

In 1983, Bokhman proposed a dualistic model of endometrial tumorigenesis based on the clinical observations and clinicopathologic correlations. The majority of endometrial cancers (approximately 70-80%), designated as type I carcinomas, follow the estrogen-related pathway. Histologically, most of the type I tumors seem to arise in the background of hyperplastic endometrium, show an endometrioid differentiation, and are of low grade. Clinically, they are overall characterized by a favorable behavior. Another 10-20% of endometrial cancers, designated as type II carcinomas, follow the estrogen-unrelated pathway and arise in the background of atrophic endometrium. Type II tumors usually occur at an older age, approximately 5-10 years later than type I tumors. They are typically high-grade carcinomas of nonendometrioid differentiation, most frequently serous, less frequently clear cell. Type II carcinomas behave as an aggressive clinical course and poor prognosis. This dualistic model was subsequently supported by the molecular studies, approximately a decade later. At present, endometrioid and serous carcinoma, which represent the major phenotypes of types I and II endometrial carcinomas, respectively, are characterized by distinctive types of genetic instability and molecular alterations. In endometrioid (type I) carcinoma, four major genetic changes are responsible for the tumorigenesis, i.e. silencing of PTEN tumor suppressor gene, presence of microsatellite instability due to alterations of the mismatch repair genes, mutation of K-ras protooncogene, and alteration of beta-catenin gene. On the other hand, p53 mutation and overexpression of Her2/neu oncogene are two major genetic alterations in serous and clear cell (type II) carcinomas. However, like in any model, there is evidence for exceptions. Many endometrial carcinomas are in the gray zone with overlapping clinical, morphologic, immunohistochemical, and molecular features of types I and II endometrial cancers. Finally, a small group of endometrial carcinoma is noted to be hereditary. It is known as the most common extracolonic malignancy in hereditary nonpolyposis colorectal cancer (Lynch syndrome), an autosomal dominantly inherited disorder of cancer susceptibility. Inactivation of the mismatch repair genes MSH2 and MSH6 seems to play a central role in the tumorigenesis.
...
PMID:Molecular carcinogenesis of endometrial cancer. 1738 85

Endometrial carcinoma is the most common malignant tumor of the female genitals in developed countries. The differences noted in epidemiology, presentation, and biological behaviors of endometrial carcinoma suggest that there are two fundamentally different pathogenic types of the disease: type I (estrogen related, endometrioid type) and type II (non-estrogen related, non-endometrioid type). The first type is more common and represents about two-thirds of cases. It occurs in women with hyperlipidemia, obesity, and signs of hyperestrogenism, including anovulatory uterine bleeding, infertility, late onset of menopause, ovarian stromal hyperplasia, and endometrial hyperplasia. The second type occurs in the absence of these features. Pathohistologically, type I tumors are composed of endometrioid carcinoma whereas type II tumors are composed of serous or clear cell carcinoma. Atypical hyperplasia is recognized as the precursor for the endometrioid type of endometrial carcinoma and endometrial intraepithelial carcinoma (EIC) as the precursor of serous carcinoma, the most common non-endometrioid type of endometrial carcinoma. In endometrioid type of endometrial carcinoma, it appears that PTEN mutation may be central to the initiation of endometrial proliferative lesions by which damage in other genes is then accumulated (e.g., DNA mismatch repair genes, K-ras, p53) in the progression to carcinoma. In contrast to endometrioid type, p53 mutations appear to be important in the conversion of atrophic endometrium to EIC and serous adenocarcinoma. Endometrial intraepithelial neoplasia (EIN) has been a recently defined precursor for the endometrioid type of endometrial carcinoma.
...
PMID:[Endometrial carcinoma and precursor lesions]. 1764 68

Endometrial carcinoma (EC) is the most common gynecological malignancy in the western world. A widely accepted dualistic model, which has been established on a morphological basis, differentiates EC into two broad categories: Type I oestrogen-dependent adenocarcinoma with an endometrioid morphology and Type II non-oestrogen-dependent EC with a serous papillary or clear cell morphology. Molecular genetic evidence indicates that endometrial carcinoma, as described in other malignancies, likely develops as the result of a stepwise accumulation of alterations in cellular regulatory pathways, such as oncogene activation and tumor suppressor gene inactivation, which lead to dysfunctional cell growth. These molecular alterations appear to be specific in Type I and Type II cancers. In type I endometrioid endometrial cancer, PTEN gene silencing in conjunction with defects in DNA mismatch repair genes, as evidenced by the microsatellite instability phenotype, or mutations in the K-ras and/or beta-catenin genes, are recognized major alterations, which define the progression of the normal endometrium to hyperplasia, to endometrial intraepithelial neoplasia, and then on to carcinoma. In contrast, Type II cancers show mutations of TP53 and Her-2/neu and seem to arise from a background of atrophic endometrium. Nevertheless, despite the great effort made to establish a molecularly-based histological classification, the following issues must still be clarified: what triggers the tumor cells to invade the myometrium and what causes vascular or lymphatic dissemination, finally culminating in metastasis? RUNX1, a transcription factor, was recently identified as one of the most highly over-expressed genes in a microarray study of invasive endometrial carcinoma. Another candidate gene, which may be associated with an initial switch to myometrial infiltration, is the transcription factor ETV5/ERM. These studies, as well as those conducted for other genes possibly involved in the mitotic checkpoint as a major mechanism of carcinogenesis in non-endometrioid endometrial cancer, could help in understanding the differences in the biology and the clinical outcome among histological types.
...
PMID:Novel molecular profiles of endometrial cancer-new light through old windows. 1806 38

Use of tamoxifen for treatment and prevention of breast cancer is becoming increasingly common. Tamoxifen has been associated with increased risk of endometrial carcinoma, although the exact mechanism of action is unknown. The aim of our study was to seek a possible correlation between endometrial carcinoma, tamoxifen exposure and MSI, PTEN, beta-catenin and K-ras abnormalities. A group of 18 patients with endometrial carcinoma following treatment with tamoxifen were selected. A control group included 15 patients with endometrial carcinoma and associated ovarian hyperthecosis and one patient with endometrial carcinoma and adult granulosa cell tumor of the ovary, chosen because both conditions are associated with increased production of estrogen and increased risk of endometrial carcinoma development. The second control group included 27 randomly selected consecutive patients with endometrial carcinoma without identifiable associated conditions. Immunostaining for beta-catenin was performed on all cases; DNA was extracted and amplified by PCR with primers for beta-catenin, K-ras and PTEN genes. BAT-25 and BAT-26 were analyzed to assess for MSI. There were 16 endometrioid endometrial carcinomas, one mixed carcinoma and one clear cell carcinoma among patients in the tamoxifen group. All patients with ovarian hyperthecosis and adult granulosa cell tumor had endometrioid endometrial carcinoma. In the random control group, there were 26 endometrioid endometrial carcinomas and one carcinosarcoma. Immunohistochemical and mutational analysis for beta-catenin showed abnormalities in 4/11 (36%) and 3/10 (30%) informative cases in the tamoxifen group; 7/16 (44%) and 4/15 (27%) informative cases, respectively in the ovarian hyperthecosis group and 1/27 random control cases (4%) (P<0.05). Patients with tamoxifen exposure had more K-ras mutations and fewer PTEN mutations and MSI as opposed to controls, but the results were not statistically significant. In conclusion, there was a direct relationship between tamoxifen exposure and overexpression of beta-catenin oncoprotein, which is known to play a major role in the pathogenesis of estrogen-driven, type I endometrial adenocarcinoma.
...
PMID:Clinicopathological and molecular analysis of endometrial carcinoma associated with tamoxifen. 1850 Feb 70

Endometrial cancer is the most common gynecological cancer. Estrogen-dependent endometrioid carcinoma is the most common type of endometrial cancer, and alterations in the expression of PTEN and K-ras have been associated with this disease. To study the roles of Pten and K-ras in endometrial cancer, we generated Pten ablation and oncogenic K-ras mutation in progesterone receptor positive cells (PR(cre/+)Pten(f/f)K-ras(G12D)). Double mutant mice dramatically accelerated the development of endometrial cancer compared to a single mutation of either gene. Histological analysis showed that all of the 1-month old double mutant female mice developed endometrial cancer with myometrial invasion. The expression of PR was downregulated in double mutant mice compared to a single mutation of either gene which resulted in decreased suppression of estrogen signaling. Therefore, these results suggest a synergistic effect of dysregulation of the Pten and K-ras signaling pathways during endometrial tumorigenesis.
...
PMID:The Synergistic Effect of Conditional Pten Loss and Oncogenic K-ras Mutation on Endometrial Cancer Development Occurs via Decreased Progesterone Receptor Action. 1988 80

Endometrial carcinoma is one of the most common cancers in women. A limited number of endometrial carcinoma cell lines are available for studies of signal transduction pathways and experimental therapeutics in vitro. However, these cell lines have not been comprehensively characterized. In this study, we used genome-wide microarray-based comparative genomic hybridization (aCGH) technology to characterize five of the more commonly used endometrial cancer cell lines. We detected DNA copy-number gains in chromosomal regions 2q, 3p, 3q, 5q, 7p, 17q, and 19q in all five cell lines. Other common sites of copy-number gains, which were detected in four of five cell lines, included segments of chromosomes 1, 6, 8, 9, 11, 12, and 16. In all five cell lines, we found DNA copy-number losses in regions 3p, 10p, 10q, 11q, 11p, 14q, 15q, 18p, and 21q. Other common sites of genetic aberrations included segments of chromosomes 1, 2, 4, 5, 6, 16, 20, and 22. The genes involved in the copy-number alterations included the oncogenes PIK3CA (3q26.3), K-ras (12p12.1), R-ras (19q13.3-qter), Raf-1 (3p25), EGFR (7p12), Akt1 (14q32.32), and Akt2 (19q13.1-q13.2). A pathway analysis showed that genes in the PI3K and Wnt pathways are commonly affected. Our characterization of genomic alterations in these five commonly used endometrial cancer cell lines provides valuable genomic information for research that focuses on these key oncogenic pathways in endometrial cancer.
...
PMID:Genomic characterization of gene copy-number aberrations in endometrial carcinoma cell lines derived from endometrioid-type endometrial adenocarcinoma. 2021 40

Endometrial cancers exhibit a different mechanism of tumorigenesis and progression depending on histopathological and clinical types. The most frequently altered gene in estrogen-dependent endometrioid endometrial carcinoma tumors is PTEN. Microsatellite instability is another important genetic event in this type of tumor. In contrast, p53 mutations or Her2/neu overexpression are more frequent in non-endometrioid tumors. On the other hand, it is possible that the clear cell type may arise from a unique pathway which appears similar to the ovarian clear cell carcinoma. K-ras mutations are detected in approximately 15%-30% of endometrioid carcinomas, are unrelated to the existence of endometrial hyperplasia. A beta-catenin mutation was detected in about 20% of endometrioid carcinomas, but is rare in serous carcinoma. Telomere shortening is another important type of genomic instability observed in endometrial cancer. Only non-endometrioid endometrial carcinoma tumors were significantly associated with critical telomere shortening in the adjacent morphologically normal epithelium. Lynch syndrome, which is an autosomal dominantly inherited disorder of cancer susceptibility and is characterized by a MSH2/MSH6 protein complex deficiency, is associated with the development of non-endometrioid carcinomas.
...
PMID:Genetics of endometrial cancers. 2039 92

<< Previous 1 2 3 4 5 6 Next >>