Molecular pathogenesis and prognostic factors in endometrial carcinoma

Salvesen, Helga B.; Akslen, Lars A.

doi:10.1034/j.1600-0463.2002.1101001.x

Cited by 72 publications

(53 citation statements)

References 186 publications

(256 reference statements)

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“…In endometrial carcinomas numerous genetic defects occur, located in oncogenes, tumor suppressor genes, mismatch repair genes, and microsatellite sequences of DNA (Inoue 2001;Salvesen 2002;Sherman 2000). Most studies on genetic defects in endometrial carcinomas focused on searching for such biomolecular damages which participate in carcinogenesis mechanisms and may be useful for prognostic and predictive purposes and for learning the mechanisms of neoplasia.…”

Section: Discussionmentioning

confidence: 99%

The coexistence of ERBB2, INT2, and CMYC oncogene amplifications and PTEN gene mutations in endometrial carcinoma

Konopka

Janiec–Jankowska

Paszko

et al. 2004

Journal of Cancer Research and Clinical Oncology

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Our data suggest that differences in the presence of genetic defects may reflect the different molecular pathways of endometrial carcinogenesis. These data also suggest that location of intragenic PTEN mutations and their coexistence with the CMYC amplification may play a crucial part in the development of various subtypes of endometrial carcinoma, but this preliminary suggestion requires further research.

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Section: Discussionmentioning

confidence: 99%

The coexistence of ERBB2, INT2, and CMYC oncogene amplifications and PTEN gene mutations in endometrial carcinoma

Konopka

Janiec–Jankowska

Paszko

et al. 2004

Journal of Cancer Research and Clinical Oncology

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“…Endometrioid adenocarcinoma, the most common subtype, is generally related to overexposure to unopposed estrogens. This subtype is often termed type I, which includes tumors that are categorized as grade 1 (well-differentiated) or grade 2 (moderately differentiated), retain progesterone and estrogen responsiveness, a significant percentage evolve from atypical endometrial hyperplasia, and finally are usually associated with loss of pTEN, ras, and/or microsatellite instability (15)(16)(17). In contrast, type II endometrial tumors are poorly differentiated (grade 3) or nonendometrioid subtypes (serous, clear cell; Ref.…”

Section: Discussionmentioning

confidence: 99%

Loss of Cables, a Cyclin-Dependent Kinase Regulatory Protein, Is Associated with the Development of Endometrial Hyperplasia and Endometrial Cancer

Zukerberg¹,

Debernardo²,

Kirley³

et al. 2004

Cancer Research

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Endometrial cancer is the most common gynecological cancer in Western industrialized countries. Cables, a cyclin-dependent kinase binding protein, plays a role in proliferation and/or differentiation. Cables mutant mice are viable, but develop endometrial hyperplasia and carcinoma in situ at a young age. Exposure to chronic low levels of estrogen results in development of endometrial cancer, similar to that observed in the postmenopausal female. In vitro and in vivo studies demonstrate that levels of Cables mRNA in benign human endometrial epithelium are up-regulated by progesterone and down-regulated by estrogen. Furthermore, nuclear immunostaining for Cables is lost in a high percentage of cases of human endometrial hyperplasia and adenocarcinoma, which are likely the product of unopposed estrogen. The loss of Cables immunostaining in the human endometrial cancer samples correlates with a marked decrease in Cables mRNA. Ectopic expression of Cables in human endometrial cells dramatically slows cell proliferation. Collectively, these data provide evidence that Cables is hormonally regulated and is involved in regulating endometrial cell proliferation. In addition, loss or suppression of Cables may be an early step in the development of endometrial cancer.

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“…1,2 The pathogenesis of uterine endometrioid adenocarcinoma has been subject to intense investigation in recent years, and several common molecular abnormalities have been identified, including inactivation of the tumor suppressor gene PTEN, mutations of the k-ras oncogene and microsatellite instability. [3][4][5][6] Additional changes that occur in a significant proportion of cases include dysregulation of the Wnt and retinoblastoma (Rb) signaling pathways. These are complex and interconnected pathways, each of which includes multiple positive and negative regulatory factors that influence cellular proliferation and differentiation.…”

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confidence: 99%

Expression of cell cycle regulatory proteins in endometrial adenocarcinoma: variations in conventional tumor areas and in microcystic, elongated and fragmented glands

et al. 2009

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Endometrial adenocarcinomas may show a distinctive pattern of invasion characterized by the presence of microcystic, elongated and fragmented glands, often most evident along the advancing tumor margin. Earlier, we have shown that these changes appear restricted to low-grade endometrioid carcinomas, many of which show focal mucinous differentiation and lymphovascular space invasion. However, the molecular alterations associated with this morphological alteration are not known. In this study, we have examined immunoreactivity for the cell cycle regulatory proteins cyclin D1, p16 and b-catenin in 22 endometrial carcinomas, specifically comparing the results in conventional tumor areas and in foci in which the glands exhibited microcystic, elongated and fragmented appearances. The conventional neoplastic glands exhibited cyclin D1 and p16 expression in most cases, with 450% tumor cells positive in 8 cases and 11 tumors, respectively. Membranous expression of b-catenin was usually preserved, with variable cytoplasmic and nuclear staining. Cyclin D1 and b-catenin predominantly stained cells at the peripheral or basal aspect of the conventional glands, whereas p16 was more uniformly expressed centrally. Tumor foci composed of microcystic, fragmented and elongated glands showed strong expression of cyclin D1 and p16, sometimes in contrast to unstained contiguous or adjacent conventional neoplastic elements, and there was also loss or fragmentation of membranous b-catenin staining. Intravascular tumor cells also expressed cyclin D1 and p16 and therefore the immunostains often highlighted subtle foci of lymphovascular invasion. The heterogenous expression of cell cycle regulatory proteins within endometrial adenocarcinoma illustrates the importance of assessing microanatomical variations in immunoreactivity, particularly at the advancing margin of tumors. The upregulation of cyclin D1 and p16, together with loss of membranous b-catenin expression in microcystic, fragmented and elongated glands, is similar to epithelial-mesenchymal transitions observed in other malignancies and suggests that this pattern of invasion represents an active rather than a degenerative cellular process. Modern Pathology (2009) 22, 725-733; doi:10.1038/modpathol.2009 published online 6 March 2009 Keywords: endometrial; carcinoma; invasion; MELF; epithelial-mesenchymal transition; immunohistochemistry Endometrial carcinomas can be divided into two major groups on the basis of clinicopathological, immunohistological and molecular features. 1,2 The more common (type 1) subgroup accounts for 80-85% of cases and mainly comprises endometrioid adenocarcinomas of low-to-intermediate grade. These tumors typically occur in perimenopausal and younger postmenopausal patients, often arise in hyperestrogenic states and are associated with atypical endometrial hyperplasia/endometrial intraepithelial neoplasia. Frequently, type 1 carcinomas are confined to the uterine corpus at the time of diagnosis (stage 1), and the prognosis in such patients is generally ...

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Molecular pathogenesis and prognostic factors in endometrial carcinoma

Cited by 72 publications

References 186 publications

The coexistence of ERBB2, INT2, and CMYC oncogene amplifications and PTEN gene mutations in endometrial carcinoma

The coexistence of ERBB2, INT2, and CMYC oncogene amplifications and PTEN gene mutations in endometrial carcinoma

Loss of Cables, a Cyclin-Dependent Kinase Regulatory Protein, Is Associated with the Development of Endometrial Hyperplasia and Endometrial Cancer

Expression of cell cycle regulatory proteins in endometrial adenocarcinoma: variations in conventional tumor areas and in microcystic, elongated and fragmented glands

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