Comparison of Mutations of Ki-RAS and p53 Immunoreactivity in Borderline and Malignant Epithelial Ovarian Tumors

Caduff, Rosmarie; Svoboda-Newman, Suzette M.; Ferguson, Amy W.; Johnston, Carolyn; Frank, Thomas

doi:10.1097/00000478-199903000-00012

Cited by 101 publications

(63 citation statements)

References 24 publications

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“…Most studies have shown a high and increasing frequency of KRAS mutations in mucinous cystadenomas, borderline tumors and carcinomas, ranging from 33 to 86%. 47,70,72,75,87,88 Several groups 75,87,88 have noted similar KRAS mutation patterns in benign, borderline and malignant mucinous areas within the same neoplasm, which suggests that KRAS mutation is an early event in mucinous tumorigenesis. It has also been noted that the rate of TP53 mutations is lower in mucinous borderline tumors than mucinous carcinomas (13 vs 40%).…”

Section: Molecular Genetic Datamentioning

confidence: 97%

“…[38][39][40][41][42][43][44][45][46][47] It has also been demonstrated that loss of BRCA1 or BRCA2 function by a variety of mechanisms is present in the majority of both sporadic and hereditary high-grade serous and endometrioid carcinomas. 48,49 Boyd and coworkers 36 36,37 demonstrated the same mutation in the carcinoma and the adjacent normal or atypical epithelium in a small number of cases.…”

Section: High-grade Serous Carcinomasmentioning

confidence: 99%

“…[38][39][40][41][42]44,45 Serous borderline tumors have a higher rate of KRAS mutations (27-36%) than high-grade serous carcinomas (0-12%). 40,46,47,[75][76][77][78] BRAF mutations, which are seen in 33-50% of serous borderline tumors of typical or micropapillary type, have not been identified in high-grade serous carcinoma. 74,76,78 A few studies analyzing and comparing serous borderline tumors and low-grade serous carcinomas have been performed only recently.…”

Section: Molecular Genetic Datamentioning

confidence: 99%

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Origins and molecular pathology of ovarian cancer

2005

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Epithelial ovarian cancer comprises the majority of malignant ovarian tumors in adult women. These neoplasms are classified into distinct morphologic categories based on the appearance of the epithelium into tumors of serous, mucinous, endometrioid, clear cell, transitional, squamous, mixed and undifferentiated type. Current data indicate that each of these histologic subtypes is associated with distinct morphologic and molecular genetic alterations: high-grade serous and possibly endometrioid carcinomas most probably arise from surface epithelial inclusion glands with TP53 mutations and dysfunction of BRCA1 and/or BRCA2; low-grade serous carcinomas probably arise in a stepwise fashion in an adenoma-borderline tumor-carcinoma sequence from typical to micropapillary borderline tumors to low-grade invasive serous carcinoma via activation of the RAS-RAF signaling pathway secondary to mutations in KRAS and BRAF; mucinous carcinomas arise via an adenoma-borderline tumor-carcinoma sequence with mutations in KRAS; low-grade endometrioid carcinomas arise from endometriosis via mutations in CTNNB1 (the gene encoding b-catenin) and PTEN. Although the morphologic data strongly support an origin of clear cell carcinoma from endometriosis, there is limited data on the genetic alterations in these uncommon tumors. Thus it is likely that most low-grade, relatively indolent ovarian carcinomas of serous, mucinous and endometrioid type arise from pre-existing cystadenomas or endometriosis whereas most high-grade serous carcinomas arise without an easily identifiable precursor lesion. Modern Pathology (2005) 18, S19-S32. doi:10.1038/modpathol.3800306Keywords: ovarian cancer; ovarian borderline tumors; histogenesis; molecular pathology Epithelial ovarian cancer comprises the majority of malignant ovarian tumors in adult women. These neoplasms are classified into distinct morphologic categories based on the appearance of the epithelium into tumors of serous, mucinous, endometrioid, clear cell, transitional, squamous, mixed and undifferentiated type. 1,2 Two types of ovarian surface epithelial lesions have been described as possible precursors of these carcinomas: lesions that appear in situ in surface epithelium or surface epithelial inclusion glands (SEIG); and preexisting benign epithelial ovarian tumors and endometriosis. The morphologic and genetic data implicating each as a precursor lesion of the major histologic subtypes of ovarian carcinoma are discussed. Surface epithelium and surface epithelial inclusion glands as precursor lesions Morphologic DataTwo types of morphologic data are available regarding the malignant potential of ovarian surface epithelium and inclusion glands, alterations in these structures and studies on microscopic ovarian carcinoma.Surface epithelium and surface epithelial inclusion glands Despite the widespread acceptance of the origin of surface epithelial cancers from the ovarian surface epithelium and its inclusion glands, only rarely have putative precursor lesions been described at these sites. Two...

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Section: Molecular Genetic Datamentioning

confidence: 97%

Section: High-grade Serous Carcinomasmentioning

confidence: 99%

Section: Molecular Genetic Datamentioning

confidence: 99%

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Origins and molecular pathology of ovarian cancer

2005

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“…KRAS mutations are the most common genetic event in 50% of mucinous borderline tumors and in 60% of primary MuOCs 8, 9, 10, 11, 1213.…”

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confidence: 99%

Distinct methylation profile of mucinous ovarian carcinoma reveals susceptibility to proteasome inhibitors

Liew

Huang

Weng

et al. 2018

Intl Journal of Cancer

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Mucinous type of epithelial ovarian cancer (MuOC) is a unique subtype with a poor survival outcome in recurrent and advanced stages. The role of type‐specific epigenomics and its clinical significance remains uncertain. We analyzed the methylomic profiles of 6 benign mucinous adenomas, 24 MuOCs, 103 serous type of epithelial ovarian cancers (SeOCs) and 337 nonepithelial ovarian cancers. MuOC and SeOC exhibited distinct DNA methylation profiles comprising 101 genes, 81 of which exhibited low methylation in MuOC and were associated with the response to glucocorticoid, ATP hydrolysis‐coupled proton transport, proteolysis involved in the cellular protein catabolic process and ion transmembrane transport. Hierarchical clustering analysis showed that the profiles of MuOC were similar to colorectal adenocarcinoma and stomach adenocarcinoma. Genetic interaction network analysis of differentially methylated genes in MuOC showed a dominant network module is the proteasome subunit beta (PSMB) family. Combined functional module and methylation analysis identified PSMB8 as a candidate marker for MuOC. Immunohistochemical staining of PSMB8 used to validate in 94 samples of ovarian tumors (mucinous adenoma, MuOC or SeOC) and 62 samples of gastrointestinal cancer. PSMB8 was commonly expressed in MuOC and gastrointestinal cancer samples, predominantly as strong cytoplasmic and occasionally weak nuclei staining, but was not expressed in SeOC samples. Carfilzomib, a second‐generation proteasome inhibitor, suppressed MuOC cell growth in vitro. This study unveiled a mucinous‐type‐specific methylation profile and suggests the potential use of a proteasome inhibitor to treat MuOC.

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“…Grade not determined (64%) 33/46 (72) (Gadducci et al, 2006) 47/71 (66) (Havrilesky et al, 2003) 16/26 (62) (Caduff et al, 1999) 14/31 (45) (Fujita et al, 1994) 11/20 (55) (Henriksen et al, 1994) 18/23 (78) (Renninson et al, 1994) 31/42 (74) (Dogan et al, 2005) 73/126 (58) (Eltabbakh et al, 1997) Clear cell (8%) 6/38 (17) (Ho et al, 2001) 0/4 (0) (Otis et al, 2000) 1/12 (8) (Caduff et al, 1999) Endometrioid (45%) 5/15 (33) (Dogan et al, 2005) 7/13 (54) (Henriksen et al, 1994) 13/27 (48) (Caduff et al, 1999) Mucinous (19%) 1/12 (8) (Dogan et al, 2005) 3/12 (25) (Renninson et al, 1994) 3/11 (27) (Henriksen et al, 1994) 3/21 (14) (Caduff et al, 1999) (Hashiguchi et al, 2001) 70/117 (60) (Saegusa et al, 2001) 28/82 (34) (Havrilesky et al, 2001) 9/73 (12) (Tachibana et al, 2003) 23/107 (21) (Hashiguchi et al, 2001) 60/134 (45) (Bali et al, 2004) RB Homozygous mutation (9%) 1/24 (4) (Sasano et al, 1990) 2/15 (13) Loss of or aberrant expression (19%) 2/25 (8) (Dodson et al, 1994) 2/26 (8) (Kim et al, 1994) 3/22 (14) (Taylor et al, 1995) 7/34 (21) (Niemann et al, 1998) 2/59 (3) (Kusume et al, 1999) 5/46 (11) (Hashiguchi et al, 2001) 7/9 (78) (Gras et al, 2001) 10/84 (12) (Havrilesky et al, 2001) 1/78 (1) (Konstantinidou et al, 2003) 28/134 (21) (Bali et al, 2004) 12/107 (37) (Hashiguchi et al, 2...…”

mentioning

confidence: 99%

Role of p53 and Rb in Ovarian Cancer

Corney

Flesken‐Nikitin

Choi

et al.

Advances in Experimental Medicine and Biology

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Ovarian cancer remains a major health concern worldwide, primarily in postmenopausal women. Among the most common genetic alterations in human sporadic epithelial ovarian cancer (EOC) are p53 mutations, defective retinoblastoma (RB) pathway (p16 INK4a /RB) and activation of oncogenes such as c-myc, K-ras and Akt. Although these alterations are frequently associated with poor clinical prognosis, their specific contributions to EOC formation remain unclear. In order to gain a better understanding of the roles of these proteins in vivo, a number of mouse models have been generated, largely based upon inducing specific genetic lesions in the ovarian surface epithelium from which the majority of carcinomas are thought to arise in humans. Here, we review the role of tumor suppressor p53 and the Rb pathway in EOC with particular attention to association of p53 to high grade serous carcinomas as opposed to low grade and benign tumors. We also provide an overview of the utility and application of genetically engineered mouse models, in particular towards rational drug design and development of improved imaging techniques in ovarian cancer.

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Comparison of Mutations of Ki-RAS and p53 Immunoreactivity in Borderline and Malignant Epithelial Ovarian Tumors

Cited by 101 publications

References 24 publications

Origins and molecular pathology of ovarian cancer

Origins and molecular pathology of ovarian cancer

Distinct methylation profile of mucinous ovarian carcinoma reveals susceptibility to proteasome inhibitors

Role of p53 and Rb in Ovarian Cancer

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