Synchronous endometrioid carcinomas of the uterine corpus and ovary: alterations in the β-catenin (CTNNB1) pathway are associated with independent primary tumors and favorable prognosis

Irving, Julie; Catasús, Lluis; Gallardo, Alberto; Bussaglia, Elena; Romero, Marisa; Matías‐Guiu, Xavier; Prat, Jaime

doi:10.1016/j.humpath.2005.03.005

Cited by 117 publications

(82 citation statements)

References 41 publications

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“…This frequency of microsatellite instability is almost double that reported for singly occurring sporadic endometrioid carcinomas of both the endometrium (19, 31 -33) and ovary (34). On the contrary, it is consistent with the frequency of hMLH1 hypermethylation and/or microsatellite instability percentage recently observed by two different groups analyzing the synchronous ovarian and endometrial carcinomas of a total of 29 patients (35,36). To date, only one study has reported a very low incidence of microsatellite instability in a series of 45 patients with synchronous ovarian and endometrial carcinomas (37).…”

Section: Discussionsupporting

confidence: 90%

The High Frequency of De novo Promoter Methylation in Synchronous Primary Endometrial and Ovarian Carcinomas

Furlan

Carnevali

Marcomini

et al. 2006

Clinical Cancer Research

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Purpose:The methylation status of hMLH1, CDKN2A, and MGMT was investigated in a panel of synchronous cancers of the ovary and endometrium, fulfilling the clinicopathologic criteria for independent primary tumors to define the possible role of epigenetic mechanisms in the development of these cancers. Experimental Design: Bisulfite-converted DNA from 31tumors (13 endometrial and 18 ovarian carcinomas) and from matched normal tissue of 13 patients was analyzed by a methylationspecific PCR assay at the CpG-rich 5 ¶ regions of all three genes. In all tumors, we also investigated the presence of microsatellite instability and hMLH1immunohistochemical expression in relation to hMLH1 hypermethylation status. Results: Methylation of hMLH1, CDKN2A, and MGMT was detected in 39%, 41%, and 48% of endometrial and ovarian tumors, respectively. hMLH1 hypermethylation was observed in all tumors of five patients, and it was invariably associated with loss of hMLH1protein and presence of microsatellite instability. CDKN2A and MGMT methylation was randomly detected among both endometrial (45% and 24% of cases, respectively) and ovarian carcinomas (39% and 39% of cases, respectively). Concordant methylation at two or three genes was observed in 35% of cases. Conclusions: Epigenetic inactivation of hMLH1, CDKN2A, and MGMT may be a common and early event in the development of synchronous primary endometrial and ovarian carcinomas and may qualify as a marker of a field cancerization encompassing the ovary and endometrium. Detection of MGMT hypermethylation may be useful to define a set of gynecologic malignancies with a specific sensitivity to alkylating chemotherapy.

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Section: Discussionsupporting

confidence: 90%

The High Frequency of De novo Promoter Methylation in Synchronous Primary Endometrial and Ovarian Carcinomas

Furlan

Carnevali

Marcomini

et al. 2006

Clinical Cancer Research

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“…Hence, the probability that two independent tumors within the same individual may harbor the same mutation by chance is more likely than what would occur for an inactivating mutation in a tumor suppressor gene, especially if activation of that oncogene is required to drive tumorigenesis. Additionally, identical gene mutations may be detected in clearly independent primaries resulting from a 'field effect' of a common oncogenic stimulus 17 and the finding of different genetic abnormalities, both in terms of subcellular localization and mutation occurrence, may reflect tumor heterogeneity rather than evidence of separate primaries. 22 In this frame, mitochondrial DNA genotyping displays advantages when the same somatic mutation is found in both endometrial and ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

“…17 We have thus performed b-catenin immunohistochemistry and CTNNB1 sequencing. Cases S3, S4, S7, S10, and S11 showed membranous b-catenin localization in both ovarian and endometrial cancer, while cases S8 and S9 displayed heterogeneous nuclear/membranous b-catenin expression in both neoplasms.…”

Section: Molecular Standard Criteria For Synchrony Diagnosismentioning

confidence: 99%

“…Cases S1 and S2 displayed heterogeneous nuclear/membranous b-catenin localization in ovarian cancer and homogeneous membranous and nuclear b-catenin expression in endometrial cancer, respectively (Table 2). Based on the identical and homogeneous b-catenin localization in endometrial and ovarian cancer, 3,17 S3, S4, S7, S10, and S11 appeared to be metastatic tumors. In S7 ( Figure 1) and S11, b-catenin-based immunohistochemistry diagnosis was in contrast with the histopathological conclusion of synchrony.…”

Section: Molecular Standard Criteria For Synchrony Diagnosismentioning

confidence: 99%

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Mitochondrial DNA genotyping efficiently reveals clonality of synchronous endometrial and ovarian cancers

et al. 2014

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Simultaneous independent primary tumors of the female genital tract occur in 1-2% of gynecological cancer patients, 50-70% of which are synchronous tumors of the endometrium and ovary. Recognition of synchrony upon multiple tumors is crucial for correct prognosis, therapeutic choice, and patient management. Current guidelines for determining synchrony, based on surgical and histopathological findings, are often ambiguous and may require further molecular analyses. However, because of the uniqueness of each tumor and of its intrinsic heterogeneity, these analyses may sometimes be inconclusive. A role for mitochondrial DNA genotyping was previously demonstrated in the diagnosis of synchronous endometrial and ovarian carcinoma. We have analyzed 11 sample pairs of simultaneously revealed endometrial and ovarian cancers and have thereby applied conventional histopathological criteria, current molecular analyses (microsatellite instability, b-catenin immunohistochemical staining/CTNNB1 mutation screening), and mitochondrial DNA sequencing to distinguish separate independent tumors from metastases, comparing the performance and the informative potential of such methods. We have demonstrated that in ambiguous interpretations where histopathological criteria and canonical molecular methods fail to be conclusive, mitochondrial DNA analysis may act as a needle of balance and allow to formulate a diagnosis in 45.5% of our cases. Additional advantages of mitochondrial DNA genotyping, besides the high level of information we demonstrated here, are the easy implementation and the need for small amounts of starting material. Our results show that mitochondrial DNA genotyping may provide a substantial contribution to indisputably recognize the metastatic nature of simultaneously detected endometrial and ovarian cancers and may change the final staging and clinical management of these patients. Modern Pathology (2014) 27, 1412-1420; doi:10.1038/modpathol.2014.39; published online 14 March 2014 Keywords: gynecological cancer; mitochondrial DNA mutations; synchronous tumors About 1-2% of women with gynecological cancers are found to have simultaneous independent primary malignancies. Synchronous tumors in the ovary and endometrium are the commonest combination (50-70%) among all synchronous female genital tract malignancies. Only a subset of these can be accurately categorized by standard histological examination. Criteria for synchrony diagnosis were first documented in 1985 1 and subsequently detailed in 1998. 2 Unfortunately, a relevant fraction of cases remains which may not be classified with confidence, either because of widespread involvement, in which case the distinction is of academic rather than practical or prognostic significance, or, more importantly, because of overlapping or

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“…(Nusse, 2008) Loss of its membranous function or a higher nuclear presence has been linked with poor survival in several studies in ovarian cancer based upon immunohistochemical studies. (Faleiro-Rodrigues et al, 2004;FaleiroRodrigues, Macedo-Pinto, Pereira, & Lopes, 2004;Irving et al, 2005;Rosen et al, 2010;Stawerski et al, 2008;Stawerski, Wagrowska-Danilewicz, Stasikowska, Gottwald, & Danilewicz, 2008;Voutilainen et al, 2006; In addition, a correlation of -Catenin protein expression has been described with tumour grade and Ki-67 expression. (Stawerski et al, 2008;Voutilainen et al, 2006) Present results are thus confirmative of earlier findings that -Catenin is associated with survival outcome.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic Pathway Signatures and Survival Outcome

Trinh¹,

Dam²,

Dirix³

et al. 2012

Ovarian Cancer - Basic Science Perspective

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Synchronous endometrioid carcinomas of the uterine corpus and ovary: alterations in the β-catenin (CTNNB1) pathway are associated with independent primary tumors and favorable prognosis

Cited by 117 publications

References 41 publications

The High Frequency of De novo Promoter Methylation in Synchronous Primary Endometrial and Ovarian Carcinomas

The High Frequency of De novo Promoter Methylation in Synchronous Primary Endometrial and Ovarian Carcinomas

Mitochondrial DNA genotyping efficiently reveals clonality of synchronous endometrial and ovarian cancers

Oncogenic Pathway Signatures and Survival Outcome

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