Molecular pathology of endometrial hyperplasia and carcinoma

Matías‐Guiu, Xavier; Catasús, Lluis; Bussaglia, Elena; Lagarda, Helena; Garcia, Arnald; Pons, Cristina; Muñoz, Josefina; Argüelles, Rosmary; Machín, Pilar Fernández; Prat, Jaime

doi:10.1053/hupa.2001.25929

Cited by 279 publications

(208 citation statements)

References 60 publications

(28 reference statements)

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“…2,4 A dualistic model of endometrial carcinogenesis is widely accepted. 5,[28][29][30][31][32][33][34] Most endometrial carcinomas are of type I, arising from precursor hyperplasia driven by estrogen excess. These tumors express ER and PR, may have microsatellite instability (20%), and may have PTEN mutation (40%).…”

Section: Discussionmentioning

confidence: 99%

Identification of prognostically relevant and reproducible subsets of endometrial adenocarcinoma based on clustering analysis of immunostaining data

et al. 2007

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Panels of immunomarkers can provide greater information than single markers, but the problem of how to optimally interpret data from multiple immunomarkers is unresolved. We examined the expression profile of 12 immunomarkers in 200 endometrial carcinomas using a tissue microarray. The outcomes of groups of patients were analyzed by using the Kaplan-Meier method, using the log-rank statistic for comparison of survival curves. Correlation between clustering results and traditional prognosticators of endometrial carcinoma was examined by either Fisher's exact test or v 2 -test. Multivariate analysis was performed using a proportional hazards method (Cox regression modeling). Seven of the 12 immunomarkers studied showed prognostic significance in univariate analysis (Po0.05) and 1 marker showed a trend toward significance (P ¼ 0.06). These eight markers were used in unsupervised hierarchical clustering of the cases, and resulted in identification of three cluster groups. There was a statistically significant difference in patient survival between these cluster groups (P ¼ 0.0001). The prognostic significance of the cluster groups was independent of tumor stage and patient age on multivariate analysis (P ¼ 0.014), but was not of independent significance when either tumor grade or cell type was added to the model. The cluster group designation was strongly correlated with tumor grade, stage, and cell type (Po0.0001 for each). Interlaboratory reproducibility of subclassification of endometrial adenocarcinoma by hierarchical clustering analysis was verified by showing highly reproducible assignment of individual cases to specific cluster groups when the immunostaining was performed, interpreted, and clustered in a second laboratory (j ¼ 0.79, concordance rate ¼ 89.6%). Unsupervised hierarchical clustering of immunostaining data identifies prognostically relevant subsets of endometrial adenocarcinoma. Such analysis is reproducible, showing less interobserver variability than histopathological assessment of tumor cell type or grade.

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Section: Discussionmentioning

confidence: 99%

Identification of prognostically relevant and reproducible subsets of endometrial adenocarcinoma based on clustering analysis of immunostaining data

et al. 2007

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“…These two types of endometrial carcinomas do not show only different morphological features, but exhibit significant clinical and molecular differences. 24 The possible effects of FLIP and TRAIL in the development of apoptotic cell death in endometrial carcinoma cells have not been addressed so far. We first assessed the viability of two endometrial carcinoma cell lines after exposition to TRAIL.…”

Section: Discussionmentioning

confidence: 99%

FLIP is frequently expressed in endometrial carcinoma and has a role in resistance to TRAIL-induced apoptosis

Dolcet

Llobet

Pallarés

et al. 2005

Laboratory Investigation

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The FLICE-inhibitory protein (FLIP) plays a key role in the regulation of apoptosis triggered by death ligands. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in some types of tumor but not in others. To assess the possible role of FLIP in apoptosis resistance in endometrial carcinoma, we performed an immunohistochemical study on a tissue microarray composed of 95 endometrial carcinomas. We found positive signals in 43% of the cases, as well as a significant difference in FLIP expression between stage I and II tumors. Moreover, we observed that endometrial carcinoma cell lines Ishikawa and KLE did not undergo apoptosis after TRAIL treatment.

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“…24 Somatic MSI and PTEN gene mutations are frequently observed in sporadic endometrial cancer (EC), ranging from 9 to 44% [25][26][27][28][29] and from 25 to 83%, 27,[30][31][32][33][34][35] respectively. Both are associated with endometrioid histology and diploidy, 36,37 and have also been detected in endometrial hyperplasia, indicating that they are early occurrences in the tumorigenic process. 32,[38][39][40] Additionally, the absence of the MMR gene product MLH1, the main cause of MSI in EC, 2 has been observed in normal endometrium adjacent to EC, 41 and PTEN mutations have been detected in null PTENexpressing glands of normal endometrium.…”

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confidence: 95%

The relationship between microsatellite instability and PTEN gene mutations in endometrial cancer

Bilbao

Rodríguez

Ramírez

et al. 2006

Intl Journal of Cancer

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Microsatellite instability (MSI) and mutations in the PTEN gene are among the molecular alterations involved in endometrial carcinogenesis. There is conflicting information regarding to their role in this type of tumor. For this reason, we have studied both molecular lesions in a large population-based series of 205 patients with sporadic endometrial cancer. MSI was found in 41 (20.0%) of the tumors and PTEN mutations were found in 74 (36.1%). There were differences in genotype between tumors with and without MSI. Tumors with MSI showed both a higher frequency of PTEN mutations (58.5% vs. 30.4%) (p 5 0.002, Fisher's exact test) and a higher number of insertions or deletions (I/D) of one nucleotide within the mononucleotide tracts of the PTEN gene (45.8% vs. 11.4% out of all I/D, p 5 0.005). Conversely, G:C to A:T transitions in CpG dinucleotides were found mostly in microsatellite stable tumors (57.7% vs. 18.2% out of all single-base substitutions, p 5 0.037). Overall, 67.6% of tumors with mutated PTEN exhibited multiple mutations or allelic imbalance (AI). Multiple PTEN mutations in the same tumor were more frequent in tumors with MSI (60% vs. 25.7%); by contrast the presence of AI accompanying PTEN mutation was higher in microsatellite stable tumors (74.3% vs. 40%) (p 5 0.028). In addition, patients with both genetic alterations were diagnosed at more advanced stage of progression (54.2% for MSI vs. 20.0% for MSS, p 5 0.006), and exhibited a worse prognosis (hazard ratio [95% confidence interval]: 3.0 [1.1-13.1], p 5 0.034, log-rank test) than patients with only the PTEN gene mutated. Our data suggest that the DNA mismatch repair system status influences: (i) both the frequency and the mutational spectrum of PTEN; (ii) the nature of one of the hits that inactivate this tumor-suppressor gene; and (iii) the clinical condition and behavior of the patients. ' 2006 Wiley-Liss, Inc.Key words: microsatellite instability; PTEN mutation; endometrial cancer Microsatellite instability (MSI) is caused by defects in the DNA mismatch repair (MMR) system, either by mutations or by epigenetic events leading to gene silencing. 1,2 Tumors with MSI are characterized by a massive instability in simple repeated sequences and mutations in many cancer-related genes, particularly those with simple repeated sequences in their coding regions. [3][4][5][6][7] Tumors with MSI display a strong microsatellite mutator phenotype (MMP), which underlies a mutational pathway for gastrointestinal cancer that differs in genotype and phenotype from cancers with microsatellite stability (MSS).The MMP pathway for colon cancer possesses several peculiar characteristics in genotype. These tumors show a paradoxically low incidence of mutations affecting the prototypical cancer genes for colon cancer, namely the APC and p53 tumor suppressor genes and the K-ras oncogene. 3,[8][9][10][11] This low mutational incidence is also accompanied by a decreased incidence of loss of heterozygosity (LOH), 1,3,12 which is reflected at the cytogenetic level in freque...

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Molecular pathology of endometrial hyperplasia and carcinoma

Cited by 279 publications

References 60 publications

Identification of prognostically relevant and reproducible subsets of endometrial adenocarcinoma based on clustering analysis of immunostaining data

Identification of prognostically relevant and reproducible subsets of endometrial adenocarcinoma based on clustering analysis of immunostaining data

FLIP is frequently expressed in endometrial carcinoma and has a role in resistance to TRAIL-induced apoptosis

The relationship between microsatellite instability and PTEN gene mutations in endometrial cancer

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