Assessing inter-component heterogeneity of biphasic uterine carcinosarcomas

Liu, Yihua; Weber, Zachary; Lucas, F. Anthony San; Deshpande, Aditya; Jakubek, Yasminka A.; Sulaiman, Raed; Fagerness, Mary; Flier, N.L.; Sulaiman, Joseph; Davis, Christel M.; Fowler, Jerry; Starks, David; Rojas-Espaillat, Luis; Lazar, Alexander J.; Davies, Gareth E.; Ehli, Erik A.; Scheet, Paul

doi:10.1016/j.ygyno.2018.08.043

Cited by 11 publications

(9 citation statements)

References 24 publications

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“…We have previously suggested that EMT is activated in ECS [65,73,84,85]. Further studies have confirmed this suggestion [25,38,39,84,86]. For example, we used real-time PCR to measure the differences in the expression of, E-cadherin, cadherin-11, SPARC, SNAIL , ZEB1 , ZEB2 , TWIST-1 , TCF4 , TGFβ1, and TGFβ2 between the epithelial and mesenchymal components of 23 ECSs.…”

Section: Epithelial-to-mesenchymal Transitionmentioning

confidence: 84%

“…Previous studies combining aberrant expression of p53 and mutational analysis estimated a TP53 mutation prevalence of 50–60% [3,12,22,27,32,33,34,35]. However, subsequent studies using Next Generation Sequencing (NGS) techniques have shown that the true frequency of TP53 mutation in ECS is very high, between 64% and 91% [29,30,36,37,38,39,40]. In effect, TP53 mutations are the most frequent molecular alterations in ECS (Table 1).…”

Section: Serous-like Molecular Alterations In Ecsmentioning

confidence: 99%

“…In addition to TP53 , ECSs show mutations in other genes that are also more frequently affected in endometrial serous carcinoma (ESC) than in endometrial endometrioid carcinoma (EEC). Accordingly, mutations of FBXW7 and PPP2R1A have been reported in 19% to 39% and 1% to 38%, respectively, in different series [36,37,38,39,40].…”

Section: Serous-like Molecular Alterations In Ecsmentioning

confidence: 99%

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Molecular Basis of Tumor Heterogeneity in Endometrial Carcinosarcoma

Leskelä

Pérez-Míes

Rosa-Rosa

et al. 2019

Cancers

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Endometrial carcinosarcoma (ECS) represents one of the most extreme examples of tumor heterogeneity among human cancers. ECS is a clinically aggressive, high-grade, metaplastic carcinoma. At the morphological level, intratumor heterogeneity in ECS is due to an admixture of epithelial (carcinoma) and mesenchymal (sarcoma) components that can include heterologous tissues, such as skeletal muscle, cartilage, or bone. Most ECSs belong to the copy-number high serous-like molecular subtype of endometrial carcinoma, characterized by the TP53 mutation and the frequently accompanied by a large number of gene copy-number alterations, including the amplification of important oncogenes, such as CCNE1 and c-MYC. However, a proportion of cases (20%) probably represent the progression of tumors initially belonging to the copy-number low endometrioid-like molecular subtype (characterized by mutations in genes such as PTEN, PI3KCA, or ARID1A), after the acquisition of the TP53 mutations. Only a few ECS belong to the microsatellite-unstable hypermutated molecular type and the POLE-mutated, ultramutated molecular type. A common characteristic of all ECSs is the modulation of genes involved in the epithelial to mesenchymal process. Thus, the acquisition of a mesenchymal phenotype is associated with a switch from E- to N-cadherin, the up-regulation of transcriptional repressors of E-cadherin, such as Snail Family Transcriptional Repressor 1 and 2 (SNAI1 and SNAI2), Zinc Finger E-Box Binding Homeobox 1 and 2 (ZEB1 and ZEB2), and the down-regulation, among others, of members of the miR-200 family involved in the maintenance of an epithelial phenotype. Subsequent differentiation to different types of mesenchymal tissues increases tumor heterogeneity and probably modulates clinical behavior and therapy response.

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Section: Epithelial-to-mesenchymal Transitionmentioning

confidence: 84%

Section: Serous-like Molecular Alterations In Ecsmentioning

confidence: 99%

Section: Serous-like Molecular Alterations In Ecsmentioning

confidence: 99%

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Molecular Basis of Tumor Heterogeneity in Endometrial Carcinosarcoma

Leskelä

Pérez-Míes

Rosa-Rosa

et al. 2019

Cancers

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“…The best reference for the genomic alterations in solid tumors is the normal tissue adjacent to the cancer nodule as it became standard in several laboratories[ 46 - 49 ]. We used such reference when profiling surgically removed tumors from persons affected by clear cell renal cell carcinoma[ 7 ], papillary thyroid cancer[ 8 ] and prostate cancer[ 10 ].…”

Section: Cancer Samplesmentioning

confidence: 99%

Powerful quantifiers for cancer transcriptomics

Iacobaş

2020

WJCO

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Every day, investigators find a new link between a form of cancer and a particular alteration in the sequence or/and expression level of a key gene, awarding this gene the title of “biomarker”. The clinician may choose from numerous available panels to assess the type of cancer based on the mutation or expression regulation (“transcriptomic signature”) of “driver” genes. However, cancer is not a “one-gene show” and, together with the alleged biomarker, hundreds other genes are found as mutated or/and regulated in cancer samples. Regardless of the platform, a well-designed transcriptomic study produces three independent features for each gene: Average expression level, expression variability and coordination with expression of each other gene. While the average expression level is used in all studies to identify what genes were up-/down-regulated or turn on/off, the other two features are unfairly ignored. We use all three features to quantify the transcriptomic change during the progression of the disease and recovery in response to a treatment. Data from our published microarray experiments on cancer nodules and surrounding normal tissue from surgically removed tumors prove that the transcriptomic topologies are not only different in histopathologically distinct regions of a tumor but also dynamic and unique for each human being. We show also that the most influential genes in cancer nodules [the Gene Master Regulators (GMRs)] are significantly less influential in the normal tissue. As such, “smart” manipulation of the cancer GMRs expression may selectively kill cancer cells with little consequences on the normal ones. Therefore, we strongly recommend a really personalized approach of cancer medicine and present the experimental procedure and the mathematical algorithm to identify the most legitimate targets (GMRs) for gene therapy.

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“…For example, UCS shares epidemiologic features and patterns of chromosomal instability with high-grade carcinomas, and also shares mutational spectra with ECs, including frequent mutations in loci encoding PI3K pathway components (6–8). Comparison of microdissected epithelial and mesenchymal components from individual patients has revealed common chromosomal alterations and mutations, arguing for a monoclonal origin (9–11). Systematic genomic characterizations of UCS have identified frequent mutations in some genes, most notably Tp53 , but such mutations also frequently occur in serous and high-grade endometrioid cancers and are not specific to UCS (6).…”

mentioning

confidence: 99%

Fbxw7 is a driver of uterine carcinosarcoma by promoting epithelial-mesenchymal transition

Cuevas

Sahoo

Kumar

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Uterine carcinosarcoma is an aggressive variant of endometrial carcinoma characterized by unusual histologic features including discrete malignant epithelial and mesenchymal components (carcinoma and sarcoma). Recent studies have confirmed a monoclonal origin, and comprehensive genomic characterizations have identified mutations such asTp53andPten. However, the biological origins and specific combination of driver events underpinning uterine carcinosarcoma have remained mysterious. Here, we explored the role of the tumor suppressorFbxw7in endometrial cancer through defined genetic model systems. Inactivation ofFbxw7andPtenresulted in the formation of precancerous lesions (endometrioid intraepithelial neoplasia) and well-differentiated endometrioid adenocarcinomas. Surprisingly, all adenocarcinomas eventually developed into definitive uterine carcinosarcomas with carcinomatous and sarcomatous elements including heterologous differentiation, yielding a faithful genetically engineered model of this cancer type. Genomic analysis showed that most tumors spontaneously acquiredTrp53mutations, pointing to a triad of pathways (p53, PI3K, and Fbxw7) as the critical combination underpinning uterine carcinosarcoma, and to Fbxw7 as a key driver of this enigmatic endometrial cancer type. Lineage tracing provided formal genetic proof that the uterine carcinosarcoma cell of origin is an endometrial epithelial cell that subsequently undergoes a prominent epithelial–mesenchymal transition underlying the attainment of a highly invasive phenotype specifically driven by Fbxw7.

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Assessing inter-component heterogeneity of biphasic uterine carcinosarcomas

Cited by 11 publications

References 24 publications

Molecular Basis of Tumor Heterogeneity in Endometrial Carcinosarcoma

Molecular Basis of Tumor Heterogeneity in Endometrial Carcinosarcoma

Powerful quantifiers for cancer transcriptomics

Fbxw7 is a driver of uterine carcinosarcoma by promoting epithelial-mesenchymal transition

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