The mutational landscape of endometrial cancer

Hong, Bo; Gallo, Matthieu Le; Bell, Daphne W.

doi:10.1016/j.gde.2014.12.004

Cited by 35 publications

(28 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent genomic analysis has recognized four molecular subgroups (POLE ultramutated, microsatellite instability hypermutated, copy number low, and copy number high) that are distinct from their histological classification (Kandoth et al, 2013). A common feature of these subgroups is the prevalence of mutations in the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway (Dedes et al, 2011; Hong et al, 2015). Activation of PI3K by growth factor receptors generates phosphatidylinositol-3,4,5-trisphosphate (PIP 3 ), which recruits AKT to the plasma membrane, where it is phosphorylated and activated by PDK1 (T308) and mTORC2 (S473) (Manning and Toker, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…PI3K/AKT signaling is negatively regulated by the tumor suppressor PTEN, a lipid phosphatase that opposes the activity of PI3K by dephosphorylating PIP 3 (Manning and Toker, 2017; Georgescu, 2010). The most common alterations in EC are loss-of-function mutations in PTEN and mutation or amplification of the catalytic subunit of PI3K, PIK3CA (Dedes et al, 2011; Hong et al, 2015). Mutations in PIK3R1, the regulatory subunit of PI3K, AKT, or factors that crosstalk with PI3K/AKT signaling, such as KRAS and EGFR, are also observed.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Crosstalk between PKCα and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium

et al. 2018

View full text Add to dashboard Cite

SUMMARY Protein kinase C (PKC) isozymes are commonly recognized as oncoproteins based on their activation by tumor-promoting phorbol esters. However, accumulating evidence indicates that PKCs can be inhibitory in some cancers, with recent findings propelling a shift in focus to understanding tumor suppressive functions of these enzymes. Here, we report that PKCα acts as a tumor suppressor in PI3K/AKT-driven endometrial cancer. Transcriptional suppression of PKCα is observed in human endometrial tumors in association with aggressive disease and poor prognosis. In murine models, loss of PKCα is rate limiting for endometrial tumor initiation. PKCα tumor suppression involves PP2A-family-dependent inactivation of AKT, which can occur even in the context of genetic hyperactivation of PI3K/AKT signaling by coincident mutations in PTEN, PIK3CA, and/or PIK3R1. Together, our data point to PKCα as a crucial tumor suppressor in the endometrium, with deregulation of a PKCα→PP2A/PP2A-like phosphatase signaling axis contributing to robust AKT activation and enhanced endometrial tumorigenesis.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Crosstalk between PKCα and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Endometrial cancers have been classically categorized into two prognostic groups on the basis of overall tumor characteristics and patient metabolic and endocrine-related risk factors [7, 27]. More recent detailed genomic profiling of endometrioid and serous endometrial carcinomas by the TCGA and other groups have led to the molecular reclassification of endometrial carcinoma into four discrete molecular subgroups with different genomic landscapes, resulting in a molecular classification scheme that is distinct from the overlaying histological classification [28, 29]. …”

Section: Introductionmentioning

confidence: 99%

Use of comprehensive genomic profiling to direct point-of-care management of patients with gynecologic cancers

Rodrı́guez-Rodrı́guez

Hirshfield

Rojas

et al. 2016

Gynecologic Oncology

View full text Add to dashboard Cite

OBJECTIVE To determine the feasibility and clinical utility of using comprehensive genomic profiling (CGP) in the course of clinical care to identify clinically relevant tumor genomic alterations for patients with either rare or refractory gynecologic cancers to facilitate point-of-care management. Use of an expert, multidisciplinary, institutional molecular tumor board (MTB) assessment is discussed regarding input on putative targeted options for individualized therapy. METHODS A prospective clinical trial is ongoing. We report on the initial 69 patients with gynecologic cancers that were either rare or refractory to standard therapy. CGP was performed by Foundation Medicine, Inc. Genomic alterations were reviewed by members of an MTB. Consensus recommendations on genomically targeted, FDA-approved, on- and off-label therapies and clinical trials were sent to the treating physician, and decisions and outcomes were assessed. RESULTS Study outcomes were available for 64 patients. The mean number of genes altered per tumor was 4.97 (median=4; range, 1–26), and the average turnaround time from testing laboratory report to generation of formal recommendations was approximately three weeks. Evaluation of genomic and clinical data by the MTB led to generation of targeted treatment options in all 64 patients, and the percentage of patients for whom one or more of these recommendations were implemented by the treating physician was 39%. Seventy percent of the patients receiving targeted therapy based on a CGP result experienced radiologic response or showed evidence of clinical benefit or stable disease. CONCLUSION These data suggest that an institutional MTB is a feasible venue for reviewing tumor genomic profiling results and generating clinical recommendations. These data also support the need for further studies and guidelines on clinical decision making with greater availability of broad genomically based diagnostics.

show abstract

“…It can cause about 74 000 deaths annually around the world and is classified into several histological subtypes including endometrioid and serous histologies (Hong et al, 2015). In recent years, the incidence of EC has been on a progressive rise due to extensive application of hormone-replacement therapy in clinic, especially for the young people.…”

Section: Introductionmentioning

confidence: 99%

Expression of ER, PR, C-erbB-2 and Ki-67 in Endometrial Carcinoma and their Relationships with the Clinicopathological Features

Yu¹,

Xiangyang²,

Li³

et al. 2015

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

The mutational landscape of endometrial cancer

Cited by 35 publications

References 35 publications

Crosstalk between PKCα and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium

Crosstalk between PKCα and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium

Use of comprehensive genomic profiling to direct point-of-care management of patients with gynecologic cancers

Expression of ER, PR, C-erbB-2 and Ki-67 in Endometrial Carcinoma and their Relationships with the Clinicopathological Features

Contact Info

Product

Resources

About