The genomics and genetics of endometrial cancer

O'Hara, Andrea; Bell, Daphne W.

doi:10.2147/agg.s28953

Cited by 59 publications

(55 citation statements)

References 178 publications

(232 reference statements)

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“…The p53 and MMR protein IHC and POLE mutation testing [5] were, however, applied to all histologic subtypes. Strong positive p53 staining is an established feature of serous ECs [3,30,31]. The ProMisE system relies on a three class p53 staining system with absent (abnormal) staining associated with TP53 stop, splice, or frameshift mutations.…”

Section: Discussionmentioning

confidence: 99%

An NRG Oncology/GOG study of molecular classification for risk prediction in endometrioid endometrial cancer

Cosgrove

Tritchler

Cohn

et al. 2018

Gynecologic Oncology

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Objectives The purpose of this study was to assess the prognostic significance of a simplified, clinically accessible classification system for endometrioid endometrial cancers combining Lynch syndrome screening and molecular risk stratification. Methods Tumors from NRG/GOG GOG210 were evaluated for mismatch repair defects (MSI, MMR IHC, and MLH1 methylation), POLE mutations, and loss of heterozygosity. TP53 was evaluated in a subset of cases. Tumors were assigned to four molecular classes. Relationships between molecular classes and clinicopathologic variables were assessed using contingency tests and Cox proportional methods. Results Molecular classification was successful for 982 tumors. Based on the NCI consensus MSI panel assessing MSI and loss of heterozygosity combined with POLE testing, 49% of tumors were classified copy number stable (CNS), 39% MMR deficient, 8% copy number altered (CNA) and 4% POLE mutant. Cancer-specific mortality occurred in 5% of patients with CNS tumors; 2.6% with POLE tumors; 7.6% with MMR deficient tumors and 19% with CNA tumors. The CNA group had worse progression-free (HR 2.31, 95%CI 1.53–3.49) and cancer-specific survival (HR 3.95; 95%CI 2.10–7.44). The POLE group had improved outcomes, but the differences were not statistically significant. CNA class remained significant for cancer-specific survival (HR 2.11; 95%CI 1.04–4.26) in multivariable analysis. The CNA molecular class was associated with TP53 mutation and expression status. Conclusions A simple molecular classification for endometrioid endometrial cancers that can be easily combined with Lynch syndrome screening provides important prognostic information. These findings support prospective clinical validation and further studies on the predictive value of a simplified molecular classification system.

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Section: Discussionmentioning

confidence: 99%

An NRG Oncology/GOG study of molecular classification for risk prediction in endometrioid endometrial cancer

Cosgrove

Tritchler

Cohn

et al. 2018

Gynecologic Oncology

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“…In addition, microsatellite instability (MSI) is predominant in 30% of type I tumors. 4 Unlike Type I, Type II has unique genomic and transcriptomic profile of mutations in p53, p16, E-cadherin, and HER2 overexpression along with low level of oestorgen receptor/progesterone receptor. 4 Recently, it has also been reported that loss of PTEN function and/or aberrant activation of upstream tyrosine kinase growth factor receptors caused PI3K/AKT signaling pathway to drive tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

“…4 Unlike Type I, Type II has unique genomic and transcriptomic profile of mutations in p53, p16, E-cadherin, and HER2 overexpression along with low level of oestorgen receptor/progesterone receptor. 4 Recently, it has also been reported that loss of PTEN function and/or aberrant activation of upstream tyrosine kinase growth factor receptors caused PI3K/AKT signaling pathway to drive tumorigenesis. 2 Mutation of fibroblast growth factor receptor 2 (FGFR2) was identified in about 12~16 % cases of primary uterine tumors 5 and endometrial tumors.…”

Section: Introductionmentioning

confidence: 99%

Antitumor effects and molecular mechanisms of ponatinib on endometrial cancer cells harboring activating FGFR2 mutations

Kim

Kwak

Kim

et al. 2015

Cancer Biology & Therapy

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Aberrant mutational activation of FGFR2 is associated with endometrial cancers (ECs). AP24534 (ponatinib) currently undergoing clinical trials has been known to be an orally available multi-targeted tyrosine kinase inhibitor. Our biochemical kinase assay showed that AP24534 is potent against wild-type FGFR1-4 and 5 mutant FGFRs (V561M-FGFR1, N549H-FGFR2, K650E-FGFR3, G697C-FGFR3, N535K-FGFR4) and possesses the strongest kinase-inhibitory activity on N549H-FGFR2 (IC 50 of 0.5 nM) among all FGFRs tested. We therefore investigated the effects of AP24534 on endometrial cancer cells harboring activating FGFR2 mutations and explored the underlying molecular mechanisms. AP24534 significantly inhibited the proliferation of endometrial cancer cells bearing activating FGFR2 mutations (N549K, K310R/N549K, S252W) and mainly induced G1/S cell cycle arrest leading to apoptosis. AP24534 also diminished the kinase activity of immunoprecipitated FGFR2 derived from MFE-296 and MFE-280 cells and reduced the phosphorylation of FGFR2 and FRS2 on MFE-296 and AN3CA cells. AP24534 caused substantial reductions in ERK phosphorylation, PLCg signaling and STAT5 signal transduction on ECs bearing FGFR2 activating mutations. Akt signaling pathway was also deactivated by AP24534. AP24534 causes the chemotherapeutic effect through mainly the blockade of ERK, PLCg and STAT5 signal transduction on ECs. Moreover, AP24534 inhibited migration and invasion of endometrial cancer cells with FGFR2 mutations. In addition, AP24534 significantly blocked anchorage-independent growth of endometrial cancer cells. We, for the first time, report the molecular mechanisms by which AP24534 exerts antitumor effects on ECs with FGFR2 activating mutations, which would provide mechanistic insight into ongoing clinical investigations of AP24534 for ECs.

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“…Our results also showed that the negative PTEN expression by immunostaining was not linked to increased grade. In fact, in the literature it has been confirmed that PTEN loss of expression is an early event in tumorigenesis and it correlates with the prognosis and response to target therapies [23,24,25,26]. …”

Section: Discussionmentioning

confidence: 99%

Expression of PTEN in Endometrial Liquid-Based Cytology

Lorito¹,

Zappacosta²,

Capanna³

et al. 2014

Acta Cytologica

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Objectives: Endometrial cytology offers a reliable alternative to biopsy in endometrial cancer detection and it may be useful in obtaining material to study prognostic and predictive markers. Over the years, new sampling devices have been developed. Molecular alterations in endometrial cancers were previously described using formalin-fixed paraffin-embedded tissues with particular attention, in endometrioid carcinomas, to the PTEN-PI3K pathway. PTEN evaluation could be useful in endometrial carcinomas for selecting patients for target therapies. Study Design: We studied 51 endometrial samples collected using the Endogyn device and 71 obtained with the Endoflower dispositive device, and processed using liquid-based cytology. Most of the cases were matched with a corresponding histological biopsy. The overall accuracy of Endoflower was 100%. Immunohistochemistry (IHC) and immunocytochemistry (ICC) for PTEN were performed using monoclonal antibody 6H2.1 from DAKO. Results: The IHC showed PTEN-null glands in 4 cases. The same cancers were negative in ICC. Among the 10 carcinomas on cytology, PTEN-null glands were found in 1 case. All the normal endometrium control cases were positive in cytology and histology. Conclusions: Our results suggest that endometrial devices provide useful material for the diagnosis and evaluation of PTEN expression.

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The genomics and genetics of endometrial cancer

Cited by 59 publications

References 178 publications

An NRG Oncology/GOG study of molecular classification for risk prediction in endometrioid endometrial cancer

An NRG Oncology/GOG study of molecular classification for risk prediction in endometrioid endometrial cancer

Antitumor effects and molecular mechanisms of ponatinib on endometrial cancer cells harboring activating FGFR2 mutations

Expression of PTEN in Endometrial Liquid-Based Cytology

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