- Human pathology

Home > G. Tumoral pathology > Molecular pathology of tumors > Endometrial carcinomas (Molecular pathology)

Endometrial carcinomas (Molecular pathology)

Tuesday 17 January 2017

Molecular pathology

Two clinicopathological variants are recognized: the oestrogen-related (type I, endometrioid carcinoma) and the non-oestrogen-related (type II, non-endometrioid carcinoma).

Whereas type I shows microsatellite instability (MSI) and mutations in PTEN, PIK3CA, K-RAS and CTNNB1 (beta-catenin), type II exhibits TP53 mutations and chromosomal instability.

Type I tumours are low-grade oestrogen-related endometrioid carcinomas (EEC) that usually develop in perimenopausal women and coexist with or are preceded by complex and atypical endometrial hyperplasia.

In contrast, type II tumours are aggressive non-endometrioid carcinomas (NEEC) (mainly serous carcinomas and clear cell carcinomas) that occur mainly in older women and are unrelated to oestrogen stimulation.

Occasionally, type II carcinomas may arise in association with so-called ‘serous endometrial intraepithelial carcinoma’, either from atrophic endometrium or endometrial polyps.

It has been shown that the molecular alterations involved in the development of EEC (type I) carcinomas differ from those of NEEC (type II) carcinomas.

EEC shows microsatellite instability (MI) and mutations in the PTEN, K-RAS, PIK3CA and CTNNB1 (beta-catenin) genes, whereas NEEC exhibit alterations of p53, loss of heterozygosity (LOH) on several chromosomes, as well as other molecular alterations (STK15, p16, E-cadherin and c-erb-B2).

Microsatellite instability - MSI

MSI has been demonstrated in 75% of EC associated with hereditary non-polyposis colon cancer (HNPCC), but also in 25–30% of sporadic EC. (MSI-associated endometrial carcinoma)

In sporadic EC, MI occurs more frequently in EEC (30%) than in NEEC, and is secondary to MLH-1 promoter hypermethylation. Although data are controversial regarding the prognostic significance of MI, it is usually associated with a high histological grade.

The MI-associated mismatch repair deficiency leads to the accumulation of many mutations in coding and non-coding DNA sequences, including short-tandem repeats, named microsatellites.

Some small short-tandem repeats, such as mononucleotide repeats, are located within the coding sequence of some important genes (BAX, IGFIIR, hMSH3, hMSH6, MBD4, CHK-1, Caspase-5, ATR, ATM, BML, RAD-50, BCL-10 and Apaf-1), and they may be potential targets in the process of tumour progression of MI+, EC.

Driver genes


  • PTEN, located on chromosome 10q23.3, is frequently abnormal in EC.
  • LOH at the PTEN region occurs in 40% of EC.
  • Somatic PTEN mutations are also common and found predominantly in EEC, occurring in 37–61% of cases.
  • PTEN mutations are found in 60–86% of MI-positive EEC, but in only 24–35% of the MI-negative tumours.
  • Identical PTEN mutations have been detected in hyperplasias coexisting with MI-positive EEC, which suggests that PTEN mutations are early events in tumour development.
  • Although data regarding the prognostic significance of PTEN mutations in EC are controversial, some results suggest an association with favourable prognostic factors.
  • Several studies have shown that EECs with PTEN mutations have genomic instability. For this reason, some authors suggest treating patients with poly (ADP- ribose) polymerase (PARP) inhibitors.

- MLH1

  • MLH1 inactivation by promoter hypermethylation is the most common cause of the microsatellite instability (MI) phenotype in endometrial carcinoma.
  • Progressive accumulation of alterations secondary to MI affects important regulatory genes and promotes carcinogenesis.


  • BAX somatic frameshift mutations are distributed heterogeneously throughout the tumour and provide selective growth advantage.

- PIK3CA / PTEN pathway

  • Phosphatidylinositol 3-kinase (PI3K)–PTEN function. Phosphorylation by PI3K converts phosphatidylinositol biphosphate (PIP2) into phosphatidylinositol triphosphate (PIP3), promoting cell proliferation and survival. PTEN regulates PI3K signalling negatively by dephosphorylation of PIP3.
  • Mutations in PIK3CA contribute to alteration of the PI3K–AKT signalling pathway in EC.
  • PI3K (phosphatidylinositol 3-kinase) is a heterodimeric enzyme consisting of a catalytic subunit (p110) and a regulatory subunit (p85).
  • The PIK3CA gene, located on chromosome 3q26.32, codes for the p110α catalytic subunit of PI3K.
  • A high frequency of mutations in the PIK3CA gene has been reported recently in EC. Mutations are located predominantly in the helical (exon 9) and kinase (exon 20) domains, but they can also occur in exons 1–7.
  • PIK3CA mutations occur in 24–39% of the cases, and coexist frequently with PTEN mutations.
  • PIK3CA mutations, particularly in exon 20, have been associated with adverse prognostic factors such as high histological grade and myometrial invasion.
  • Although described initially in EEC, PI3KCA mutations also occur in NEEC and mixed EEC–NEEC.
  • Furthermore, different gene expression profiles in the PI3K–AKT signalling pathway serve to separate two subgroups of high-grade EC with distinct molecular alterations (PI3K–AKT pathway versus p53 alterations) that may play different roles in endometrial carcinogenesis.
  • Moreover, mutations in PIK3RI, the gene encoding p85α, the inhibitory subunit of PI3K, have been detected in 43% of EEC and 12% of NEEC.

- RAS-RAF-MEK-ERK signalling pathway

  • The RAS-RAF-MEK-ERK signalling pathway plays an important role in tumorigenesis.
  • The frequency of K-RAS mutation in EC ranges between 10 and 30%. In some series, K-RAS mutations have been reported to be more frequent in EEC showing MI.
  • BRAF, another member of the RAS–RAF–MEK–ERK pathways, is mutated very infrequently in EC.
  • RAS effectors such as RASSF1A are thought to provide an inhibitory growth signal, which needs to be inactivated during tumorigenesis.
  • RASSF1A inactivation by promoter hypermethylation may contribute significantly to increased activity of the RAS–RAF–MEK–ERK signalling pathway.


  • Several studies suggest that the fibroblast growth factor (FGF) signalling pathway is important in EC.
  • It has been shown that EC presents frequent inactivation of SPRY-2, a protein involved in the negative regulation of the FGF receptor (FGFR) pathway by promoter methylation.
  • Reduced SPRY2 immunoexpression is seen in almost 20% of EC and is associated strongly with increased cell proliferation.
  • Moreover, somatic mutations in the receptor tyrosine kinase FGFR2 have been detected recently in 6–12% of EC, particularly in EEC.
  • Interestingly, FGFR2 mutations and K-RAS mutations are mutually exclusive events, while mutations in FGFR2 and PTEN frequently coexist. FGFR2 is of special interest as a potential target therapy, and FGFR-2 inhibitors are currently under consideration.


  • The beta-catenin gene (CTNNB1) maps to 3p21. Beta-catenin is a component of the E-cadherin–catenin unit, which plays an important role in cell differentiation and maintenance of normal tissue architecture.
  • Mutations in exon 3 of CTNNB1 result in stabilization of the beta-catenin protein, cytoplasmic and nuclear accumulation, and participation in signal transduction and transcriptional activation through the formation of complexes with DNA binding proteins.
  • Mutations in exon 3 of CTNNB1 with nuclear accumulation of beta-catenin occur in 14–44% of EC.
  • Alterations in CTNNB1 have been described in endometrial hyperplasias that contain squamous metaplasia (morules).
  • Although data are controversial regarding the prognostic significance of CTNNB1 mutations in EC, they probably occur in tumours associated with a good prognosis.

- TP53

  • In contrast to EEC, NEEC show TP53 mutations (90%), markedly reduced expression of E-cadherin (80–90%), c-erb-B2 (HER-2) amplification (30%), alterations in genes involved in regulation of the mitotic spindle checkpoint (STK15) and loss of heterozygosity at multiple loci reflecting chromosomal instability.
  • While TP53 mutations occur in 90% of NEEC, they are present in only 10–20% of EEC, mainly grade 3 tumours.

- E-cadherin

  • Reduced expression of E-cadherin is frequent in EC, and may be caused by LOH or promoter hypermethylation. In fact, LOH at 16q22.1 is seen in almost 60% of NEEC, but in only 22% of EEC. c-erb-B2 overexpression and amplification are also seen more frequently in NEEC (43% and 29%, respectively) than in EEC.


  • The most typical molecular feature of NEEC is the presence of widespread chromosomal gains and losses which reflect the presence of aneuploidy.
  • cDNA arrays have demonstrated that NEEC usually show up-regulation of genes (STK15, BUB1, CCNB2) involved in the regulation of the mitotic spindle checkpoint.
  • One of these genes, STK15, essential for chromosome segregation and centrosome functions, is amplified frequently in NEEC.
  • Recently documented potential biomarkers of serous carcinoma are epithelial cell adhesion molecule (EpCAM), claudin-3 and claudin-4 receptors, serum amyloid A, folate binding protein, mesothelin and insulin-like growth factor-II mRNA binding protein 2 (IMP2).

Among NEEC, clear cell carcinomas show specific features. Endometrial clear cell carcinomas appear to represent a heterogeneous group of tumours that may arise through different pathogenetic pathways.

Based on morphological similarities between ovarian and endometrial clear cell carcinomas, it has been suggested that both tumour types may exhibit similar alterations, including mutations in PIK3CA and PTEN.

Mutation of the ARID1A gene and loss of the corresponding protein BAF250a have been described as frequent events in clear cell and endometrioid carcinomas of the ovary.

In a recent study, however, these changes have been found in 29% of grades 1 or 2 and 39% of grade 3 EECs, 18% of serous NEEC and 26% of clear cell NEEC. Uterine low-grade endometrioid carcinomas have also shown loss of ARID1A expression (26%) and ARID1A mutations (40%).

Expression profiling

cDNA array studies have shown that the expression profiling of EEC differs from that of NEEC.

Genes up-regulated in serous carcinomas were IGF2, PTGS1, FOLR and p16, whereas genes up-regulated in EEC included TFF3, FOXA2 and MSX2. Moreover, two members of the secreted frizzled related protein family (SFRP1 and SFRP4) were down-regulated more frequently in EC with MI.

Interestingly, by comparing the expression profiles of similar histological subtypes of ovarian and endometrial carcinomas it was found that clear cell carcinomas had a similar profile, regardless of the organ of origin. In contrast, differences were striking between endometrioid and serous carcinomas of ovarian and endometrial origin.

The classic perception that cancer resulted mainly from alterations in coding genes has been challenged recently by demonstration of the important roles of non-coding RNAs, such as microRNA and long non-coding RNA (lncRNA).

Non-coding RNAs

MicroRNAs or miRNAs

Among the miRNAs that have been demonstrated to be up-regulated in EC are miR-185, miR-106a, miR-181a, miR-210, miR-423, miR-103, miR-107, miR-Let7c, miR-205, miR-200c, miR-449, miR-429, miR-650, miR-183, miR-572, miR-200a, miR-182, miR-622, miR-34a and miR-205.

In contrast, other miRNAs have been found to be down-regulated, including miR-Let7e, miR-221, miR-30c, miR-152, miR-193, miR-204, miR-99b, miR-193b, miR-204, miR-99b, miR-193b, miR-411, miR-133, miR-203, miR-10a, miR-31, miR-141, miR-155, miR-200b and miR-487b.

These miRNAs target important genes in tumour development and progression, such as KCNMB1, IGFBP-6, ENPP2, TBL1X, CNN1, MYH11, KLF2, TGFB1/1, MYL9, SNCAIP, RAMP1, FOXO1, FOXC1 E2F3, MET and Rictor.

In one series, high levels of miR-205 expression were associated with poor patient overall survival; the miRNA signature was different between EEC and serous carcinoma, and included miR-19a, miR-19b, miR-30e-5p, miR-101, miR-452, miR-15a, miR-29c and miR-382.

The miRNAs Lin28B and let-7b were involved in the regulation of the HMGA-2 gene, a factor that regulates epithelial to mesenchymal transition, and which is expressed frequently in MMMT and NEEC.

Long Non-Coding RNAs

Some of lncRNA may play a role in EC. NC25 is a candidate tumour suppressor lncRNA, mapped to 6q13, that has been shown to be expressed in EC, and to exhibit mutations in almost half of EC samples that have been tested.

Another lncRNA that may have a role in EC is the PTEN pseudogene, PTENP1, which can regulate PTEN’s tumour suppressor role by competitive binding to common miRNAs.

Apoptosis, hypoxia, radiation therapy

There is a great deal of evidence suggesting that alteration of apoptosis is important in the development and progression of EC. Several of the molecular abnormalities that have been detected in EC may be associated with apoptosis deregulation.

EEC show a high frequency of mutations in PTEN, leading to constitutively active AKT which, in turn, suppresses apoptosis triggered by various stimuli.

Moreover, the recent evidence that NF-κB activation is frequent in endometrial carcinoma may explain the presence of apoptosis resistance by activation of target genes such as FLIP and Bcl-xL.

p53 alterations, which are characteristic of NEEC, may also occur in endometrioid tumours, particularly in those neoplasms showing overlapping features between types I and II tumours, and they may have an impact on apoptosis at several different levels.

Also, members of the Bcl-2 family of genes are abnormal in EC. In EC, divergent observations have been reported with respect to Bcl-2 and Bcl-xL. Some authors have found up-regulated Bcl-xL and Bcl-2 in EC compared to normal tissue, and they have also been reported to be involved in development of metastases. Many pathways can control Bcl-2 expression, and typical EC molecular alterations such as those involved in exacerbated PI3K–AKT signalling could trigger Bcl-2 family members’ overexpression.

However, other ‘non-canonical’ molecular events in EEC, such as those involving the NF-κB pathway which plays an important role in tumorigenesis, have been correlated in immunohistochemical studies with strong immunoreactivity for Bcl-xL.

The Bax family contains three former members: Bax, Bak and Bok. All Bax family members contain Bcl-2 homology domains 1–3 and are therefore capable of binding to anti-apoptotic Bcl-2 proteins. This is thought to be the mechanism by which Bcl-2 anti-apoptotic proteins inhibit cell death. Once activated, Bax and Bak trigger permeabilization of the outer mitochondrial membrane that, in turn, will promote release of cytochrome C and other mitochondrial pro-apoptotic factors to the cytosol, such as second mitochondria-derived activator of caspase (Smac)/DIABLO, Omi/HtrA2 protease, endonuclease G and apoptosis-inducing factor (AIF). Interestingly, Bax is a target gene for mutations in EEC with MI, and may have a role in resistance to apoptosis in these tumours.

Cancer cells can evade the extrinsic apoptotic pathway by several mechanisms.

FLICE-like inhibitory protein (FLIP), one of the most important regulators of death receptor signalling (Figure 10), is a protein that shares high homology with caspase-8 but lacks proteolytic activity.

Like caspase-8, it contains two death-effector domains (DED) that allow it to interact either with DED within Fas-associated death domain protein (FADD) or caspase-8, thereby inhibiting death-inducing signalling complex (DISC) assembly and caspase-8 activation. Hence, FLIP represents a potent inhibitor of cell death initiated by death receptors.

Moreover, FLIP overexpression seems to play a key role in tumour evasion of the immune system. Thus, FLIP-induced cell survival through inhibition of the extrinsic apoptotic pathway appears to be critical for the survival of many tumour cells. Direct evidence for the role of FLIP in the resistance of endometrial carcinoma cells to apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL) is provided by treatment with specific small interfering RNAs (siRNA) targeting FLIP.

Transfection of endometrial carcinoma cell lines with FLIP siRNA results in a marked decrease in cell viability after TRAIL exposition. This is accompanied by activation of both caspase-8 and caspase-3, suggesting activation of the extrinsic pathway.

Moreover, in EEC, FLIP can be regulated transcriptionally by casein kinase-2 (CK2), a Ser/Thr kinase implicated in the development and progression of many neoplasias.

These data point further to CK2 as an important modulator of TRAIL sensitivity. In fact, the CK2 beta regulatory subunit has been found overexpressed in endometrial cancer compared to normal tissue and is thought to regulate cell proliferation and anchorage-independent cell growth.

Recent studies have shown that FLIP may be regulated by a cellular complex, including CK2–BRAF–KSR1.

Interestingly, this regulation allows connection of apoptosis resistance with the RAS–RAF–MEK–ERK signalling pathway.

The KSR1 (kinase suppressor of RAS 1) is considered a scaffold protein that regulates the MAP kinase pathway. KSR1 interacts with different kinases of the RAF–MEK–ERK signalling pathway to enhance its activation and also modulates the apoptotic response to death receptors. Recently, it has been shown that the expression of KSR1 is increased in EC, suggesting its possible role in endometrial carcinogenesis.

Tumour hypoxia is known to render tumours more resistant to radiotherapy. By reacting with the radiation-created broken ends of DNA, oxygen fixes the damage and thus enhances radiation-induced cell death.

This phenomenon, known as the ‘oxygen enhancement effect’, could render oxygenated cells three times more radiosensitive than hypoxic cells.

Under hypoxic conditions, the oxygen enhancement effect is lost and cells become more radioresistant. Although the absence of oxygen is the major factor inducing radioresistance under hypoxic conditions, there is increasing evidence that signalling pathways activated under hypoxia may modulate cancer cell radioresistance.

Some investigators have addressed the molecular mechanisms involved in resistance to radiotherapy in EC, including progesterone receptor (PR) expression and a single specific polymorphism in the gene coding for PR (so-called PROGINS allele). De-novo MLH-1 promoter methylation is found occasionally during EC progression in patients receiving radiotherapy.

By comparing immunohistochemically tissue microarrays from post-radiation recurrences of EC and a group of primary EC, interesting information has been obtained regarding the mechanisms of radioresistance. It has been shown that post-radiation recurrences exhibited increased expression of beta-catenin.

Recent work has revealed hypoxia-induced beta-catenin nuclear translocation in EC Ishikawa and HEC-1A cell lines. Moreover, hypoxia induces an increase in TCF-4 reporter (Wnt reporter) activity in both endometrial cell lines.

Hypoxia-inducible factor 1-alpha (HIF-1α) is another candidate that could confer radioresistance to EC cells. HIF-1 is the most important mediator of hypoxia, as it controls the expression of more than 100 genes. It has been shown recently that HIF-1α expression increases in post-radiation recurrences compared to primary EC. HIF-1α controls the classical NF-κB activation pathway and survival under hypoxia through RelA (p65) nuclear accumulation. Possibly, HIF-1α expression results in increased radioresistance.


- Molecular pathology of endometrial carcinoma. Matias-Guiu X, Prat J.
Histopathology. 2013 Jan;62(1):111-23. doi : 10.1111/his.12053 PMID: 23240673


- Molecular pathology of endometrial carcinoma. Matias-Guiu X, Prat J.
Histopathology. 2013 Jan;62(1):111-23. doi : 10.1111/his.12053 Review.
PMID: 23240673

- Endometrial carcinoma: molecular alterations involved in tumor development and progression. Yeramian A, Moreno-Bueno G, Dolcet X, Catasus L, Abal M, Colas E, Reventos J, Palacios J, Prat J, Matias-Guiu X. Oncogene. 2013 Jan 24;32(4):403-13. doi : 10.1038/onc.2012.76 Epub 2012 Mar 19. Review. PMID: 22430211


Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol. Oncol. 1983; 15; 10–17.

Matias-Guiu X, Catasús L, Bussaglia E et al. Molecular pathology of endometrial hyperplasia and carcinoma. Hum. Pathol. 2001; 32; 569–577.

Prat J, Gallardo A, Cuatrecasas M, Catasús L. Endometrial carcinoma: pathology and genetics. Pathology 2007; 39; 72–87.

Llobet D, Pallares J, Yeramian A et al. Molecular pathology of endometrial carcinoma; practical aspects from the diagnostic and therapeutical view points. J. Clin. Pathol. 2009; 62; 777–785.

Duggan BD, Felix JC, Muderspach LI, Tourgeman D, Zheng J, Shibata D. Microsatellite instability in sporadic endometrial carcinoma. J. Natl Cancer Inst. 1994; 86; 1216–1221.

Kobayashi K, Sagae S, Kudo H, Koi S, Nakamura Y. Microsatellite instability in endometrial carcinomas: frequent replication errors in tumors of early onset and/or of poorly differentiated type. Genes Chromosom. Cancer 1995; 14; 128–132.

Risinger JI, Berchuck A, Kohler MF, Watson P, Lynch HT, Boyd J. Genetic instability of microsatellites in endometrial carcinoma. Cancer Res. 1993; 53; 5100–5103.

Catasús L, Machin P, Matias-Guiu X, Prat J. Microsatellite instability in endometrial carcinomas clinicopathologic correlations in a series of 42 cases. Hum. Pathol. 1998; 29; 1160–1164.

Esteller M, Catasús Ll, Matias-Guiu X et al. hMLH1 promoter hypermethylation is an early event in human endometrial tumorigenesis. Am. J. Pathol. 1999; 155; 1767–1772.

Catasús L, Matias-Guiu X, Machin P, Muñoz J, Prat J. BAX somatic frameshift mutations in endometrioid adenocarcinomas of the endometrium: evidence for a tumor progression role in endometrioid carcinomas with microsatellite instability. Lab. Invest. 1998; 78; 1439–1444.

Catasús L, Matias-Guiu X, Machin P et al. Frameshift mutations at coding mononucleotide repeat microsatellites in endometrial carcinomas with microsatellite instability. Cancer 2000; 88; 2290–2297.

Mutter GL, Lin MC, Fitzgerald JT et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J. Natl Cancer Inst. 2000; 92; 924–931.

Tashiro H, Blazes MS, Wu R et al. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res. 1997; 57; 3935–3940.

Bussaglia E, del Rio E, Matias-Guiu X, Prat J. PTEN mutations in endometrial carcinomas. A molecular and clinicopathologic analysis of 38 cases. Hum. Pathol. 2000; 31; 312–317.

Nagase S, Sato S, Tezuka F, Wada Y, Yajima A, Horii A. Deletion mapping on chromosome 10q25–q26 in human endometrial cancer. Br. J. Cancer 1996; 74; 1979–1983.

Shen WH, Balajee AS, Wang J et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 2007; 128; 157–170.

Oda K, Stokoe D, Taketani Y, McCormick F. High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Res. 2005; 65; 10669–10673.

Velasco A, Bussaglia E, Pallares J et al. PIK3CA gene mutations in endometrial carcinoma: correlation with PTEN and K-RAS alterations. Hum. Pathol. 2006; 37; 1465–1472.

Catasús L, Gallardo A, Cuatrecasas M, Prat J. PIK3CA mutations in the kinase domain (exon 20) of uterine endometrial adenocarcinomas are associated with adverse prognostic parameters. Mod. Pathol. 2008; 21; 131–139.

Rudd ML, Price JC, Fogoros S et al. A unique spectrum of somatic PIK3CA (p110alpha) mutations within primary endometrial carcinomas. Clin. Cancer Res. 2011; 17; 1331–1340.

Catasús L, Gallardo A, Cuatrecasas M, Prat J. Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis. Mod. Pathol. 2009; 22; 522–529.

Hayes MP, Douglas W, Ellenson LH. Molecular alterations of EGFR and PIK3CA in uterine serous carcinoma. Gynecol. Oncol. 2009; 113; 370–373.

Catasús L, D’Angelo E, Pons C, Espinosa I, Prat J. Expression profiling of 22 genes involved in the PI3K–AKT pathway identifies two subgroups of high-grade endometrial carcinomas with different molecular alterations. Mod. Pathol. 2010; 23; 694–702.

Urick ME, Rudd ML, Godwin AK, Sgroi D, Merino M, Bell DW. PIK3R1 (p85α) is somatically mutated at high frequency in primary endometrial cancer. Cancer Res. 2011; 15; 4061–4067.

Lagarda H, Catasús L, Argüelles R, Matias-Guiu X, Prat J. K-ras mutations in endometrial carcinoma with microsatellite instability. J. Pathol. 2001; 193; 193–199.

Moreno-Bueno G, Sanchez-Estevez C, Palacios J, Hardisson D, Shiozawa T. Low frequency of BRAF mutations in endometrial and in cervical carcinomas. Clin. Cancer Res. 2006; 15; 3865.

Pallarés J, Velasco A, Eritja N et al. Promoter hypermethylation and reduced expression of RASSF1A are frequent molecular alterations of endometrial carcinoma. Mod. Pathol. 2008; 21; 691–699.

Velasco A, Pallares J, Santacana M et al. Promoter hypermethylation and expression of sprouty 2 in endometrial carcinoma. Hum. Pathol. 2011; 42; 185–193.

Pollock PM, Gartside MG, Dejeza LC et al. Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes. Oncogene 2007; 26; 7158–7162.

Dutt A, Salvesen HB, Chen TH et al. Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc. Natl Acad. Sci. USA 2008; 105; 8713–8717.

Gatius S, Velasco A, Azueta A et al. FGFR-2 alterations in endometrial carcinoma. Mod. Pathol. 2011; 24; 1500–1510.

Fukuchi T, Sakamoto M, Tsuda H, Maruyama K, Nozawa S, Hirohashi S. Beta-catenin mutations in carcinoma of the uterine endometrium. Cancer Res. 1998; 58; 3526–3528.

Kobayashi K, Sagae S, Nishioka Y, Tokino T, Kudo R. Mutations of the beta-catenin gene in endometrial carcinomas. Jpn. J. Cancer Res. 1999; 90; 55–59.

Machin P, Catasús L, Pons C, Muñoz J, Matias-Guiu X, Prat J. CTNNB1 mutations and beta-catenin expression in endometrial carcinomas. Hum. Pathol. 2002; 33; 206–212.

Palacios J, Moreno-Bueno G, Catasús L, Matias-Guiu X, Prat J, Gamallo C. Beta and gamma-catenin expression in endometrial carcinoma. Relationship with clinicopathological features and microsatellite instability. Virchows Arch. 2001; 193; 193–199.

Moreno-Bueno G, Hardisson D, Sánchez C et al. Abnormalities of the APC/beta-catenin pathway in endometrial cancer. Oncogene 2002; 14; 7981–7990.

Tashiro H, Isacson C, Levine R, Kurman RJ, Cho KR, Hedrick L. P53 gene mutations are common in uterine serous carcinoma and occurs early in their pathogenesis. Am. J. Pathol. 1997; 150; 177–185.

Sherman ME, Bur ME, Kurman RJ. P53 in endometrial cancer and its putative precursors: evidence for diverse pathways of tumorigenesis. Hum. Pathol. 1995; 26; 1268–1274.

Hayes MP, Ellenson LH. Molecular alterations in uterine serous carcinoma. Gynecol. Oncol. 2010; 116; 286–289.

Morrison C, Zanagnolo V, Ramirez N et al. HER-2 is an independent prognostic factor in endometrial cancer: association with outcome in a large cohort of surgically staged patients. J. Clin. Oncol. 2006; 24; 2376–2385.

Tritz D, Pieretti M, Turner S, Powell D. Loss of heterozygosity in usual and special variant carcinomas of the endometrium. Hum. Pathol. 1997; 28; 607–612.

Guan B, Mao TL, Panuganti PK et al. Mutation and loss of expression of ARID1A in uterine low-grade endometrioid carcinoma. Am. J. Surg. Pathol. 2011; 35; 625–632.

Wiegand KC, Lee AF, Al-Agha OM et al. Loss of BAF250a (ARID1A) is frequent in high-grade endometrial carcinomas. J. Pathol. 2011; 224; 328–333.

Moreno-Bueno G, Sánchez-Estévez C, Cassia R et al. Differential gene expression profile in endometrioid and nonendometrioid endometrial carcinoma: STK15 is frequently overexpressed and amplified in nonendometrioid carcinomas. Cancer Res. 2003; 63; 5697–5702.

Risinger JI, Maxwell GL, Chandramouli GV et al. Microarray analysis reveals distinct gene expression profiles among different histologic types of endometrial cancer. Cancer Res. 2003; 63; 6–11.

Maxwell GL, Chandramouli GV, Dainty L et al. Microarray analysis of endometrial carcinomas and mixed mullerian tumors reveals distinct gene expression profiles associated with different histologic types of uterine cancer. Clin. Cancer Res. 2005; 11; 4056–4066.

Cao QJ, Belbin T, Socci N et al. Distinctive gene expression profiles by cDNA microarrays in endometrioid and serous carcinomas of the endometrium. Int. J. Gynecol. Pathol. 2004; 23; 321–329.

Risinger JI, Maxwell GL, Chandramouli GV et al. Gene expression profiling of microsatellite unstable and microsatellite stable endometrial cancers indicates distinct pathways of aberrant signaling. Cancer Res. 2005; 65; 5031–5037.

Tafe LJ, Garg K, Chew I, Tornos C, Soslow RA. Endometrial and ovarian carcinomas with undifferentiated components: clinically aggressive and frequently underrecognized neoplasms. Mod. Pathol. 2010; 23; 781–789.

Castilla MÁ, Moreno-Bueno G, Romero-Pérez L et al. Micro-RNA signature of the epithelial–mesenchymal transition in endometrial carcinosarcoma. J. Pathol. 2011; 223; 72–80.

Ratner ES, Tuck D, Richter C et al. MicroRNA signatures differentiate uterine cancer tumor subtypes. Gynecol. Oncol. 2010; 118; 251–257.

Devor EJ, Goodheart MJ, Leslie KK. Toward a microRNA signature of endometrial cancer. Proc. Obstet. Gynecol. 2011; 2; 1–7.

Karaayvaz M, Zhang C, Liang S, Shroyer KR, Ju J. Prognostic significance of miR-205 in endometrial cancer. PLoS ONE 2012; 7; e35158.

Tsuruta T, Kozaki K, Uesugi A et al. miR-152 is a tumor suppressor microRNA that is silenced by DNA hypermethylation in endometrial cancer. Cancer Res. 2011; 71; 6450–6462.

Yanokura M, Banno K, Kobayashi Y et al. MicroRNA and endometrial cancer: roles of small RNAs in human tumors and clinical applications. Oncol. Lett. 2010; 1; 935–940.

Romero-Pérez L, Castilla MA, López-García MA et al. Molecular events in endometrial carcinosarcomas and the role of high mobility group AT-hook 2 in endometrial carcinogenesis. Hum. Pathol. 2012; doi : 10.1016/j.humpath.2012.05.013

Perez DS, Hoage TR, Pritchett JR et al. Long, abundantly expressed non-coding transcripts are altered in cancer. Hum. Mol. Genet. 2008; 17; 642–655.

Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 2010; 465; 1033–1038.

Pallares J, Martinez-Guitarte JL, Dolcet X et al. Abnormalities in NF-kB family and related proteins in endometrial carcinoma. A tissue microarray study. J. Pathol. 2004; 13; 569–577.

Dolcet X, Llobet D, Pallares J, Rue M, Comella JX, Matias-Guiu X. FLIP is frequently expressed in endometrial carcinoma and has a role in resistance to TRAIL-induced apoptosis. Lab. Invest. 2005; 85; 885–894.

Llobet D, Eritja N, Encinas M et al. CK2 controls Trail and Fas sensitivity by regulating flip levels in endometrial carcinoma cells. Oncogene 2008; 27; 2513–2524.

Pallares J, Llobet D, Santacana M et al. CK2beta is expressed in endometrial carcinoma and has a role in apoptosis resistance and cell proliferation. Am. J. Pathol. 2009; 174; 287–296.

Llobet D, Eritja N, Domingo M et al. Dolcet KSR1 is overexpressed in endometrial carcinoma and regulates proliferation and TRAIL-induced apoptosis by modulating FLIP levels. Am. J. Pathol. 2011; 178; 1529–1543.

Santacana M, Yeramian A, Velasco A et al. Immunohistochemical features of post-radiation vaginal recurrences of endometrioid carcinomas of the endometrium. Role for proteins involved in resistance to apoptosis and hypoxia. Histopathology 2012; 60; 460–471.

Yeramian A, Santacana M, Sorolla A et al. Nuclear factor beta/p100 promotes endometrial carcinoma cell survival under hypoxia in a HIF-1alpha in an independent manner. Lab. Invest. 2011; 91; 859–871.

Dedes KJ, Wetterskog D, Mendes-Pereira AM et al. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci. Transl. Med. 2010; 2; 53ra.

Serra V, Markman B, Scaltriti M et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008; 68; 8022–8030.
CrossRef,PubMed,CAS,Web of Science® Times Cited: 215
Shoji K, Oda K, Kashiyama T et al. Genotype-dependent efficacy of a dual PI3K/mTOR inhibitor, NVP-BEZ235, and an mTOR inhibitor, RAD001, in endometrial carcinomas. PLoS ONE 2012; 7; e37431.

Llobet D, Eritja N, Encinas M et al. The multikinase inhibitor sorafenib induces apoptosis and sensitizes endometrial cancer cells to TRAIL by different mechanisms. Eur. J. Cancer 2010; 46; 836–850.

Dolcet X, Llobet D, Encinas M et al. Proteasome inhibitors induce death but activate NF-KB on endometrial carcinoma cell lines and primary culture explants. J. Biol. Chem. 2006; 281; 22118–22130.

Sorolla A, Yeramian A, Valls J et al. Blockade of NFκB activity by Sunitinib increases cell death in Bortezomib-treated endometrial carcinoma cells. Mol. Oncol. 2012; 6; 530–541.