Endometrial Cancer

Overview

Literature Analysis

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Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (38)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

GeneLocationAliasesNotesTopicPapers
PTEN 10q23.3 BZS, DEC, CWS1, GLM2, MHAM, TEP1, MMAC1, PTEN1, 10q23del -PTEN mutations in Endometrial Cancer
431
TP53 17p13.1 P53, BCC7, LFS1, TRP53 -TP53 Mutations in Endometrial Cancer
218
MSH6 2p16 GTBP, HSAP, p160, GTMBP, HNPCC5 -MSH6 and Endometrial Cancer
99
PIK3CA 3q26.3 MCM, CWS5, MCAP, PI3K, CLOVE, MCMTC, p110-alpha -PIK3CA and Endometrial Cancer
75
JAZF1 7p15.2-p15.1 TIP27, ZNF802 -JAZF1 and Endometrial Cancer
31
ARID1A 1p35.3 ELD, B120, OSA1, P270, hELD, BM029, MRD14, hOSA1, BAF250, C1orf4, BAF250a, SMARCF1 -ARID1A and Endometrial Cancer
27
CYP1B1 2p22.2 CP1B, GLC3A, CYPIB1, P4501B1 -CYP1B1 and Endometrial Cancer
25
ESR1 6q25.1 ER, ESR, Era, ESRA, ESTRR, NR3A1 -ESR1 and Endometrial Cancer
20
HSD17B2 16q24.1-q24.2 HSD17, SDR9C2, EDH17B2 -HSD17B2 and Endometrial Cancer
13
SUZ12 17q11.2 CHET9, JJAZ1 -SUZ12 and Endometrial Cancer
12
PPP2R1A 19q13.41 PR65A, PP2AAALPHA, PP2A-Aalpha -PPP2R1A and Endometrial Cancer
11
YWHAE 17p13.3 MDS, HEL2, MDCR, KCIP-1, 14-3-3E -YWHAE and Endometrial Cancer
11
POLE 12q24.3 FILS, POLE1, CRCS12 -POLE and Endometrial Cancer
9
GPER1 7p22.3 mER, CEPR, GPER, DRY12, FEG-1, GPR30, LERGU, LyGPR, CMKRL2, LERGU2, GPCR-Br -GPER and Endometrial Cancer
9
PIK3R1 5q13.1 p85, AGM7, GRB1, IMD36, p85-ALPHA -PIK3R1 and Endometrial Cancer
6
RBL2 16q12.2 Rb2, P130 Prognostic
-RBL2 and Endometrial Cancer
6
PIK3CB 3q22.3 PI3K, PIK3C1, P110BETA, PI3KBETA -PIK3CB and Endometrial Cancer
6
ETV5 3q28 ERM -ETV5 and Endometrial Cancer
5
SFRP4 7p14.1 FRP-4, FRPHE, sFRP-4 -SFRP4 and Endometrial Cancer
5
ADIPOR2 12p13.31 PAQR2, ACDCR2 -ADIPOR2 and Endometrial Cancer
4
ESR2 14q23.2 Erb, ESRB, ESTRB, NR3A2, ER-BETA, ESR-BETA -ESR2 and Endometrial Cancer
4
HSD17B1 17q11-q21 HSD17, EDHB17, EDH17B2, SDR28C1 -HSD17B1 and Endometrial Cancer
4
BAG1 9p12 HAP, BAG-1, RAP46 Overexpression
-BAG1 overexpression in Endometrial Cancer
4
PAEP 9q34 GD, GdA, GdF, GdS, PEP, PAEG, PP14 -PAEP and Endometrial Cancer
4
ADIPOR1 1q32.1 CGI45, PAQR1, ACDCR1, CGI-45, TESBP1A -ADIPOR1 and Endometrial Cancer
4
LEPR 1p31 OBR, OB-R, CD295, LEP-R, LEPRD -LEPR and Endometrial Cancer
3
EBAG9 8q23 EB9, PDAF -EBAG9 and Endometrial Cancer
3
POLD1 19q13.3 CDC2, MDPL, POLD, CRCS10 -POLD1 and Endometrial Cancer
3
PAPPA 9q33.2 PAPA, DIPLA1, PAPP-A, PAPPA1, ASBABP2, IGFBP-4ase -PAPPA and Endometrial Cancer
3
HTRA1 10q26.3 L56, HtrA, ARMD7, ORF480, PRSS11, CARASIL -HTRA1 and Endometrial Cancer
3
KLLN 10q23 CWS4, KILLIN -killin protein, human and Endometrial Cancer
2
ERRFI1 1p36 MIG6, RALT, MIG-6, GENE-33 -ERRFI1 and Endometrial Cancer
2
TRIM27 6p22 RFP, RNF76 -TRIM27 and Endometrial Cancer
2
PIK3R2 19q13.2-q13.4 p85, MPPH, P85B, MPPH1, p85-BETA -PIK3R2 and Endometrial Cancer
2
ARID5B 10q21.2 MRF2, DESRT, MRF-2 -ARID5B mutations in Endometrial Carcinoma
1
CTNND1 11q11 CAS, p120, CTNND, P120CAS, P120CTN, p120(CAS), p120(CTN) -CTNND1 and Endometrial Cancer
1
NUTM2A 10q23.2 FAM22A -NUTM2A and Endometrial Cancer
1
ARHGEF5 7q35 P60, TIM, GEF5, TIM1 -ARHGEF5 and Endometrial Cancer
1

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

Xiao YT, Luo LM, Zhang R
Effect of lentivirus mediated cyclooxygenase-2 gene shorthairpinRNA on invasiveness of endometrial carcinoma.
Eur J Gynaecol Oncol. 2015; 36(1):44-8 [PubMed] Related Publications
OBJECTIVE: This study aims to explore the effects of lentivirus mediated cyclooxygenase-2 gene shorthairpinRNA (COX-2-shRNA) on invasiveness of endometrial carcinoma HEC-1B cells.
MATERIALS AND METHODS: Double-stranded DNA oligonucleotide of COX-2-shRNA was designed and synthesized, and the recombinant lentiviral vector COX-2-ShRNA (LV-COX-2-ShRNA) was constructed. LV-COX-2-ShRNA, pHelper 1, and pHelper 2 were transferred into 293T cells, followed by lentiviral packaging. The virus titer was tested according to expression level of GFP in 293T cells. HEC-1B cells were infected with recombinant lentivirus. The silencing of COX-2 gene was assessed by real-time PCR and western-blot, and the in vivo invasiveness of HEC-1B cells was analyzed by transwell invasion assay.
RESULTS: Recombinant lentiviral vector expressing siRNA targeting COX-2 gene was successfully constructed to harvest the recombinant lentivirus with the concentrated virus suspension titer of 5 x 10(7)Tu/ml. Compared with control group, the inhibitory rate of COX-2 expression in HEC-1B cells in siRNA group were 61.87% and 67.48% at mRNA and protein level, respectively. The mean number of cells penetrating matrigel was 16.6, which was significantly less than the control group 50.2 and non-specific siRNA infection group 47.2, the invasion inhibition rate being 64.8% (p < 0.01).
CONCLUSION: RNA interference can inhibit the invasiveness of HEC-in cells.

Flicker K, Smolle E, Haybaeck J, Moinfar F
Genomic characterization of endometrial stromal sarcomas with array comparative genomic hybridization.
Exp Mol Pathol. 2015; 98(3):367-74 [PubMed] Related Publications
INTRODUCTION: The endometrial stromal sarcoma (ESS) is a very rare uterine sarcoma, counting for 1-3% of all gynecologic malignancies. ESS represents 0.2-8% of all uterine malignant tumors and accounts for about 10% of all uterine sarcomas. With regard to chromosomal aberrations, very little is known about benign and malignant endometrial stromal tumors.
METHODS: 30 tumors, consisting of 4 cases of benign endometrial stromal nodule (ESN), 22 cases of low-grade ESS and 4 cases of undifferentiated endometrial sarcoma (UES), were analyzed by array-comparative genomic hybridization (aCGH).
RESULTS: ESN did not show many copy number changes (CNCs) by aCGH. Frequent losses could be identified on chromosomes 7p and 19, and gains on chromosomes 1q, 6p and 8q. Low-grade ESS presented as a very heterogeneous group. 90% (20/22) of cases displayed aberrations. Most frequent changes were losses on chromosomes 7 and 22, and gains on chromosome 1q or 11. UES showed a high number of chromosomal aberrations and on every chromosome CNCs were detected. Most frequent changes were losses on chromosomes 1q, 2q (3/4, 75%) and 13, and gains on chromosomes 1q and 17p.
CONCLUSION: Our data shows an increasing number of CNCs from ESN to low-grade ESS and to UES. However, the chromosomal aberrations differ considerably between the investigated ESN-, low-grade ESS- and UES cases and thus, a linear tumor progression seems to be unlikely.

Yoneyama K, Ishibashi O, Kawase R, et al.
miR-200a, miR-200b and miR-429 are onco-miRs that target the PTEN gene in endometrioid endometrial carcinoma.
Anticancer Res. 2015; 35(3):1401-10 [PubMed] Related Publications
Endometrioid endometrial carcinoma (EEC) is a common malignancy of the female genital tract. However, no adequate biomarker is currently available for predicting the prognosis of this cancer. Recent studies have revealed dysregulated expression of several microRNAs (miRNAs) in various cancer tissues, and therefore, these cancer-associated miRNAs (also called onco-miRs) could be promising prognostic biomarkers of cancer progression or metastasis. In this study, in order to identify onco-miRs and their possible targets involved in EEC, we performed microarray-based integrative analyses of miRNA and mRNA expression in specimens excised from EEC lesions and adjacent normal endometrial tissues. Using integrated statistical analyses, we identified miR-200a, miR-200b and miR-429 as highly up-regulated onco-miRs in EECs. Conversely, we detected expression of a tumor-suppressor gene, phosphatase and tensin homolog (PTEN), which was predicted in silico using a miRNA-targeting mRNA prediction algorithm, as a target of the three miRNAs and which was down-regulated in EECs. Furthermore, these miRNAs were validated to target PTEN experimentally using luciferase assays and real-time polymerase chain reaction. These results suggest that the occurrence of EEC is, at least in part, mediated by miRNA-induced suppression of PTEN expression.

Dong R, Pu H, Wang Y, et al.
TESTIN was commonly hypermethylated and involved in the epithelial-mesenchymal transition of endometrial cancer.
APMIS. 2015; 123(5):394-400 [PubMed] Related Publications
We previously reported frequent loss of TESTIN in human endometrial carcinoma, which significantly suppressed tumor proliferation and invasion. Herein, we further explored the mechanisms underlying TESTIN loss and its roles in the epithelial-mesenchymal transition (EMT, a key step for tumor spreading). Methylation-specific PCR was performed to investigate the promoter status of TESTIN in a panel of endometrial cancer and normal endometrium tissues. The expression of TESTIN mRNA was determined by real-time PCR. Up- and down-regulation of TESTIN were achieved by transient transfection with pcDNA3.1-TESTIN and shRNA-TESTIN plasmids, respectively. The EMT alterations were observed under the optical microscope and EMT-related markers were detected by real-time PCR and western blot. Compared to the control (3.6%), TESTIN was hypermethylated in 43.7% endometrial cancer tissues (p < 0.001). Moreover, TESTIN hypermethylation was significantly correlated with advanced tumor stage, deep myometrial invasion and lymphatic node metastasis. In vitro, the demethylating agent dramatically restored the expression of TESTIN. In addition, up-regulation of TESTIN significantly suppressed the EMT procedure; whereas down-regulation of TESTIN enhanced EMT. In conclusion, we demonstrated that loss of TESTIN was mainly caused by hypermethylation, which might be a potent prognostic marker. Furthermore, we proved that TESTIN significantly suppressed the EMT procedure, proposing restoration of TESTIN to be a novel therapeutic strategy for endometrial carcinoma.

Wang H, Bao W, Jiang F, et al.
Mutant p53 (p53-R248Q) functions as an oncogene in promoting endometrial cancer by up-regulating REGγ.
Cancer Lett. 2015; 360(2):269-79 [PubMed] Related Publications
P53 mutation plays a pivotal role in tumorigenesis of endometrial cancer (EC), here we report that the gain-of-function mutant p53-R248Q targets the proteasome activator REGγ to promote EC progression. Increased p53 expression significantly correlated with high pathological grade and lymph node metastasis in EC specimens. Manipulation of p53-R248Q in EC cells caused coincident changes in REGγ expression, and chromatin immunoprecipitation coupled with PCR further indicated that p53-R248Q bound to the REGγ gene promoter at a p53 responsive element. Silencing of REGγ in EC cells attenuated the cell proliferation, migration and invasion abilities, whereas overexpression of p53-R248Q rescued these activities. Overexpression of REGγ also induced an epithelial-mesenchymal transition phenotype. Moreover, a mouse xenograft tumor model showed that REGγ promoted tumor growth, further demonstrating a p53-R248Q-REGγ oncogenic pathway. Finally, examination of EC and normal endometrium specimens confirmed the oncogenic role of REGγ, in that REGγ was more highly overexpressed in p53-positive specimens than in p53-negative specimens. Our data suggest that REGγ is a promising therapeutic target for EC with the p53-R248Q mutation.

Coenegrachts L, Garcia-Dios DA, Depreeuw J, et al.
Mutation profile and clinical outcome of mixed endometrioid-serous endometrial carcinomas are different from that of pure endometrioid or serous carcinomas.
Virchows Arch. 2015; 466(4):415-22 [PubMed] Related Publications
Clinical outcome of 23 patients with mixed endometrioid and serous endometrial carcinomas (mixed EEC-SC) was compared to that of pure endometrioid (EEC) and pure serous (SC) carcinomas. Hotspot mutation frequencies in KRAS, PIK3CA, PTEN, and TP53 and microsatellite instability (MSI) status were determined in mixed EEC-SC, as well as in their EEC and SC microdissected components separately, and alterations were compared to frequencies in pure EEC and SC. Relapse-free (RFS) and overall survival (OS) differed significantly between mixed EEC-SC and pure EEC and SC, revealing that outcome of mixed EEC-SCs was intermediate to that of pure EEC and pure SC. PTEN mutations were absent in pure SC, but occurred in 20 % of pure EEC, and 13 % of mixed EEC-SC. In contrast, TP53 mutations were more frequent in pure SC (17 %) and mixed EEC-SC (22 %) than in pure EEC (2 %). Mutations in mixed EEC-SC were shared by the two microdissected components in 30 %, whereas in 35 %, some mutations were component-specific. Mutation analysis confirms similarities between the EEC and SC components of mixed EEC-SC with pure EEC and pure SC, respectively. However, PTEN and KRAS mutations were more frequent in the SC component of mixed EEC-SC than in pure SC, while TP53 mutations were more frequent in the EEC component of mixed EEC-SC than in pure EEC. Presence of different clonal mutation pattern between EEC and SC components of mixed EEC-SC raises the possibility of divergent tumor heterogeneity or biclonal origin in some cases.

Bakkum-Gamez JN, Wentzensen N, Maurer MJ, et al.
Detection of endometrial cancer via molecular analysis of DNA collected with vaginal tampons.
Gynecol Oncol. 2015; 137(1):14-22 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
OBJECTIVE: We demonstrate the feasibility of detecting EC by combining minimally-invasive specimen collection techniques with sensitive molecular testing.
METHODS: Prior to hysterectomy for EC or benign indications, women collected vaginal pool samples with intravaginal tampons and underwent endometrial brushing. Specimens underwent pyrosequencing for DNA methylation of genes reported to be hypermethylated in gynecologic cancers and recently identified markers discovered by profiling over 200 ECs. Methylation was evaluated individually across CpGs and averaged across genes. Differences between EC and benign endometrium (BE) were assessed using two-sample t-tests and area under the curve (AUC).
RESULTS: Thirty-eight ECs and 28 BEs were included. We evaluated 97 CpGs within 12 genes, including previously reported markers (RASSF1, HSP2A, HOXA9, CDH13, HAAO, and GTF2A1) and those identified in discovery work (ASCL2, HTR1B, NPY, HS3ST2, MME, ADCYAP1, and additional CDH13 CpG sites). Mean methylation was higher in tampon specimens from EC v. BE for 9 of 12 genes (ADCYAP1, ASCL2, CDH13, HS3ST2, HTR1B, MME, HAAO, HOXA9, and RASSF1) (all p<0.05). Among these genes, relative hypermethylation was observed in EC v. BE across CpGs. Endometrial brush and tampon results were similar. Within tampon specimens, AUC was highest for HTR1B (0.82), RASSF1 (0.75), and HOXA9 (0.74). This is the first report of HOXA9 hypermethylation in EC.
CONCLUSION: DNA hypermethylation in EC tissues can also be identified in vaginal pool DNA collected via intravaginal tampon. Identification of additional EC biomarkers and refined collection methods are needed to develop an early detection tool for EC.

Bednarek M, Constantinou M, Kqpczyfiskil L, et al.
[Evaluation of genomic imbalance in endometrial hyperplasia and carcinoma].
Ginekol Pol. 2014; 85(11):828-32 [PubMed] Related Publications
OBJECTIVE: The main goal of our study was to identify the earliest and specific genetic changes which could be associated with an increased risk of neoplastic transformation in a group of patients with endometrial hyperplasia. Another goal was to characterize genetic changes associated with advanced forms of cancer.
MATERIAL AND METHODS: The study involved forty-four (44) female patients, including five (5) patients with no histopathologically confirmed hyperplastic features, twenty-six (26) patients with histopathologically confirmed endometrial hyperplasia, and thirteen (13) patients with diagnosed carcinoma of the endometrium. The study was conducted using a custom-made 4x180 K microarray of BlueGnome.
RESULTS: Copy number variations (CNV) were found in the cases without endometrial hyperplasia. Such changes occur with varying frequency in the genome of healthy female population. Significant genome imbalance was identified in the twenty-six (26) (100%) patients with diagnosed hyperplasia and in eleven (11) subjects (84.6%) with diagnosed endometrial cancer. Other not yet reported, changes localized in characteristic regions of the genome were also found.

Pamuła-Piłat J, Rubel T, Rzepecka IK, et al.
Gene expression profiles in three histologic types, clear-cell, endometrioid and serous ovarian carcinomas.
J Biol Regul Homeost Agents. 2014 Oct-Dec; 28(4):659-74 [PubMed] Related Publications
Ovarian carcinoma is the most lethal type of gynecologic malignancy in the Western world. Majority of early stage ovarian cancers are asymptomatic and this is the main reason that more than two-thirds of patients are diagnosed with advanced disease. Ovarian tumors are heterogeneous and the different histologic subtypes are further classified as benign, borderline (low-grade) and malignant (high-grade) to reflect their behavior. The aim of the study was to analyze gene expression profiles in three histologic types of ovarian carcinoma in an attempt to find the molecular differences among serous, endometrioid and clear cell subtypes. The analysis of gene expression was performed on 57 samples of ovarian carcinoma. RNA was isolated from the ovarian cancer tissues. The gene expression changes were determined by microarray analysis and quantitative real time polymerase chain reaction (qRT-PCR). Measurement of relative gene expression levels was used to identify molecular differences among three histologic types of ovarian carcinoma (clear-cell, endometrioid and serous). Unsupervised statistical analysis revealed four biological subtypes among three histotypes under study. The endometrioid ovarian carcinoma was divided into two molecular subtypes. The biggest molecular differences were observed between clear-cell and serous carcinomas (1070 genes, FDR 0.05), the smallest between endometrioid and serous carcinomas (81 genes, FDR 0.05). The biggest group of differentially expressed genes was involved in transport and metabolism. This finding can explain the differences in the response to chemotherapy observed among different histologic types of ovarian carcinomas. In conclusion, we found TCF2 (HNF1B) gene as a suitable marker for ovarian clear cell carcinoma. Gene expression profiling also shed light on the molecular mechanisms of different chemoresistance among the analyzed histotypes.

Hu ZY, Tang LD, Zhou Q, et al.
Aberrant promoter hypermethylation of p16 gene in endometrial carcinoma.
Tumour Biol. 2015; 36(3):1487-91 [PubMed] Related Publications
Previous studies demonstrated that the loss of function of the p16INK4A gene is mainly caused by the hypermethylation of p16 gene promoter; however, whether or not it is associated with the incidence of endometrial carcinoma (EC) remains unclear. In the current study, we conducted a meta-analysis to investigate the effects of p16 gene promoter hypermethylation on the incidence of EC. Detailed research publications were searched from Embase, PubMed, and ISI Web of Knowledge for composition in English or Chinese. The pooled data were collected and analyzed by Review Manager 5.2. Odds ratios (ORs) were calculated and summarized respectively. Six eligible studies, including 261 patients were selected and analyzed. The pooled OR was 0.42, test for overall effect, Z = 10.19, P < 0.0001, indicating that p16 gene promoter hypermethylation was significantly correlated with the EC patients. The results of our study strongly suggest that p16 gene promoter hypermethylation is correlated with an increased risk of EC. P16 gene promoter hypermethylation plays a critical role in endometrial carcinogenesis.

Win AK, Reece JC, Ryan S
Family history and risk of endometrial cancer: a systematic review and meta-analysis.
Obstet Gynecol. 2015; 125(1):89-98 [PubMed] Related Publications
OBJECTIVE: To obtain precise estimates of endometrial cancer risk associated with a family history of endometrial cancer or cancers at other sites.
DATA SOURCES: For the systematic review, we used PubMed to search for all relevant studies on family history and endometrial cancer that were published before December 2013. Medical Subject Heading terms "endometrial neoplasm" and "uterine neoplasm" were used in combination with one of the key phrases "family history," "first-degree," "familial risk," "aggregation," or "relatedness."
METHODS OF STUDY SELECTION: Studies were included if they were case-control or cohort studies that investigated the association between a family history of cancer specified to site and endometrial cancer. Studies were excluded if they were review or editorial articles or not translated into English or did not define family history clearly or used spouses as control participants.
TABULATION, INTEGRATION, AND RESULTS: We included 16 studies containing 3,871 women as cases and 49,475 women as controls from 10 case-control studies and 33,510 women as cases from six cohort studies. We conducted meta-analyses to estimate the pooled relative risk (95% confidence interval [CI]) of endometrial cancer associated with a first-degree family history of endometrial, colorectal, breast, ovarian, and cervical cancer to be: 1.82 (1.65-1.98), 1.17 (1.03-1.31), 0.96 (0.88-1.04), 1.13 (0.85-1.41), and 1.19 (0.83-1.55), respectively. We estimated cumulative risk of endometrial cancer to age 70 years to be 3.1% (95% CI 2.8-3.4) for women with a first-degree relative with endometrial cancer and the population-attributable risk to be 3.5% (95% CI 2.8-4.2).
CONCLUSION: Women with a first-degree family history of endometrial cancer or colorectal cancer have a higher risk of developing endometrial cancer than those without a family history. This study is likely to be of clinical relevance to inform women of their risk of endometrial cancer.

Yang M, Li L, Wang J, et al.
Heterogeneous nuclear ribonucleoproteins (hnRNPs) and human transformer-2-beta1 (hTra2-beta1)-regulated estrogen receptor-alpha improves prognosis of endometrial cancer.
Eur J Gynaecol Oncol. 2014; 35(6):701-7 [PubMed] Related Publications
PURPOSE OF INVESTIGATION: Heterogeneous nuclear ribonucleoprotein (hnRNP) family possesses decreasing effect towards endometrial cancer (EC) and human transformer-2-betal (hTra2-betal) performs an intimate relationship with EC, either. Recent study shows that hnRNPs and hTra2-betal regulate the genetic expression, which is concerned with estrogen receptor (ER).
MATERIALS AND METHODS: The present study was designed to investigate the link between ER and hnRNPs or hTra2-betal in the prognosis of EC patients by Real-time PCR and immunohistochemisty (IHC).
RESULTS: Results showed that ER protein expression presented a significant change in the recurrence and outcome of EC patients, and the nucleus hTra2-betal protein expression was also increased in the recurrent patients, indicating that the three might be important in ER expression in the prognosis therapy of EC patients.
CONCLUSION: The present findings provide an insight of pharmaceutical targeting therapy and prognosis of EC.

Lapińska-Szumczyk S, Supernat A, Żaczek AJ, et al.
[Endometrial cancer in young women--clinical and molecular aspects].
Ginekol Pol. 2014; 85(10):754-9 [PubMed] Related Publications
OBJECTIVES: The aim the study was to compare two groups of endometrial cancer patients (below and above 45 years of age) in the aspect of clinicopathological and molecular data.
MATERIAL AND METHODS: The study encompassed 456 primary tumour samples retrospectively collected from a cohort of endometrial cancer patients, primarily treated by surgery Molecular analysis covered: copy number variations of 10 genes (TOP2A, ERBB1, ERBB2, ERBB3, ERBB4, MYC, CCND1, ESR1, PIK3CA, RAD21) analyzed by quantitative PCR; mRNA expression of 6 genes (SCGB2A2, RAD27, RUNX1, SNAI1, SNAI2, PROM1) analyzed with the use of reverse transcription quantitative PCR; protein expression analysis of 8 markers (PGR, ESR1; ERBB1, ERBB2, ERBB3, ERBB4, TOP2A, pAKT1) performed with the use of immunohistochemistry.
RESULTS: The younger group of patients was characterized by less frequent hypertension (p <0.00007), less frequent myometrial infiltration (p=0.002) and longer overall survival (p=0.003). Apart from RAD21 gene aberrations, which were more frequent in younger patients (p=0.02), the study revealed no statistically significant differences between the groups.
CONCLUSIONS: The study showed no molecular differences in the profile of younger and older endometrial cancer patients. Data on both the prognostic and predictive significance of RAD21 in endometrial cancer are still insufficient. The clinical profile of younger patients with endometrial carcinoma was slightly better when compared to elderly patients. Younger patients were characterized by longer overall survival.

Church DN, Stelloo E, Nout RA, et al.
Prognostic significance of POLE proofreading mutations in endometrial cancer.
J Natl Cancer Inst. 2015; 107(1):402 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
BACKGROUND: Current risk stratification in endometrial cancer (EC) results in frequent over- and underuse of adjuvant therapy, and may be improved by novel biomarkers. We examined whether POLE proofreading mutations, recently reported in about 7% of ECs, predict prognosis.
METHODS: We performed targeted POLE sequencing in ECs from the PORTEC-1 and -2 trials (n = 788), and analyzed clinical outcome according to POLE status. We combined these results with those from three additional series (n = 628) by meta-analysis to generate multivariable-adjusted, pooled hazard ratios (HRs) for recurrence-free survival (RFS) and cancer-specific survival (CSS) of POLE-mutant ECs. All statistical tests were two-sided.
RESULTS: POLE mutations were detected in 48 of 788 (6.1%) ECs from PORTEC-1 and-2 and were associated with high tumor grade (P < .001). Women with POLE-mutant ECs had fewer recurrences (6.2% vs 14.1%) and EC deaths (2.3% vs 9.7%), though, in the total PORTEC cohort, differences in RFS and CSS were not statistically significant (multivariable-adjusted HR = 0.43, 95% CI = 0.13 to 1.37, P = .15; HR = 0.19, 95% CI = 0.03 to 1.44, P = .11 respectively). However, of 109 grade 3 tumors, 0 of 15 POLE-mutant ECs recurred, compared with 29 of 94 (30.9%) POLE wild-type cancers; reflected in statistically significantly greater RFS (multivariable-adjusted HR = 0.11, 95% CI = 0.001 to 0.84, P = .03). In the additional series, there were no EC-related events in any of 33 POLE-mutant ECs, resulting in a multivariable-adjusted, pooled HR of 0.33 for RFS (95% CI = 0.12 to 0.91, P = .03) and 0.26 for CSS (95% CI = 0.06 to 1.08, P = .06).
CONCLUSION: POLE proofreading mutations predict favorable EC prognosis, independently of other clinicopathological variables, with the greatest effect seen in high-grade tumors. This novel biomarker may help to reduce overtreatment in EC.

Liu Y, Broaddus RR, Zhang W
Identifying aggressive forms of endometrioid-type endometrial cancer: new insights into molecular subtyping.
Expert Rev Anticancer Ther. 2015; 15(1):1-3 [PubMed] Related Publications
Clinical heterogeneity represents a great challenge for cancer therapeutics. Molecular classification of patients into different subtypes based on genetic or epigenetic characteristics has the potential to revolutionize the clinical care and mechanistic understanding of a wide spectrum of cancers, including endometrial carcinoma, the most common gynecological cancer affecting women.

Liu JY, Yang Y, Liu ZZ, et al.
Association between the CYP1B1 polymorphisms and risk of cancer: a meta-analysis.
Mol Genet Genomics. 2015; 290(2):739-65 [PubMed] Related Publications
The previous, published data on the association between CYP1B1 polymorphisms and cancer risk remained controversial. To derive a more precise estimation of the association between the CYP1B1 polymorphisms and cancer risk, we performed a meta-analysis to investigate the association between cancer susceptibility and CYP1B1 Leu432Val, Asn453Ser, Arg48Gly, and Ala119Ser polymorphisms. For Asn453Ser and Arg48Gly polymorphisms, significantly decreased endometrial cancer was observed among Caucasians. For Ala119Ser polymorphism, we found that individuals with the minor variant genotypes had a high risk of prostate cancer. For Leu432Val polymorphism, we found that individuals with the minor variant genotypes had a higher risk of endometrial cancer and lung cancer and had a lower risk of ovarian cancer. In summary, this meta-analysis suggests that Leu432Val polymorphism is associated with ovarian cancer, lung cancer, and endometrial cancer risk; Asn453Ser and Arg48Gly polymorphisms are associated with endometrial cancer risk among Caucasians, Ala119Ser polymorphism is associated with prostate cancer risk, and Ala119Ser polymorphism is associated with breast cancer risk in Caucasians. In addition, our work also points out the importance of new studies for Ala119Ser polymorphism in endometrial cancer, because high heterogeneity was observed (I (2) > 75 %).

Romani C, Calza S, Todeschini P, et al.
Identification of optimal reference genes for gene expression normalization in a wide cohort of endometrioid endometrial carcinoma tissues.
PLoS One. 2014; 9(12):e113781 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
Accurate normalization is a primary component of a reliable gene expression analysis based on qRT-PCR technique. While the use of one or more reference genes as internal controls is commonly accepted as the most appropriate normalization strategy, many qPCR-based published studies still contain data poorly normalized and reference genes arbitrarily chosen irrespective of the particular tissue and the specific experimental design. To date, no validated reference genes have been identified for endometrial cancer tissues. In this study, 10 normalization genes (GAPDH, B2M, ACTB, POLR2A, UBC, PPIA, HPRT1, GUSB, TBP, H3F3A) belonging to different functional and abundance classes in various tissues and used in different studies, were analyzed to determine their applicability. In total, 100 endometrioid endometrial cancer samples, which were carefully balanced according to their tumor grade, and 29 normal endometrial tissues were examined using SYBR Green Real-Time RT-PCR. The expression stability of candidate reference genes was determined and compared by means of geNorm and NormFinder softwares. Both algorithms were in agreement in identifying GAPDH, H3F3A, PPIA, and HPRT1 as the most stably expressed genes, only differing in their ranking order. Analysis performed on the expression levels of all candidate genes confirm HPRT1 and PPIA as the most stably expressed in the study groups regardless of sample type, to be used alone or better in combination. As the stable expression of HPRT1 and PPIA between normal and tumor endometrial samples fulfill the basic requirement of a reference gene to be used for normalization purposes, HPRT1 expression showed significant differences between samples from low-grade and high-grade tumors. In conclusion, our results recommend the use of PPIA as a single reference gene to be considered for improved reliability of normalization in gene expression studies involving endometrial tumor samples at different tumor degrees.

Nallapalle SR, Daripally S, Prasad VT
Promoter polymorphism of FASL confers protection against female-specific cancers and those of FAS impact the cancers divergently.
Tumour Biol. 2015; 36(4):2709-24 [PubMed] Related Publications
We investigated risk association of FAS (-1377 G>A and -670 A>G) and FASL (-844 T>C) promoter polymorphisms with breast, ovarian, cervical, and endometrial cancers and report that the FASL -844 CC genotype was protective against breast, ovarian, cervical, and endometrial cancers (P ≤ 0.01). On the other hand, FAS -1377 GA and AA variants increased risk of breast cancer. However, the GA variant of FAS -1377 was also found to be a risk factor for cervical cancer. In contrast, FAS -670 AG variant significantly lowered risk of breast cancer. Further, we also observed that risk association of co-occurrence of FAS and/or FASL variants with the cancers varied as compared to the presence of individual polymorphisms. Although risk and protective haplotypes of FAS SNPs were observed across the cancer phenotypes, the association of the haplotypes was significant for breast cancer alone with a 3-fold enhanced risk. The protective effect of the FASL CC genotype seen in this study suggests that similar biomolecular mechanisms involving FASL might play a role in female-specific cancers.

Lai HC, Wang YC, Yu MH, et al.
DNA methylation as a biomarker for the detection of hidden carcinoma in endometrial atypical hyperplasia.
Gynecol Oncol. 2014; 135(3):552-9 [PubMed] Related Publications
OBJECTIVE: Women with atypical hyperplasia (AH) are often found to have endometrial carcinoma (EC) at hysterectomy. The purpose of this study was to evaluate whether the hypermethylation of specific genes found by methylomic approaches to the study of gynecologic cancers is a biomarker for EC in women with AH.
METHODS: We evaluated the methylation of AJAP1, HS3ST2, SOX1, and PTGDR from 61 AH patients undergoing hysterectomy. Endometrial biopsy samples were analyzed by bisulfite conversion and quantitative methylation-specific polymerase chain reaction. A methylation index was used to predict the presence of cancer. To confirm the silencing effects of DNA methylation, immunohistochemical analysis of AJAP1, HS3ST2, and SOX1 was performed using tissue microarray.
RESULTS: Fourteen (23%) patients had EC at hysterectomy. AJAP1, HS3ST2, and SOX1 were highly methylated in the EC patients' biopsy samples (p≤0.023). AJAP1, HS3ST2, and SOX1 protein expression was significantly higher in patients with AH only (p≤0.038). The predictive value of AJAP1, HS3ST2, and SOX1 methylation for EC was 0.81, 0.72, and 0.70, respectively. Combined testing of both AJAP1 and HS3ST2 methylation had a positive predictive value of 56%, methylation of any one of AJAP1, SOX1, or HS3ST2 had a 100% negative predictive value.
CONCLUSIONS: Hypermethylation of AJAP1, HS3ST2, and SOX1 is predictive of EC in AH patients. Testing for methylation of these genes in endometrial biopsy samples may be a hysterectomy-sparing diagnostic tool. Validation of these new genes as biomarkers for AH screening in a larger population-based study is warranted.

Wang L, Lu H, Li J, et al.
The association between XRCC1 genetic polymorphisms and the risk of endometrial carcinoma in Chinese.
Gene. 2015; 554(2):155-9 [PubMed] Related Publications
Accumulated evidences report that X-ray repair cross-complementing group 1 gene (XRCC1) genetic polymorphisms play an important role in the development of endometrial carcinoma (EC). This study aims to evaluate the association of XRCC1 c.1161G>A and c.1804C>A genetic polymorphisms with the risk of EC. A total of 218 EC patients and 243 cancer-free controls were included in this study. The genotypes of XRCC1 genetic polymorphisms were determined by the created restriction site-polymerase chain reaction (CRS-PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) methods. We found that these two genetic polymorphisms were statistically associated with the risk of EC. As for c.1161G>A, in comparison with GG wild genotype, the AA genotype was significantly associated with the increased risk of EC (OR=2.36, 95% CI 1.28-4.37, χ(2)=7.71, P=0.005). As for c.1804C>A, the CC genotype significantly increased the risk of EC in comparison with CC wild genotype (OR=2.77, 95% CI 1.38-5.58, χ(2)=8.54, P=0.003). Our data indicate that the A allele of c.1161G>A and c.1804C>A genetic polymorphisms could contribute to increase the risk of EC (for c.1161G>A: A versus (vs.) G, OR=1.34, 95% CI 1.02-1.76, χ(2)=4.56, P=0.033; for c.1804C>A: A vs. C, OR=1.34, 95% CI 1.01-1.77, χ(2)=4.03, P=0.045). Our results indicate that the XRCC1 c.1161G>A and c.1804C>A genetic polymorphisms significantly influenced the risk of EC in Chinese populations, and might be used as molecular markers for evaluating EC risk.

Hevir-Kene N, Rižner TL
The endometrial cancer cell lines Ishikawa and HEC-1A, and the control cell line HIEEC, differ in expression of estrogen biosynthetic and metabolic genes, and in androstenedione and estrone-sulfate metabolism.
Chem Biol Interact. 2015; 234:309-19 [PubMed] Related Publications
Estrogens have important roles in the pathogenesis of endometrial cancer. They can have carcinogenic effects through stimulation of cell proliferation or formation of DNA-damaging species. To characterize model cell lines of endometrial cancer, we determined the expression profiles of the estrogen receptors (ERs) ESR1, ESR2 and GPER, and 23 estrogen biosynthetic and metabolic genes, and investigated estrogen biosynthesis in the control HIEEC cell line and the Ishikawa and HEC-1A EC cell lines. HIEEC and Ishikawa expressed all ERs to different extents, while HEC-1A cells lacked expression of ESR1. Considering the estrogen biosynthetic and metabolic enzymes, these cells showed statistically significant different gene expression profiles for SULT2B1, HSD3B2, CYP19A1, AKR1C3, HSD17B1, HSD17B7, HSD17B12, CYP1B1, CYP3A5, COMT, SULT1A1, GSTP1 and NQO2. In these cells, E2 was formed from E1S and E1, while androstenedione was not converted to estrogens. HIEEC and Ishikawa had similar profiles of androstenedione and E1 metabolism, but hydrolysis of E1S to E1 was weaker in Ishikawa cells. HEC-1A cells were less efficient for activation of E1 into the potent E2, but metabolized androstenedione to other androgenic metabolites better than HIEEC and Ishikawa cells. This study reveals that HIEEC, Ishikawa, and HEC-1A cells can all form estrogens only via the sulfatase pathway. HIEEC, Ishikawa, and HEC-1A cells expressed all the major genes in the production of hydroxyestrogens and estrogen quinones, and in their conjugation. Significantly higher CYP1B1 mRNA levels in Ishikawa cells compared to HEC-1A cells, together with lack of UGT2B7 expression, indicate that Ishikawa cells can accumulate more toxic estrogen-3,4-quinones than HEC-1A cells, as also for HIEEC cells. This study provides further characterization of HIEEC, Ishikawa, and HEC-1A cells, and shows that they differ greatly in expression of the genes investigated and in their capacity for E2 formation, and thus they represent different in vitro models.

Rudd ML, Mohamed H, Price JC, et al.
Mutational analysis of the tyrosine kinome in serous and clear cell endometrial cancer uncovers rare somatic mutations in TNK2 and DDR1.
BMC Cancer. 2014; 14:884 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
BACKGROUND: Endometrial cancer (EC) is the 8th leading cause of cancer death amongst American women. Most ECs are endometrioid, serous, or clear cell carcinomas, or an admixture of histologies. Serous and clear ECs are clinically aggressive tumors for which alternative therapeutic approaches are needed. The purpose of this study was to search for somatic mutations in the tyrosine kinome of serous and clear cell ECs, because mutated kinases can point to potential therapeutic targets.
METHODS: In a mutation discovery screen, we PCR amplified and Sanger sequenced the exons encoding the catalytic domains of 86 tyrosine kinases from 24 serous, 11 clear cell, and 5 mixed histology ECs. For somatically mutated genes, we next sequenced the remaining coding exons from the 40 discovery screen tumors and sequenced all coding exons from another 72 ECs (10 clear cell, 21 serous, 41 endometrioid). We assessed the copy number of mutated kinases in this cohort of 112 tumors using quantitative real time PCR, and we used immunoblotting to measure expression of these kinases in endometrial cancer cell lines.
RESULTS: Overall, we identified somatic mutations in TNK2 (tyrosine kinase non-receptor, 2) and DDR1 (discoidin domain receptor tyrosine kinase 1) in 5.3% (6 of 112) and 2.7% (3 of 112) of ECs. Copy number gains of TNK2 and DDR1 were identified in another 4.5% and 0.9% of 112 cases respectively. Immunoblotting confirmed TNK2 and DDR1 expression in endometrial cancer cell lines. Three of five missense mutations in TNK2 and one of two missense mutations in DDR1 are predicted to impact protein function by two or more in silico algorithms. The TNK2(P761Rfs*72) frameshift mutation was recurrent in EC, and the DDR1(R570Q) missense mutation was recurrent across tumor types.
CONCLUSIONS: This is the first study to systematically search for mutations in the tyrosine kinome in clear cell endometrial tumors. Our findings indicate that high-frequency somatic mutations in the catalytic domains of the tyrosine kinome are rare in clear cell ECs. We uncovered ten new mutations in TNK2 and DDR1 within serous and endometrioid ECs, thus providing novel insights into the mutation spectrum of each gene in EC.

Radenbaugh AJ, Ma S, Ewing A, et al.
RADIA: RNA and DNA integrated analysis for somatic mutation detection.
PLoS One. 2014; 9(11):e111516 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
The detection of somatic single nucleotide variants is a crucial component to the characterization of the cancer genome. Mutation calling algorithms thus far have focused on comparing the normal and tumor genomes from the same individual. In recent years, it has become routine for projects like The Cancer Genome Atlas (TCGA) to also sequence the tumor RNA. Here we present RADIA (RNA and DNA Integrated Analysis), a novel computational method combining the patient-matched normal and tumor DNA with the tumor RNA to detect somatic mutations. The inclusion of the RNA increases the power to detect somatic mutations, especially at low DNA allelic frequencies. By integrating an individual's DNA and RNA, we are able to detect mutations that would otherwise be missed by traditional algorithms that examine only the DNA. We demonstrate high sensitivity (84%) and very high precision (98% and 99%) for RADIA in patient data from endometrial carcinoma and lung adenocarcinoma from TCGA. Mutations with both high DNA and RNA read support have the highest validation rate of over 99%. We also introduce a simulation package that spikes in artificial mutations to patient data, rather than simulating sequencing data from a reference genome. We evaluate sensitivity on the simulation data and demonstrate our ability to rescue back mutations at low DNA allelic frequencies by including the RNA. Finally, we highlight mutations in important cancer genes that were rescued due to the incorporation of the RNA.

Moir-Meyer GL, Pearson JF, Lose F, et al.
Rare germline copy number deletions of likely functional importance are implicated in endometrial cancer predisposition.
Hum Genet. 2015; 134(3):269-78 [PubMed] Related Publications
Endometrial cancer is the most common invasive gynaecological cancer in women, and relatively little is known about inherited risk factors for this disease. This is the first genome-wide study to explore the role of common and rare germline copy number variants (CNVs) in predisposition to endometrial cancer. CNVs were called from germline DNA of 1,209 endometrioid endometrial cancer cases and 528 cancer-unaffected female controls. Overall CNV load of deletions or DNA gains did not differ significantly between cases and controls (P > 0.05), but cases presented with an excess of rare germline deletions overlapping likely functional genomic regions including genes (P = 8 × 10(-10)), CpG islands (P = 1 × 10(-7)) and sno/miRNAs regions (P = 3 × 10(-9)). On average, at least one additional gene and two additional CpG islands were disrupted by rare deletions in cases compared to controls. The most pronounced difference was that over 30 sno/miRNAs were disrupted by rare deletions in cases for every single disruption event in controls. A total of 13 DNA repair genes were disrupted by rare deletions in 19/1,209 cases (1.6%) compared to one gene in 1/528 controls (0.2%; P = 0.007), and this increased DNA repair gene loss in cases persisted after excluding five individuals carrying CNVs disrupting mismatch repair genes MLH1, MSH2 and MSH6 (P = 0.03). There were 34 miRNA regions deleted in at least one case but not in controls, the most frequent of which encompassed hsa-mir-661 and hsa-mir-203. Our study implicates rare germline deletions of functional and regulatory regions as possible mechanisms conferring endometrial cancer risk, and has identified specific regulatory elements as candidates for further investigation.

Kim TH, Yoo JY, Kim HI, et al.
Mig-6 suppresses endometrial cancer associated with Pten deficiency and ERK activation.
Cancer Res. 2014; 74(24):7371-82 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
PTEN mutations are the most common genetic alterations in endometrial cancer. Loss of PTEN and subsequent AKT activation stimulate estrogen receptor α-dependent pathways that play an important role in endometrial tumorigenesis. The major pathologic phenomenon of endometrial cancer is the loss of ovarian steroid hormone control over uterine epithelial cell proliferation and apoptosis. However, the precise mechanism of PTEN/AKT signaling in endometrial cancer remains poorly understood. The progesterone signaling mediator MIG-6 suppresses estrogen signaling and it has been implicated previously as a tumor suppressor in endometrial cancer. In this study, we show that MIG-6 also acts as a tumor suppressor in endometrial cancers associated with PTEN deficiency. Transgenic mice, where Mig-6 was overexpressed in progesterone receptor-expressing cells, exhibited a relative reduction in uterine tumorigenesis caused by Pten deficiency. ERK1/2 was phosphorylated in uterine tumors and administration of an ERK1/2 inhibitor suppressed cancer progression in PR(cre/+)Pten(f/f) mice. In clinical specimens of endometrial cancer, MIG-6 expression correlated inversely with ERK1/2 phosphorylation during progression. Taken together, our findings suggest that Mig-6 regulates ERK1/2 phosphorylation and that it is crucial for progression of PTEN-mutant endometrial cancers, providing a mechanistic rationale for the evaluation of ERK1/2 inhibitors as a therapeutic treatment in human endometrial cancer.

Mahdi H, Mester JL, Nizialek EA, et al.
Germline PTEN, SDHB-D, and KLLN alterations in endometrial cancer patients with Cowden and Cowden-like syndromes: an international, multicenter, prospective study.
Cancer. 2015; 121(5):688-96 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
BACKGROUND: Endometrial cancer has been recognized only recently as a major component of Cowden syndrome (CS). Germline alterations in phosphatase and tensin homolog (PTEN; PTEN_mut+), succinate dehydrogenase B/C/D (SDHB-D; SDHx_var+), and killin (KLLN_Me+) cause CS and Cowden syndrome-like (CSL) phenotypes. This study was aimed at identifying the prevalence and clinicopathologic predictors of germline PTEN_mut+, SDHx_var+, and KLLN_Me+ in CS/CSL patients presenting with endometrial cancer.
METHODS: PTEN and SDHB-D mutation and KLLN promoter methylation analyses were performed for 371 prospectively enrolled patients (2005-2011). PTEN protein was analyzed from patient-derived lymphoblast lines. The PTEN Cleveland Clinic (CC) score is a weighted, regression-based risk calculator giving the a priori risk for PTEN_mut+. Demographic and clinicopathologic features were correlated with the specific gene.
RESULTS: Germline PTEN_mut+, SDHx_var+, and KLLN_Me+ were found in 7%, 9.8%, and 10.5% of informative samples, respectively. Predictors of PTEN_mut+ included an age ≤ 50 years (odds ratio [OR] for an age < 30 years, 6.1 [P = .015]; OR for an age of 30-50 years, 4.4 [P = .001]), macrocephaly (OR, 14.4; P < .001), a higher CC score (OR for a 1-U increment, 1.35; P < .001), a PTEN protein level within the lowest quartile (OR, 5.1; P = .039), and coexisting renal cancer (OR, 5.7; P = .002). KLLN_Me+ patients were on average 8 years younger than KLLN_Me- patients (44 vs 52 years, P = .018). Predictors of KLLN_Me+ were a younger age and a higher CC score. On the other hand, no clinical predictors of SDH_var+ were found.
CONCLUSIONS: Clinical predictors of PTEN and KLLN alterations, but not SDHx_var+, were identified. These predictors should alert the treating physician to potential heritable risk and the need for referral to genetic professionals. High-risk cancer surveillance and prophylactic surgery of the uterus may be considered for KLLN_Me+ patients similarly to PTEN_mut+ patients.

Zhao J, Liu T, Yu G, Wang J
Overexpression of HABP1 correlated with clinicopathological characteristics and unfavorable prognosis in endometrial cancer.
Tumour Biol. 2015; 36(2):1299-306 [PubMed] Related Publications
Hyaluronic acid binding protein 1 (HABP1/gC1qR/p32), a ubiquitous multifunctional protein belonging to the hyaladherin family, has been implicated in the tumorigenesis, progression, invasion, and metastasis of several malignant tumors. However, the role of HABP1 in endometrial cancer has not yet been studied. This study aimed to detect the expression of HABP1 in endometrial cancer and explore its role in the clinicopathological features and prognosis of endometrial cancer. We analyzed HABP1 expression by immunohistochemistry in 188 endometrial cancer specimens, 43 benign endometrial lesion specimens, and 41 normal endometrium specimens and assessed using Western blot analysis. Statistical analysis showed that HABP1 was overexpressed in endometrial cancer and benign endometrial lesion compared with normal endometrium (P < 0.001 and P = 0.012, respectively). In addition, HABP1 expression was significantly higher in endometrial cancer than in benign endometrial lesion (P < 0.001). High HABP1 expression was significantly associated with advanced International Federation of Gynecology and Obstetrics stage (P = 0.019), higher histologic grade (P < 0.001), deep myometrial invasion (P = 0.013), lymphovascular space invasion (P = 0.010), lymph node metastasis (P = 0.015), and recurrence (P = 0.009). Patients with high HABP1 expression had a poorer overall survival (OS) and disease-free survival (DFS) than patients with low HABP1 expression (P = 0.015 and P = 0.012, respectively). Multivariate Cox regression analysis showed that the HABP1 expression status was an independent prognostic factor of OS and DFS (P = 0.025 and P = 0.022, respectively) in patients with endometrial cancer. Our results indicated that overexpression of HABP1 may serve as a new biomarker to predict the progression and prognosis of endometrial cancer.

Maiques O, Cuevas D, García Dios DA, et al.
FISH analysis of PTEN in endometrial carcinoma. Comparison with SNP arrays and MLPA.
Histopathology. 2014; 65(3):371-88 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
AIMS: To check the usefulness of a standardized protocol of PTEN FISH in 31 endometrial carcinomas (ECs) in comparison with SNP array (SNPA), multiplex ligation-dependent probe amplification (MLPA), and immunohistochemistry.
METHODS AND RESULTS: Fluorescence in-situ hybridization analysis showed two PTEN copies in 17 cases, three copies in nine cases, hemizygous deletion in two cases, and diverse cell populations with different PTEN copy number in three cases. A good correlation was seen between FISH and SNPA, particularly in cases with three copies. FISH identified two cases with entire deletion of chromosome 10, but did not identify a focal deletion of PTEN. Five cases with PTEN deletion and duplication of the second allele by SNPA were interpreted as normal by FISH. Concordance between FISH and MLPA was seen in 15 cases with two copies, and in two cases with PTEN deletion. Six cases were interpreted as amplified by MLPA, but showed polyploidy by FISH. FISH was superior to SNPA and MLPA in assessing the tumours with diverse cell populations with different PTEN copies.
CONCLUSIONS: The results show good concordance between FISH, SNPA and MLPA. SNPA was superior in tumours with deletion of one copy and duplication of the second allele. FISH was superior in assessing tumour heterogeneity.

Giannakis M, Hodis E, Jasmine Mu X, et al.
RNF43 is frequently mutated in colorectal and endometrial cancers.
Nat Genet. 2014; 46(12):1264-6 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
We report somatic mutations of RNF43 in over 18% of colorectal adenocarcinomas and endometrial carcinomas. RNF43 encodes an E3 ubiquitin ligase that negatively regulates Wnt signaling. Truncating mutations of RNF43 are more prevalent in microsatellite-unstable tumors and show mutual exclusivity with inactivating APC mutations in colorectal adenocarcinomas. These results indicate that RNF43 is one of the most commonly mutated genes in colorectal and endometrial cancers.

Guo C, Ren F, Wang D, et al.
RUNX3 is inactivated by promoter hypermethylation in malignant transformation of ovarian endometriosis.
Oncol Rep. 2014; 32(6):2580-8 [PubMed] Related Publications
The aim of the present study was to investigate the role of epigenetic inactivation of the runt-related transcription factor 3 gene (RUNX3) in the malignant transformation of ovarian endometriosis. Samples obtained by microdissection and scraping included 30 malignant ovarian endometriotic cyst tissues and 30 corresponding eutopic endometrium tissues from the endometriosis-associated ovarian carcinoma (EAOC) group, 19 benign ovarian endometriotic cyst tissues and 22 corresponding eutopic endometrium tissues from the endometriosis (EM) group and 22 normal eutopic endometrium tissues from the control endometrium (CE) group. RUNX3 methylation status was determined by methylation-specific PCR and bisulfite sequencing, while levels of RUNX3 and ERα protein expression were evaluated using immunohistochemistry. The percentage of RUNX3 methylation and negative RUNX3 protein expression in the malignant ovarian endometriotic cysts from the EAOC group was significantly higher than that in the benign ovarian endometriotic cysts from the EM group. The percentage of RUNX3 methylation and negative RUNX3 protein expression in the eutopic endometrium from the EAOC group was significantly higher than that in the EM and CE groups. An inverse correlation between positive RUNX3 protein expression and methylation was observed and a positive correlation was shown between RUNX3 methylation and ERα protein expression. In the malignant ovarian endometriotic cysts from the EAOC group, there was no significant correlation between methylation frequency of the RUNX3 gene and histological type. However, the percentage of RUNX3 gene methylation was significantly higher in the tissue samples from patients with surgical stage IC EAOC than the percentage in patients with stage IA and IB disease. These results suggest that RUNX3 inactivation by promoter hypermethylation plays a role in the progression of malignant transformation of ovarian EM and is closely related to estrogen metabolism. Negative protein expression and abnormal RUNX3 methylation in the eutopic endometrium could be used as diagnostic markers in patients with ovarian EM who may be at an increased risk of developing EAOC.

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