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Supplemental Digital Content is available in the text, Background: Fusion genes may play an important role in tumorigenesis, prognosis, and drug resistance; however, studies on fusion genes in endometrial cancer (EC) are rare. This study aimed to identify new fusion genes and to explore their clinical significance in EC. Methods: A total of 28 patients diagnosed with EC were enrolled in this study. RNA sequencing was used to obtain entire genomes and transcriptomes. STAR-comparison and STAR-fusion prediction were applied to predict the fusion genes. Chi-square tests and Student t tests were used to verify the clinical significance with SPSS 13.0 software. Results: New fusion genes were found, and the number of fusion genes varied from 3 to 110 among all patients with EC. The type of fusion genes varied and included messenger RNA (mRNA)-mRNA, long non-coding RNA (lncRNA)-lncRNA, and lncRNA-mRNA. There were six fusion genes with high fusion rates, namely, RP11–123O10.4–GRIP1, RP11–444D3.1–SOX5, RP11–680G10.1–GSE1, NRIP1–AF127936.7, RP11–96H19.1–RP11–446N19.1, and DPH7–PTP4A3. Further studies showed that these fusion genes are related to stage, grade, and recurrence, in which NRIP1–AF127936.7 and DPH7–PTP4A3 were found only in stage III patients with EC. DPH7–PTP4A3 was found in grades 2 and 3, and recurrent patients with EC. Conclusion: Fusion genes play an essential role in EC. Six genes that are overexpressed with high fusion rates are identified. NRIP1–AF127936.7 and DPH7–PTP4A3 might be related to stage, and DPH7–PTP4A3 be related to grade and recurrence.

To explore the impact of 2009 International Federation of Gynecology and Obstetrics (FIGO) staging system alteration for stage I endometrioid adenocarcinoma on its' prognosis assessing.A retrospective study was carried out on 244 cases with endometrial carcinoma admitted in Peking University People's Hospital from Jan.1995 to Feb.2008.(1) All 244 patients were divided into FIGO 2009 Ia group (n = 200) and FIGO 2009 Ib group (n = 44) according to FIGO 2009 staging system, while they were divided into FIGO 1988 Ia group (n = 34), FIGO 1988 Ib group (n = 156) and FIGO 1988 Ic group (n = 29). The others 25 cases were stage IIa (n = 16) and stage IIIa with merely positive abdominal cytology (n = 9) according to FIGO 1988 staging system.(2) The higher percentage of low-grade in FIGO 1988 Ia group than that in FIGO 2009 Ia group (P = 0.003). Compared with FIGO 2009 Ia group, the age of the patients, surgery extent, the percentage of lymph node excision and received chemotherapy and radiotherapy, there were no difference in FIGO 1988 Ia and Ib group, respectively (P0.05). There were 5.9% (2/34) and 6.7% (10/150) found relapse among FIGO 1988 Ia group and FIGO 1988 Ib group, and there were 2.9% (1/34) and 2.7% (4/150) for the two groups died of carcinoma. Compared with FIGO 2009 Ia group, there were not significant difference [7.5% (13/200) vs. 3.0% (6/200); P0.05]. The 5 years and 10 years progression-free survival (PFS) of FIGO 1988 Ia group and Ib group were (97.0 ± 3.0)%, (90.9 ± 6.5)% and (95.3 ± 2.1)%, (90.2 ± 3.6)%, respectively, in which there were not significant difference compared with that in FIGO 2009 Ia group [(96.1 ± 1.6)%, (89.6 ± 3.2)%; P0.05]. The 5 years and 10 years overall survival (OS) in FIGO 1988 Ia group and Ib group were 100%, (93.8 ± 6.0)% and (96.9 ± 1.8)%, (95.2 ± 2.5)%, respectively, in which there were did not significant difference with that in FIGO 2009 Ia group [(97.9 ± 1.2)%, (93.4 ± 2.8)%; P0.05].(3) There were not significant difference between FIGO 1988 Ic group and FIGO 2009 Ib group (P0.05) for the age of the patients, grade, surgery extent, lymph node excision, the percentage of received chemotherapy and radiotherapy. Between FIGO 1988 Ic group and FIGO 2009 Ib group, there were 3.4% (1/29) and 6.8% (3/44) cases found relapse, respectively. And there were 0 and 2.3% (1/44) cases died of carcinoma in the two groups, in which there were not differ much either (P0.05). The 5 years and 10 years PFS in FIGO 1988 Ic group were all 100%, while they were 100% and (90.9 ± 6.2)% in FIGO 2009 Ib group. The 5 years and 10 years OS in FIGO 1988 Ic group were all 100%, but were 100% and (95.0 ± 4.9)% in FIGO 2009 Ib group, in which they all did not significantly differ much (P0.05). (4) The patients in FIGO 2009 Ia group were younger than those in FIGO 2009 Ib group (P0.01). The percentage of low grade in FIGO 2009 Ia group were higher than that in FIGO 2009 Ib group (P = 0.029). The percentages of received chemotherapy and radiotherapy in FIGO 2009 Ia group were lower than that in FIGO 2009 Ib group remarkably (P0.01). But there were not significant difference in the uterine excision extent and the percentage of lymph node excision between the two groups (P0.05). There were not significantly differ in the relapse rates and the death rates between the FIGO 2009 Ia group and FIGO 2009 Ib group (P0.05). There were also not significant difference in PFS and OS between the two groups (P0.05).There were not significant difference in the prognosis between FIGO 2009 stage Ia and FIGO 1988 stage Ia and Ib. There were also not significant difference in the prognosis between FIGO 2009 stage Ia and FIGO 2009 stage Ib, which may be due to received more chemotherapy and radiotherapy in FIGO 2009 stage Ib patients.

To explore the lymph nodes (LN) metastasis characters of the endometrial carcinoma and its relation with the patients' prognosis.A retrospective study was carried out on 227 cases of endometrial carcinoma who admitted to our department and underwent LN excision from Jul.2000 to Feb.2008.Among 227 cases who underwent pelvic LN excision, there were 22 cases (9.7%) presented LN metastasis. There were 12 cases with positive external iliac LN from 20 cases of patients with data in LN grouping. Para-aortic LN excision was carried out on 138 patients. There were 6 cases with positive para-aortic LN, 5 cases of them together with pelvic LN metastasis. Those patients with cervix involvement, annex metastasis, deep myometrium infiltration, grade 2-3 and negative estrogen receptor occurred pelvic LN metastasis more frequently than the others (P0.05). Among the 6 cases with positive para-aortic LN, there were 3 cases (3/6) with deep myometrium infiltration. For those whose para-aortic LN was negative, it was only 16.7% (22 cases). But there were no difference statistically between them (P0.05). There were significant difference in 3 years disease-free survival rate between patients with positive pelvic LN or negative pelvic LN [(81.8 ± 8.2)% vs (97.4 ± 1.2)%, P = 0.004]. While there were not significant difference in 3 years disease-free survival rate between patients with positive para-aortic LN or negative para-aortic LN [100% vs (96.7 ± 1.6)%, P0.05]. Single factor analysis showed that the age more than 50 years, annex metastasis and pelvic LN metastasis related with the recurrence (P0.01). But cervix involvement, deep myometrium infiltration, para-aortic LN metastasis, pathology type, tumor grade and estrogen receptor did not relate with the recurrence (P0.05). Cox regression analysis showed that annex metastasis and the age of patients were independent risk factors affecting the recurrence (P = 0.011, P = 0.025).The most common site of pelvic LN metastasis is the external iliac LN for endometrial carcinoma patients. The patients with positive para-aortic LN always accompanied pelvic LN metastasis. Those patients with cervical involvement, annex metastasis, deep myometrium infiltration, poor differentiation and negative estrogen receptor be more likely exist pelvic LN metastasis. Pelvic LN metastasis may affect the prognosis of endometrial carcinoma patients.

To explore the clinicopathological characteristics in atypical endometrial hyperplasia patients.A retrospective study was carried out on 79 cases with atypical endometrial hyperplasia patients admitted to Department of Gynecology, Peking University People's Hospital from Mar. 2007 to Jul. 2010. All patients were divided into two groups, hyperplasia group (merely atypical endometrial hyperplasia, 49 cases, 62%) and cancerization group (atypical endometrial hyperplasia accompanying endometrial carcinoma, 30 cases, 38%).The mean age of 79 cases were (50 ± 11) years old, while they were (50 ± 10) and (51 ± 11) years old for hyperplasia group and cancerization group, there were not difference (P = 0.994). The gravidity and delivery frequencies were also not differently between two groups. The rates of complicated other diseases were 47% (23/49) and 43% (13/30), which was not significantly different (P = 0.755). The body mass index (BMI) of cancerization group was higher than that of hyperplasia group [(27.9 ± 5.4) vs. (25.2 ± 2.9) kg/m², P = 0.024]. There were 50% (15/30) and 31% (15/49) menopause cases in two groups, respectively. Among them there were 13/15 and 8/15 cases showed vaginal bleeding. Among premenopausal patients, there were 12/15 and 68% (23/34) showed abnormal vaginal bleeding, but there were not significantly different between two groups (all P0.05). The uterine cavity mass found by ultrasonography in the cancerization group patients was more than that in hyperplasia group [73% (22/30) vs. 51% (25/49), P = 0.050]. There were 23 cases (29%), 44 cases (56%) and 12 cases (15%) were diagnosed by dilatation and curettage (DG), hysteroscopy and hysterectomy, respectively. The rates of diagnosing atypical endometrial hyperplasia by DG and hysteroscopy were 87% (21/23) and 93% (41/44), respectively. The rate of diagnosis of canceration were 6/12 and 12/16, respectively. While, the rate of missed diagnosis of canceration in the atypical endometrial hyperplasia patients by DG and hysteroscopy were 6/13 and 19% (4/21), respectively. Which all did not shown significantly different (P0.05).Hysteroscopy or DG should be chosen on those peri-menopausal patients with abnormal bleeding, while those atypical endometrial hyperplasia patients with high BMI and uterine cavity mass diagnosed with DG and ultrasonography should consider the possibility of canceration.

To explore the clinical significance of CP2, CA125, salicylic acid (SA) and carcinoembryonic antigen (CEA) in endometrial carcinoma patients.A retrospective study was carried out on 154 cases of endometrial carcinoma with tumor markers test results who were admitted to our department from Aug 1992 to Nov 2004.The patients were followed up for (38+/-28) months. 23.4%, 36.8%, 19.0% and 30.3% of cases were with abnormal values of CP2, SA, CA125 and CEA. CP2 abnormal level was related with the stage, cell differentiation, adnexa metastasis, positive peritoneal cytology and pelvic lymph node metastasis (P=0.002, P=0.040, P=0.019, P=0.019, P=0.005). SA abnormal level was related with the adnexa metastasis and positive peritoneal cytology (P=0.021, P=0.000). CA125 abnormal level was related with the cell differentiation, cervical metastasis and pelvic lymph node metastasis (P=0.014, P=0.006, P=0.018). The survival was related with CP2, CA125 and CEA (P=0.016, P=0.000, P=0.016), especially CA125.Among the commonly used tumor markers, CP2 is related with many clinical pathological parameters. CA125 elevation may strongly suggest worse prognosis.

To analyze if there are membrane estrogen receptors (ER) in endometrial carcinoma and if there is some relationship between membrane ER and nuclear ER.The cell membrane and total cell ERalpha and ERbeta expressions of high and moderate differentiation endometrial carcinoma cells (Ishikawa and HEC-1A cells) were analyzed. Intermittent immunofluorescence dyeing and fluorescent microscopy were carried out with the cells treated with polyformaldehyde and Triton X-100. Intermittent immunofluorescence dyeing and flow cytometry were carried out with the live cells and the cells treated with Triton X-100 respectively.There were fluorescences on the membrane of the Ishikawa and HEC-1A cells which were treated with polyformaldehyde. When the cells were treated with Triton X-100, the fluorescences were also seen inside the cells. The fluorescence intensity of ERalpha and ERbeta in Ishikawa cell membrane (1.09 +/- 0.21, 1.27 +/- 0.33) was stronger than the control, but there were no significant differences (P0.05). When treated with Triton X-100, the total cell fluorescence intensity of ERalpha and ERbeta in Ishikawa cell (4.21 +/- 0.34, 4.69 +/- 1.96) was stronger than the membrane (P0.05). The ERalpha and ERbeta fluorescence intensity of HEC-1A cell membrane (1.58 +/- 0.13, 1.49 +/- 0.04) were stronger than the control (P0.05). The fluorescence intensity of ERalpha and ERbeta of the HEC-1A cell (2.34 +/- 0.33, 2.52 +/- 0.15) was stronger than the membrane also (P0.05). The membrane ERalpha fluorescence intensity of Ishikawa was lower than HEC-1A (P = 0.028). But the total cell ERalpha fluorescence intensity of Ishikawa was higher than HEC-1A (P = 0.002).There are membrane ER on endometrial carcinoma cells Ishikawa and HEC-1A. The membrane ER must have some similarity to the nuclear receptor. There is no direct correlation between the quantity of the membrane ER and nuclear ER.

To investigate the regulation of 17beta-estradiol on the membrane estrogen receptor alpha.The Ishikawa cells were treated with 10(-6) mol/L 17beta-estradiol for 0, 3, 10, 30 minutes and 2, 12, 48 hours, respectively. Another group of Ishikawa cells was treated with 10(-12) mol/L, 10(-10) mol/L, 10(-8) mol/L and 10(-6) mol/L 17beta-estradiol for 30 minutes, respectively. The cells were marked with anti-ERalpha and measured with FACS.The fluorescence intensity of mERalpha increased gradually with the application of estradiol. It reached the peak at the end of 30 minutes. Then it began to decrease gradually. When the cells were treated at low concentration of estradiol the fluorescence intensity of mERalpha was high, especially at 10(-10) mol/L estradiol. Then with the rise of the concentration, the fluorescence intensity decreased.The quantity of mERalpha reached the peak at the end of 30 minutes when treated with estradiol. Then it decreased gradually. When treated with estradiol at different concentrations, its quantity could reach the peak at physiological concentration.

To explore the effects of chemotherapy in recurrent endometrial carcinoma.A retrospective study was carried out on the clinical data of 20 cases of recurrent endometrial carcinoma hospitalized from May. 1992 to Jun. 2002.The recurrence rate of these 20 cases was 11.0%. The recurrence occurred (17 +/- 10) months after the first therapy. Eleven of the 20 patients (55.0%) had accepted chemotherapy with (6 +/- 4) courses and were followed up for (17 +/- 16) months after the second therapy. Fifteen cases (75.0%) died of cancer, 4 cases survived with tumor, and only 1 case (5.0%) was tumor-free. Univariate model revealed that chemotherapy and number of chemotherapy course were related with the prognosis (P = 0.0146, P = 0.0353). Radiotherapy affected the prognosis too (P = 0.0414). But pathologic subtype, stage, tumor cell differentiation, age, recurrent time, surgery, chemotherapy scheme, drug infusion way , and endocrine therapy had no relation with the prognosis (P = 0.5517, 0.5763, 0.1879, 0.880, 0.453, 0.0672, 0.0795, 0.5956, and 0.2035). Multivariate model revealed that chemotherapy had influence on the prognosis (beta = -1.349, OR = 0.259, P = 0.026).Combined treatment raises the survival of the recurrent endometrial carcinoma patients, in which chemotherapy plays a leading role and influences the prognosis remarkably.

To investigate the role of estrogen receptor-related receptor (ERR), a subfamily of orphan receptors, in the tumorigenesis of endometrial carcinoma and to evaluate the clinical significance.A total of 46 cases of endometrial carcinoma tissues and 24 cases of normal endometrium tissues were collected. Semi-quantitative reverse transcription polymerase chain reaction and immunohistochemistry were used to measure the expressions of ERR. All samples were classified into two groups according to ERalpha status.It was positively correlated between the ERR (alpha, beta, gamma) mRNA and protein expression (r = 0.462, P = 0.009; r = 0.689, P = 0.016 and r = 0.673, P = 0.001). The expression rate and level of ERRalpha mRNA in ERalpha-positive endometrial carcinoma (42%, 0.24 +/- 0.18) were lower than in normal endometrium (78%, 0.42 +/- 0.23; P = 0.019, P = 0.021). No significant difference was observed in the expression of ERRbeta mRNA between endometrial carcinoma (23%, 0.21 +/- 0.16) and normal endometrium (22%, 0.27 +/- 0.15; P0.05). In ERalpha-positive endometrial carcinoma, the expression level of ERRgamma mRNA (0.93 +/- 0.24) was higher than normal endometrium (0.72 +/- 0.21; P = 0.023). The numbers of patients of Federal International Gynecological Oncology (FIGO) stage II-IV and of deep myometrial invasion in ERRalpha mRNA positive endometrial carcinoma group were more than those in ERRalpha mRNA negative group (P = 0.017 and P = 0.033). ERRgamma mRNA positive patients had a lower occurrence of lymph metastases than negative patients (P = 0.021).ERR may be closely related with the tumorigenesis of endometrial carcinoma, similar to ER. ERRalpha may serve as a biomarker of poor prognosis and ERRgamma as a favorable biomarker in endometrial carcinoma.

To study the effectiveness of adjuvant endocrine therapy on the prognosis of endometrial carcinoma and to analyze the influence of progesterone receptor on the curative effect of adjuvant endocrine therapy.A retrospective study was carried out on 171 patients of endometrial carcinoma with similar pathological examination. 82 of the 171 patients with endometrial carcinoma (48.0%), aged (57 +/- 9) years, underwent endocrine therapy, mainly by progesterone (245 +/- 51) mg/d for (1.3 +/- 0.9) years. 55 cases (67.1%), aged (57 +/- 10) years, underwent endocrine therapy for more-than-one-year (more-than-one-year subgroup), and 27 cases (32.9%), aged (59 +/- 9) years, underwent endocrine therapy for less-than-one-year (less-than-one-year subgroup). 24 of the 82 patients (29.3%) underwent adjuvant radiotherapy. 89 of the 171 patients (52.0%), aged (57 +/- 11) years, were in the control group 31 of the 89 patients in the control group (34.8%) underwent adjuvant radiotherapy, and 39 patients (43.8%) underwent adjuvant endocrine therapy. Follow-up was performed by correspondence, phone call, or outpatient department visit for 3 approximately 4 years.The rate of recurrence and/or metastasis of the endocrine therapy group was 13.4%, not significantly different from that of the control group (23.6%, P0.05); the death rate of the endocrine therapy group was 12.2%, not significantly different from that of the control group (20.2%, P0.05). The rate of recurrence and/or metastasis of the less- than-one-year subgroup was 25.9%, significantly higher than that of the more-than-one-year subgroup (7.3%, P = 0.012); the death rate of the less- than-one-year subgroup was 22.2%, significantly higher than that of the more-than-one-year subgroup (7.3%, P = 0.036). Cox regression showed that stage, the operation, tumor cell differentiation, and duration of endocrine therapy significantly affected the recurrence/metastasis remarkably (OR = 5.199, OR = 0.507, OR = 1.796, OR = 0.538) and the death rater (OR = 5.488, OR = 0.482, OR = 1.516, OR = 0.547). The rate of recurrence/metastasis of the endocrine therapy group patients with positive progesterone receptor was 4.7%, significantly higher than that of the patients with negative progesterone receptor (26.7%, P = 0.034).The prognosis of endometrial carcinoma patients can be improved with adjuvant endocrine therapy, especially for those with positive progesterone receptor. Endocrine therapy should be continued no less than 1 year.

To explore the relationship between expression of ERR alpha mRNA and estrogen and progesterone and to elucidate the function of ERR alpha in endometrial carcinoma.The expression of ERR alpha mRNA was examined by reverse transcription polymerase chain reaction. Endometrial carcinoma cell line Ishikawa was dealt with different concentrations of 17beta-estradiol (10(-10) mol/L, 10(-8) mol/L and 10(-6) mol/L) for 15 min, 30 min and 24 h and 17beta-estradiol and ER inhibitor-ICI182780 were given concomitantly to observe the change of ERR alpha mRNA. Different concentrations of progesterone (10(-8) mol/L, 10(-7) mol/L, 10(-6) mol/L and 10(-5) mol/L) were also given to Ishikawa cell line for 24 h to observe the change of ERR alpha mRNA.The expression level of ERR alpha mRNA was slightly higher than that of the control group after being stimulated for 15 min, 30 min and 24 h by 10(-10) mol/L 17beta-estradiol. However the expression level of ERR alpha mRNA was significantly lower than that of the control group after being stimulated for 15 min, 30 min and 24 h by 10(-8) mol/L and 10(-6) mol/L of 17beta-estradiol. When 10(-6) mol/L of ICI182780 and 10(-8) mol/L of 17beta-estradiol were given simultaneously to Ishikawa cell line, this down-regulation was blocked. After being stimulated for 24 h by 10(-7) mol/L, 10(-6) mol/L and 10(-5) mol/L of progesterone, the expression levels of ERR alpha mRNA were significantly higher than that of the control group, but no change was found in 10(-8) mol/L of progesterone.17Beta-estradiol can down-regulate the expression of ERR alpha mRNA and this regulation is mediated by estrogen receptor. Progesterone can up-regulate the expression of ERR alpha mRNA.

To report the associate medical disorders of the patients with endometrial carcinoma and analyze the medical disorders' effects on the treatment and prognosis.One hundred and forty-six cases of endometrial carcinoma associated with medical disorders who admitted to our center from July, 1971 to Oct, 2001 were analyzed retrospectively. And the other 161 cases without medical disorders who admitted to our center during the same time were chosen as control.Among the 146 patients with medical disorders, the ordinary disorders were hypertension in 104 patients (71.2%), diabetes mellitus in 30 patients (20.5%) and coronary heart disease in 29 patients (19.9%). Those patients with medical disorders were elder than the control (P0.001). The medical disorders were independent of stage, tumor cell differentiation and pathological classification (P0.05). The operation ratio of those patients with medical disorders were less than the control. But there was no significance (P0.05). The radiotherapy and chemotherapy ratio of them was significantly higher than the control (P0.01). Univariate analysis of the cases followed up showed that the prognosis were independent of the associated medical disorders, such as hypertension, diabetes mellitus and coronary heart disease (P0.05). Multivariate analysis showed that the prognosis were related to the stage and tumor cell differentiation affected the prognosis remarkable. But the prognosis was independent of age and associated medical disorders.The endometrial carcinoma often associates with hypertension, diabetes mellitus, coronary heart disease, and so on. The incidence rate of medical disorders increases with the aging of the patients. The medical disorders might affect the therapy to a certain extent. But they do not affect the prognosis remarkably.