Gene expression signatures differentiate uterine endometrial stromal sarcoma from leiomyosarcoma

ObjectiveEndometrial stromal sarcoma (ESS) and leiomyosarcoma (LMS) are the two most common uterine sarcomas, but both are rare tumors. The aim of the present study was to compare the global gene expression patterns of ESS and LMS.MethodsGene expression profiles of 7 ESS and 13 LMS were analyzed using the HumanRef-8 BeadChip from Illumina. Differentially expressed candidate genes were validated using quantitative real-time PCR and immunohistochemistry.ResultsUnsupervised hierarchical clustering using all 54,675 genes in the array separated ESS from LMS samples. We identified 549 unique probes that were significantly differentially expressed in the two malignancies by greater than 2-fold with 1% FDR cutoff using one-way ANOVA with Benjamini–Hochberg correction, of which 336 and 213 were overexpressed in ESS and LMS, respectively. Genes overexpressed in ESS included SLC7A10, EFNB3, CCND2, ECEL1, ITM2A, NPW, PLAG1 and GCGR. Genes overexpressed in LMS included CDKN2A, FABP3, TAGLN, JPH2, GEM, NAV2 and RAB23. The top 100 genes overexpressed in LMS included those coding for myosin light chain and caldesmon, but not the genes coding for desmin or actin. CD10 was not overexpressed in ESS. Results for selected genes were validated by quantitative real-time PCR and immunohistochemistry.ConclusionsWe present the first study in which gene expression profiling was shown to distinguish between ESS and LMS. The molecular signatures unique to each of these malignancies may aid in expanding the diagnostic battery for their differentiation, and may provide a molecular basis for prognostic studies and therapeutic target discovery.     

Interferon regulatory factor-1 expression in human uterine endometrial carcinoma

OBJECTIVES: The objective was to investigate the expression of interferon regulatory factors 1 (IRF-1) in human uterine endometrial carcinoma. METHODS: Formalin-fixed, paraffin-embedded, archival tissue specimens from 76 human endometrial carcinomas and stained with polyclonal anti-IRF-1 antibody, using immunohistochemistry, localization, and immunostaining, were evaluated quantitatively using the H score together with 30 normal endometrium and 16 postmenopausal endometrium. RESULTS: The expression of IRF-1 was highest in normal endometrium, and decreased with the grade of endometrioid adenocarcinoma from grade 1 to grade 3. Postmenopausal endometrium was virtually unstained. CONCLUSIONS: Expression of IRF-1 is altered in human endometrioid adenocarcinoma compared with normal endometrium and postmenopausal endometrium. The loss of IRF-1 expression does not contradict with the tumor-suppressor function. The intensity of IRF-1 expression in each grade of endometrioid adenocarcinoma could be useful prognostic and therapeutic indicators.     

Gene expression profiling in two morphologically different uterine cervical carcinoma cell lines derived from a single donor using a human cancer cDNA array

PURPOSE: To examine the differentially expressed cancer-related genes in two morphologically different uterine cervical carcinoma cell lines derived from the same patient by an Affymetrix Human Cancer G110 Array carrying 1700 cancer-associated genes. In addition, to investigate specific gene expression depending on histological type, we examined expression of the selected genes in a panel of established cervical carcinoma cell lines derived from cervical adenocarcinoma and squamous cell carcinoma (SCC). EXPERIMENTAL DESIGN: Two distinct human uterine cervical carcinoma cell lines SKG-IIIa and SKG-IIIb derived from a single donor were screened using a cDNA microarray. The array results were additionally validated using semiquantitative RT-PCR. Expressions of the 10 selected genes were analyzed in the nine established cervical carcinoma cell lines using RT-PCR. RESULTS: The cDNA microarray analysis showed that 16 genes in SKG-IIIa were upregulated more than 10-fold compared to SKG-IIIb, and seven genes in SKG-IIIb were upregulated. Semiquantitative RT-PCR analysis of a subset of these differentially expressed genes gave results consistent with microarray findings. Among the 10 selected genes, insulin-like growth factor-binding protein-3, inhibitor of apoptosis protein 1, and cadherin-13 were more frequently expressed in SCC cell lines. 1-8D gene of interferon-inducible genes, Sno oncogenes, and transforming growth factor-beta II receptor were expressed in both SCC and adenocarcinoma cell lines. CONCLUSIONS: Our experimental data demonstrated that multiple genes are differentially expressed in uterine cervical carcinoma cell lines. It is suggested that these genes are involved with the differences in morphological characteristics and carcinogenesis of cervical carcinoma.     

Gene expression profiling in human endometrial cancer tissue samples: utility and diagnostic value

OBJECTIVE: Recently, gene expression profiling techniques have been used on several human cancers to classify tumor subgroups with a specific biological behavior, which were previously undetected by the conventional histopathologic staging systems. In the current study, the clinical usefulness and prognostic value of gene expression profiling in human endometrial carcinomas were studied. METHODS: A macro cDNA array, containing cDNAs of 588 genes selected from different areas of cancer research, was used to generate gene expression profiles of tumor tissue samples. The gene expression profiles of 12 endometrial cancers, 3 benign (e.g. noncancer) endometrial tissue samples and 3 myometrial tissue samples, taken from human surgical specimen, were compared. RESULTS: The efficacy to generate a gene expression profile of these tissue samples was 77%. The RNA samples could be randomly taken from the tissue samples and were highly reproducible. Cluster analysis of gene expression profiles of the different samples showed that the benign endometrial and the myometrial samples clustered separately from the tumor samples, indicating that the gene expression profiles were tissue specific and not patient specific. Cluster analysis of the tumor samples revealed two distinct tumor clusters. Ranking of the tumors in the two clusters showed high similarity with the histopathologic classification [International Federation of Gynecology and Obstetrics (FIGO) grading]. CONCLUSION: Classification of endometrial tumors on basis of their gene expression profiles showed similarity with the FIGO grading system.     

Molecular profiling of endometrial cancers from African-American and Caucasian women

OBJECTIVE: It is widely recognized that racial disparity in survival exists between African-American and Caucasian women with endometrial cancer (EC). Differential mutation frequencies in select genes have been postulated to explain these survival differences. The purpose of this study was to test the hypothesis that African-American women with EC have a distinct gene expression profile compared to Caucasian women with EC. METHODS: Microarray-based expression profiling using the Affymetrix U133A oligonucleotide array was performed on a series of ECs from African-American (n = 14) and Caucasian (n = 25). The two groups were matched for possible confounding variables including stage, histologic grade, and subtype. A model-based class comparison analysis was performed to generate a list of differentially expressed genes using a P value of <0.001. RESULTS: The class comparison analysis of genes differentially expressed by tumors from the two groups revealed 16 genes differentially expressed at P < 0.001, which was not statistically significant (P = 0.68). In addition, hierarchical clustering analysis did not segregate these tumors into two distinct groups based on race. CONCLUSION: These data indicate that there is no discernible difference in global gene expression profiles of ECs from African-American and Caucasian women. Thus, racial disparities in clinical outcomes are unlikely to reflect differences in gene expression and may instead be attributable to other epidemiologic, clinical, or pathologic factors.     

Global gene expression profiling of human endometrial receptivity

Scientific knowledge on the molecular changes that occur during the window of implantation is fundamental for the understanding of human reproduction. To gain a global molecular understanding of human endometrial receptivity, we have compared gene expression profiles of pre-receptive (day LH + 2) versus receptive (LH + 7) in well characterized human endometrial biopsies. The samples were analyzed using the Affymetrix HG-95A array, a high density oligonucleotide microarray comprising more than 12,000 genes. In this work, we present part of our results and a comparison with similar works published in the literature. Identified genes include not only genes previously documented to be involved in implantation but also genes for which a role in endometrial receptivity, or even endometrial expression, has not been previously described. Collectively, these studies identify new candidate markers that may be used to diagnose unequivocally the receptive endometrium.     

Flow cytometric DNA analysis of uterine endometrial carcinoma

The DNA content in individual cells from 40 cases of histopathologically normal endometria, 15 of endometrial hyperplasia and 68 of endometrial adenocarcinoma was measured by flow cytometry. An aneuploid cell population was found in 50% of malignant endometria, but in the remaining endometrial carcinomas, the flow cytometrical findings showed no difference from those of benign tissue. Aneuploidy was more common (77.8%) in poorly differentiated tumors than in highly differentiated tumors (35.5%). Two and more aneuploid cell populations were found in 8 cases of 34. The DNA indices of aneuploid tumors were classified into 3 groups: hyperdiploidy, low hyperdiploidy (DNA index range: 1.04-1.2) and high hyperdiploidy (DNA index range: More than 1.2). The proportion of tumors with a high DNA index tended to increase as tumors became less differentiated. In normal endometria the fraction of cells with DNA content corresponding to the s-phase (s-fraction) was 8 +/- 3% on average in the proliferative phase. In well differentiated diploid tumors the s-fraction was 12 +/- 6%, but in moderately and poorly differentiated tumors it was higher (16.0% and 19.0%).     

Stage II endometrial carcinoma: two modalities of treatment

Forty-five cases of Stage II endometrial cancer are analyzed with regard to histologic grade, therapy, site of recurrence, survival, and cause of death. This group represents 5% of all endometrial cancer patients registered at the Southern California Cancer Center from 1954 to 1974. Thirty-two (71.2%) were classified as poorly differentiated tumors. A significant analysis of survival data comparing the 26 patients treated by RT alone, and 17 patients managed by surgery and RT, could not be obtained because of the small number of patients. However, the frequency of residual tumor in the uterus and intraperitoneal recurrence in the RT only group suggests that RT plus surgery should provide a better survival than RT alone.     

A case of uterine endometrial carcinoma 15 months post-partum

A case of uterine endometrial carcinoma 15 months post-partum, who did have none of typical risk factors of uterine endometrial carcinoma, is presented. The occurrence of post-partum uterine endometrial carcinoma is extremely rare condition probably due to anti-carcinogenic effects of progesterone. Progesterone refractory cells in the uterine endometrium, which could be an origin of the endometrial carcinoma, might have existed.     

Effects of a selective COX-2 inhibitor in patients with uterine endometrial cancers

Purpose  

COX-2 is highly expressed in endometrial cancers, suggesting that a selective COX-2 inhibitor could be valuable for treating endometrial cancers that overexpress COX-2. In this study, we investigated the anti-tumor effects of the selective COX-2 inhibitor etodolac on endometrial cancer patients.     

Treatment of endometrial carcinoma - evidence based criteria

The evaluation of decisions in treating endometrial cancer according to levels of evidence and grades for recommendation is gaining importance. This can help to evaluate results of studies and publications for guidelines and standards in treating endometrial cancer. - Concerning endometrial cancer there are some publications with a high level of evidence especially in early stages whereas data of treating progressive and advanced disease with a high level of evidence is lacking. - There are some studies with an acceptable level of evidence evaluating radiation and surgical treatment in stages I and II. In stages III and IV further data concerning evaluation of hormonal treatment and chemotherapy is pending.     

Port-site metastasis after laparoscopic surgery for endometrial carcinoma: two case reports

BACKGROUND: Although studies have reported good results with laparoscopic-assisted vaginal hysterectomy (LAVH) to treat endometrial cancer, it has been associated with recurrent disease at trocar insertion sites. Long-term follow-up is necessary to detect possible adverse effects of this technique. CASES: We present two case reports of stage IIB endometrial cancer with port-site metastasis 39 and 48 months after initial surgery with LAVH. CONCLUSION: Although LAVH is a good technique to treat patients with endometrial cancer, port-site metastasis is a possible complication and should be taken into consideration until a randomized study shows the long-term benefits and risks of laparoscopic over standard treatment.     

Up-regulation of DNA methyltransferase 3B expression in endometrial cancers

OBJECTIVE: To understand the role of epigenetic regulation in the pathogenesis of endometrial cancer, we have characterized DNA methyltransferase 3B (DNMT3B) gene expression in normal, Grade I and Grade III endometrioid cancers, and examined DNMT3B promoter activities in endometrial cancer cell lines. METHODS: DNMT3B expression was measured in normal, Grade I, and Grade III endometrioid cancer samples. Real-time PCR and Western blot analysis were performed to compare DNMT3B mRNA and protein levels. DNMT3B levels were also compared among endometrial cell lines including those for Ishikawa, KLE, AN3, RL-95, HEC-1A, and HEC-1B. DNMT3B promoter reporter plasmids were constructed. Promoter activities in well and poorly differentiated cell lines were compared by in vitro reporter gene transfection. RESULTS: DNMT3B was significantly up-regulated in both Grade I and Grade III cancers as compared to normal controls. Western blot analysis confirmed the increased DNMT3B protein expression in cancer tissues. It was also found that the well-differentiated endometrial cell line, Ishikawa, expressed lower levels of DNMT3B than the poorly differentiated KLE cells, the expression patterns similar to those observed in tumor specimens. CONCLUSION: The results suggest that DNMT3B overexpression may play a significant role in endometrial cancer development. In addition, the transfection experiments indicated that DNMT3B promoters are more active in the poorly differentiated endometrial cancer cell lines, suggesting that the in vitro assay provides a useful model for studying the DNMT3B transactivation mechanism related to tumor transformation.     

生存素在正常子宫内膜、增生子宫内膜及子宫内膜癌中的表达研究

目的探讨生存紊(surviving)在正常子宫内膜、增生子宫内膜以及子宫内膜癌中的表达；并探讨生存紊与子宫内膜癌的临床分期、病理级别及浸润子宫肌层深度的关系。方法取正常周期、单纯增生、不典型增生子宫内膜各20例；萎缩性子宫内膜10例以及子宫内膜癌20例，应用人生存紊多克隆抗体，采用免疫组织化学SSCP法，观察其表达情况。结果生存紊在20例分泌期子宫内膜中全部表达，细胞浆呈均匀染色；20例增殖期子宫内膜，60％呈细胞浆均匀染色染色；10例萎缩型子宫内膜均不表达生存紊；20例单纯增生子宫内膜全部表达生存紊，细胞浆均匀染色；20例非典型增生子宫内膜全部表达生存紊，但问质细胞表达弱于腺上皮细胞；30例子宫内膜癌细胞100％表达生存紊，特点是100％浆表达，间质细胞表达明显弱于腺上皮细胞，同时43．33％核表达，且核表达率与临床期别、病理级别、侵犯基层深度有密切关系，统计学差异显著结论生存紊不是子宫内膜癌特有的标志蛋白，但可能是预后判断和监测治疗的指标。     

In-situ carcinoma of the uterine cervix showing superficial endometrial spread

Superficial spread of invasive carcinoma cervix over the endometrial surface is extremely rare and may follow radiation therapy (3, 5). Ferenczy et al. (1) have reported an instance of carcinoma in situ of ecto cervix spreading on the endometrial surface via the endo-cervical canal. This paper reports another in situ lesion of the cervix showing superficial endometrial spread.     

子宫峡部内膜癌的临床病理特征及预后

目的分析子宫峡部内膜癌的临床病理特点及预后相关因素。方法对天津医科大学总医院1980年1月至2005年12月收治的349例子宫内膜癌,按肿瘤部位分为峡部内膜癌（UIE）组与非峡部内膜癌组,比较两组临床病理特征及预后。结果UIE占10.0%（35/349）。与非峡部内膜癌相比,UIE组阴道排液及腹痛的比例较高（P〈0.05）。UIE组更容易发生深肌层浸润、宫颈侵犯、脉管浸润、浆膜受累、腹腔细胞学阳性以及盆/腹腔淋巴结转移,临床分期、手术病理分期较高（P均〈0.05）,具有较低的5年生存率（P〈0.05）。多因素分析显示峡部癌灶并非是预后不良的独立性相关因素。结论子宫峡部内膜癌具有特殊的临床病理特征,其可增强其他预后不良因素的作用而影响预后。