Association of 20q13.2 copy number changes with the advanced stage of ovarian cancer-tissue microarray analysis

Overrepresentations in 20q have been reported in a number of ovarian cancers by comparative genomic hybridization. In order to study the relation of the increased copy number of 20q13.2 with tumor phenotype in ovarian cancer, we applied FISH on a tissue microarray. The TMA technology enables us to analyze a large number of different malignancy, histology, stage and grade tumors. Overall, the frequency of 20q13.2 alterations in epithelial ovarian cancer was 25.50% (10.74% gains and 14.76% amplifications). There was not statistically significant difference between the frequencies of 20q13.2 copy number changes in different grade tumors. The frequency of gains and amplifications increased significantly from stage I to stage II to stage III tumors. Our results showed strong association between increases 20q13.2 copies and advanced tumor stage. We concluded that genetic alterations in 20q13.2 may be of prognostic significance for stage progression of the ovarian cancer.     

Role of Ca-125 in the differential diagnosis of adnexal mass in breast cancer patients

OBJECTIVES: Serum CA-125 is of value in differential diagnosis of benign and malignant adnexal masses, especially in postmenopausal women. In ovarian cancer preoperative CA-125 levels are related to tumor stage, histologic grade, but are not an independent prognostic factor. Design: The aim of our study was to determine CA-125 serum level in women with ovarian tumor treated previously because of breast cancer. MATERIALS AND METHODS: Due to our research, we examined 51 women operated on for adnexal masses in the Department of Oncological Gynaecology in Bydgoszcz, 1996 - 2002. All those patients were treated because of breast cancer previously. RESULTS: In 19 women (37,3%) benign ovarian tumors were found, in 4 cases (7,8) - primary ovarian cancer whereas in 28 patients (54,9%) breast cancer metastases were detected. Based on CA-125 levels before surgery, correlation between CA-125 concentration and malignant histologic type was observed. CONCLUSIONS: 1. Higher CA-125 serum levels were found in a group of patients with metastatic adnexal masses compared to primary ovarian cancer. 2. In a group of women with breast cancer and ovarian tumor, metastatic adnexal masses were observed in more than 50% of cases.     

DNA flow cytometry of ovarian tumors with correlation to histopathology

Tissue samples from 49 women with seven benign and 42 malignant ovarian tumors were examined by means of DNA flow cytometry (FCM). The FCM data (DNA-ploidy and the number of S-phase fractions) were compared with the International Federation of Gynecology and Obstetrics (FIGO) stage, the histologic grade of differentiation and in some cases with the clinical outcome. The benign ovarian tumors were all diploid with a mean of 2.1% (+/- 1.66) S-phase fractions. Adenocarcinomas with the histologic grade 1 were diploid and had a mean of 2.1% (+/- 1.17) S-phase fractions. Grade 2 adenocarcinomas were aneuploid in eight of nine cases and revealed an increased proliferative activity (7.7% +/- 2.67 S-phase fractions). A high number of aneuploid cases (nine of 13) and an increased DNA synthesis were found in grade 3 adenocarcinomas (12.0% +/- 5.72 S-phase fractions). Four of six malignant nonepithelial tumors also had high numbers of S-phase fractions (9.7-14.5%). A significant correlation between the histologic grade and the DNA synthesis, FIGO stage, and DNA-ploidy was found. DNA-FCM may be used as an additional diagnostic tool supplementing routine histopathologic examination of ovarian tumors for better biological characterization, especially for those with uncertain grading, for grade 2 neoplasms, and for malignant nonepithelial tumors.     

CyclinD1、C-erbB2及bcl-2基因在卵巢上皮性肿瘤中的表达及其临床意义

目的 :检测癌基因CyclinD1、C erbB2及bcl 2在卵巢上皮肿瘤中的表达 ,探讨它们在卵巢肿瘤发生、发展中的作用及临床、病理意义。方法 :应用免疫组化SP法检测72例恶性卵巢肿瘤、12例交界性卵巢肿瘤、2 1例良性肿瘤及 10例正常卵巢组织中Cy clinD1、C erbB2及bcl 2基因的表达情况。结果 :1.卵巢恶性、交界性及良性肿瘤中Cy clinD1阳性率依次为 2 7.78%、33.3%、9.5 2 %。恶性及交界性肿瘤阳性率明显高于良性肿瘤 ,其阳性率与组织学分级呈负相关 ,而与患者年龄、临床分期、组织学类型无关 ;2 .卵巢恶性、交界性及良性肿瘤中C erbB2的阳性率依次为 5 6 .9%、4 1.6 7%、14.2 8%。恶性及交界性肿瘤阳性率明显高于良性肿瘤 ,差异有显著性。C erbB2阳性表达在组织分化差及期别晚的肿瘤中较分化好、期别早者高 ;3.卵巢恶性、交界性、良性肿瘤中bcl 2的阳性表达率依次为 6 3.89%、5 0 %、2 8.5 %。恶性及交界性肿瘤与良性肿瘤之间的表达差异有显著性。组织分化差、期别早的肿瘤中bcl 2的阳性率较分化好、期别晚者高 ;4 .两种及两种以上基因同时表达率 (5 1.4 % )显著高于单基因表达 (2 7.79% )。CyclinD1与C erbB2基因表达呈负相关。结论 :CyclinD1、C erbB2及bcl 2基因在卵巢癌发生、发展中起重要作用 ,表明细胞?     

Immunohistochemical localization of metallothionein in benign and malignant epithelial ovarian tumors

Abstract. McCluggage WG, Strand K, Abdulkadir A. Immunohistochemical localization of metallothionein in benign and malignant epithelial ovarian tumors.
Metallothioneins (MTs) are a group of low-molecular-weight proteins that are overexpressed in a variety of human neoplasms and are related to differentiation and prognosis in some tumor types. This study investigated immunohistochemically detectable metallothionein expression in benign and malignant ovarian surface epithelial tumors of serous, mucinous, and endometrioid types. MT expression was observed in 56% of carcinomas ( n = 139) and in 2% of benign neoplasms ( n = 81). Of the malignant tumors, MT expression was found in 68% of endometrioid, 56% of mucinous, and 52% of serous neoplasms. There was increased MT expression in grade 3 carcinomas (64%) as compared with grade 2 (60%) and grade 1 (23%). The overexpression of MT in malignant as opposed to benign ovarian surface epithelial tumors may suggest a role in tumorigenesis. Analogous to the situation in endometrial carcinomas, there is a tendency toward higher expression in poorly differentiated tumors. Whether high MT expression is an independent prognostic factor and increased expression indicates chemotherapy resistance in ovarian cancer, as has been previously suggested, should be determined by further studies.     

Quantitative biochemical analysis of lactate dehydrogenase in human ovarian tissues: correlation with tumor grade

Abstract.   Šimaga Š, Osmak M, Babič D, Šprem M, Vukelič B, Abramič M. Quantitative biochemical analysis of lactate dehydrogenase in human ovarian tissues: correlation with tumor grade. Int J Gynecol Cancer 2005; 15: 438–444.
In an attempt to identify glycolytic capacity of normal and neoplastic human ovary, total lactate dehydrogenase (LDH) activity was measured in tissue cytosol originating from 69 patients (18 with benign ovarian tumor, 34 with ovarian carcinoma, six with nonepithelial ovarian malignant tumors, and 11 with tumor metastatic to ovary) and compared to the LDH activity of normal ovarian tissues ( n = 19). Median value of total LDH-specific activity expressed as U/mg protein was 0.546 in normal tissues, 0.584 in benign tumors, 1.071 in malignancies metastatic to ovaries, 0.872 in nonepithelial primary ovarian tumors, and 0.818 in primary carcinomas. A significant rise in LDH-specific activity was found in malignant primary and secondary tumors of epithelial and nonepithelial origin, but not in benign neoplasms, compared to the activity in normal tissue. Ovarian carcinomas of serous histologic type did not differ in LDH activity from mucinous tumors. However, poorly differentiated carcinomas (grade 3) showed significantly enhanced activity of this glycolytic enzyme when compared to its grade 1 counterpart. The subgroup of grade 1 tumors did not differ in LDH activity from normal and benign ovarian tissue. Obtained results suggest that direct correlation might exist between ovarian epithelial tumor grade and lactate dehydrogenase activity.     

抗细胞凋零基因bcl-2和bax与卵巢上皮性肿瘤的关系

目的:研究抗凋零基因bcl-2和bax与卵巢上皮性肿瘤发生及预后的关系。方法:通过免疫组化方法,用抗bcl-2及抗bax抗体检测卵巢上皮肿瘤76份(良性27份、交界性24份、恶性25份)中bcl-2和bax的表达产物,并以正常卵巢12份做对照。结果:正常卵巢组织12份中bcl-2和bax阳性检出率为0,在良性、交界性及恶性肿瘤组织中bcl-2和bax的阳性检出率分别为7.4%(2/27)、16.7%(4/24)、36.0%(9/25),22.2%(6/27)、45.8%(11/24)、56.0%(14/25),良性与恶性肿瘤之间差异有显著性(P<0.05),而且bax的表达率比bcl-2高(P<0.05),bax在恶性肿瘤组Ⅰ级与Ⅲ级间差异有显著性(P<0.05)。结论:抗细胞凋零基因bcl-2和bax过度表达可能与卵巢上皮性肿瘤发生有关,推测bax不仅参与细胞凋零的调控,而且可能与肿瘤分化及预后有关。     

Tumor cytosol dipeptidyl peptidase III activity is increased with histological aggressiveness of ovarian primary carcinomas

OBJECTIVE: Proteolytic enzymes have been implicated in the progression of various human malignancies, including ovarian cancer. The enhanced expression of dipeptidyl peptidase III (DPP III) was found in endometrial carcinomas of various histological types and grade. The aim of this study was to assess activity of DPP III in ovarian tissue specimens and to correlate it with clinico-pathological data. METHODS: DPP III hydrolytic activity toward Arg-Arg-2-naphthylamide was determined in 108 ovarian tissue cytosol specimens of 79 patients. The data obtained for 41 ovarian primary carcinoma specimens were stratified according to clinical stage, histological grade and type, and age of the patients. RESULTS: Median DPP III activity expressed as milliunits per milligram protein was 6 in normal ovarian tissues (n = 29), 6.5 in benign ovarian tumors (n = 19), 19.5 in primary ovarian carcinomas (n = 41), 12.5 in nonepithelial primary ovarian tumors (n = 7), and 22.1 in metastatic ovarian malignancies (n = 12). A significant rise in median DPP III specific activity was observed in malignant ovarian tumors (of epithelial, nonepithelial, and metastatic origin), but not in benign ovarian tumors, compared to the activity in normal tissue. A significant difference of DPP III expression was found between the group of normal tissues and tumors of clinical stage I and II, of grade 2 and 3, of serous and mucinous histologic type. CONCLUSIONS: DPP III activity of benign ovarian tumors equaled that in normal ovarian tissue. In malignant neoplasms of the ovary it increased with growing histologic grade.     

c-myc amplification in ovarian cancer

The c-myc oncogene codes for a DNA binding protein that appears to play an important role in the regulation of cell growth. c-myc gene amplification has been documented to occur in both hematopoietic and solid neoplasms and often indicates more biologically aggressive tumors. Southern hybridization analysis was performed on high-molecular-weight DNA isolated from primary ovarian carcinomas. Major structural rearrangements of c-myc were not detected. Five of seventeen (29.4%) tumor samples demonstrated amplification of the myc oncogene. The 5 patients with ovarian carcinomas associated with c-myc amplification exhibited a median survival of 17 months. Of the 12 patients without evidence of tumor-associated c-myc amplification, 5 have exhibited disease-free survival for an average of 36.8 months and are currently alive. The remaining 7 patients, the majority of whom had advanced-stage, poorly differentiated lesions with a normal c-myc copy number, exhibited a median survival of 9 months. There was no apparent relationship between c-myc amplification, grade of tumor differentiation, and response to platinol-based chemotherapy. These data do not suggest a prognostic role for c-myc amplification in primary ovarian cancer. However, c-myc amplification is a common finding in advanced-stage ovarian cancer.     

Cell proliferation activity unrelated to COX-2 expression in ovarian tumors

The objective of this study was to assess the expression of Cyclooxygenase-2 (COX-2) and cell proliferation activity (Ki67 expression) in benign, borderline, and malignant serous and mucinous ovarian tumors. Expression of COX-2 and Ki67 proteins were evaluated by immunohistochemistry, in paraffin-embedded sections of ovarian epithelial tumors. The study included 113 serous (67 benign, 15 borderline, and 31 malignant) and 85 mucinous (48 benign, 28 borderline, and 9 malignant) tumors, removed from women who underwent laparotomy between January 1997 and December 2003. From benign to malignant tumors, there was a progressive positive trend in COX-2 expression in both serous and mucinous tumors, more evident in mucinous ones (P < 0.001). Comparing histologic types, COX-2 expression was more prominent in serous than in mucinous benign tumors (P < 0.01), but this difference was not significant in the borderline (P= 0.11) or malignant categories (P= 0.71). There was a progressive Ki67 positivity in line with the tumor histologic gradient for both serous (P < 0.01) and mucinous lesions (P < 0.01), but this increasing expression did not correlate with COX-2 expression in the present series (P= 0.78). There was a higher COX-2 expression in serous ovarian adenomas than in mucinous ones. COX-2 positivity increases in line with the morphologic gradient, from benign to malignant in both histologic types, but it was more prominent in mucinous lesions, pointing to different oncogenic pathways related to different histologic types. A correlation between the expression of COX-2 and Ki67 was not found, suggesting that COX-2 may be required for carcinogenesis, but this pathway is not responsible for cell proliferation in ovarian tumors.     

k-ras mutation may be an early event in mucinous ovarian tumorigenesis.

We explored the possible pathogenetic pathway for mucinous ovarian tumorigenesis by examining the k-ras mutational patterns in ovarian mucinous tumors (OMTs) with benign, borderline, and invasive epithelium in which the different types of mucinous epithelium are in close proximity. Sixteen patients with ovarian mucinous borderline tumors (OMBTs) and 4 patients with grade 1 ovarian mucinous adenocarcinomas (OMCs) were selected for the presence of a single histologic section which contained a clear "transition" zone from benign mucinous epithelium to borderline mucinous epithelium, and in four cases, to invasive epithelium. A PixCell II Laser Capture Microscope was used to microdissect and retrieve benign, borderline, and invasive epithelium separately from the 20 OMTs. Normal ovarian stroma from the same histologic section in each case was also microdissected and retrieved for use as a control. k-ras mutations were detected in these samples by PCR-SSCP analysis followed by direct PCR cycle sequencing. k-ras mutations were found in 8/16 (50%) of the OMBTs and 2/4 (50%) of the grade 1 OMCs. In 6 of these 10 cases (4 in OMBTs, 2 in grade 1 OMCs), the same k-ras mutation was found in both the benign and borderline (and invasive) regions. In 3 cases in which k-ras mutations were identified, the mutation was found in either the benign or borderline tissue samples alone, and in one case, two distinct mutations were found. No k-ras mutations were identified in the normal ovarian stroma. The presence of a k-ras mutation in adjacent benign and borderline regions of a single OMT may suggest a progression in the development of OMTs from benign to borderline and grade 1 OMCs. k-ras mutations, when they occur, are likely early genetic changes but may not alone be sufficient for malignant transformation of ovarian epithelium.     

钙黏素6基因在卵巢肿瘤组织中的表达及突变的研究

目的　通过研究卵巢肿瘤组织中钙黏素 (cadherin) 6基因的表达、突变及其临床意义 ,以寻找与卵巢肿瘤发生相关的分子水平标志物。方法　应用RT PCR技术和PCR 单链构象多态性方法分别检测恶性卵巢肿瘤组织 (4 1份 )、良性卵巢肿瘤组织 (15份 )、正常卵巢组织 (17份 )中cadherin 6mRNA的表达及cadherin 6基因的突变情况 ,并分析其临床意义。结果　正常卵巢组织、良性卵巢肿瘤组织、恶性卵巢肿瘤组织中cadherin 6mRNA阳性率分别为 71%、5 3%、2 4 % ,前两者显著高于后者 (P<0 0 5 )。cadherin 6mRNA阳性率与恶性卵巢肿瘤手术病理分期有关 ,Ⅲ～Ⅳ期恶性卵巢肿瘤组织中 ,cadherin 6mRNA阳性率 (5 % )显著低于Ⅰ～Ⅱ期 (4 5 % ,P <0 0 1)。 4 1例恶性卵巢肿瘤患者中 ,2例出现cadherin 6基因突变 ,而在正常卵巢组织和良性卵巢肿瘤组织中无cadherin 6基因突变。结论　cadherin 6mRNA在晚期恶性卵巢肿瘤组织中表达缺失。提示cadherin 6mRNA表达可作为判断恶性卵巢肿瘤预后的一个指标     

Prognostic significance of p53, Her-2, and EGFR overexpression in borderline and epithelial ovarian cancer

The objective of the study was to evaluate the prognostic effect of p53, Her-2, and EGFR in borderline and epithelial ovarian cancer. Tumor tissue from 85 patients with borderline and 783 patients with epithelial ovarian cancer stage I-IV were analyzed immunohistochemically for p53 positivity and over-expression of Her-2 and EGFR. In the ovarian cancer (OC) group 415 patients (53%) had p53-positive tumors, 272 (35%) had tumors with Her-2 over-expression, and 483 (62%) had over-expression of EGFR. In the OC group the classical prognostic factors (older age, higher FIGO stage, and poorer differentiated stage) had significant prognostic value in both uni- and multivariate analyses. Multivariate analyses in the OC group proved p53 positivity to increase mortality significantly depending on the grade of the tumor. Her-2 likewise increased the risk of mortality significantly in this group depending on the grade of the tumor. EGFR on the other hand did not have any additional prognostic effect in the OC group after adjustment for the classical prognostic and molecular factors was made. In the borderline group Her-2 and EGFR over-expression in combination, adjusted for age and p53, significantly improved the prognosis.     

ERBB2 amplification is superior to protein expression status in predicting patient outcome in serous ovarian carcinoma

OBJECTIVE: The objective of this study was to evaluate the frequency and clinical significance of ERBB2 gene amplification in serous ovarian carcinoma. In addition, concordance of the findings of ERBB2 immunohistochemistry and ERBB2 amplification was assessed. METHODS: Tissue microarray constructed of 401 serous ovarian carcinomas was examined by chromogenic in situ hybridization (CISH) using probe for ERBB2 gene and by immunohistochemistry using CB11 monoclonal antibody against ERBB2 protein. RESULTS: Amplification (>5 copies per cell) of ERBB2 was detected in 7% and low copy number increase (three-five copies) in 14% of the carcinomas. Increased copy number of ERBB2 was associated with poor prognosis, that is, poor response to therapy (P = 0.024), shorter disease-free (P < 0.0001) and overall survival (P < 0.0001). ERBB2 copy number status was identified as an independent prognostic factor for overall survival. Increased copy number of ERBB2 was also associated with high tumor grade, greater patient age, large residual tumor size, high proliferation index, aberrant p53 and negative progesterone receptor status. A significant association was found between ERBB2 amplification and ERBB2 protein overexpression. However, a substantial number of cases showed discrepant results by the two methods, especially in cases with low-level amplification or moderate protein overexpression. Overexpression of ERBB2 protein was associated with poor overall survival, but the prognostic value was weaker than that of ERBB2 gene copy number status. CONCLUSION: ERBB2 amplification positive tumors identified by CISH constitute a subgroup of serous ovarian carcinomas associated with aberrant p53, negative progesterone receptor status and aggressive behavior, a suitable group for testing the effect of trastuzumab in clinical trials.     

The role of 18F-fluoro-deoxyglucose positron emission tomography (18F-FDG PET) in diagnosis of ovarian cancer

We evaluated the clinical significance of ¹⁸F-FDG PET to detect malignant ovarian neoplasms and tumor spread. 40 patients (median age: 57.5 years) underwent laparotomy because of clinical suspicion of malignant ovarian tumors or recurrent disease. The results of the preoperatively performed PET were correlated with the postoperative histologic diagnosis and the intraoperatively assessed tumor spread. In 10 of 40 patients benign tumors were found, among which a tubo-ovarian abscess was the only one diagnosed as false positive. 4/30 malignant neoplasms did not originate from the coelomic epithelium, but all were correctly recognized as malignant tumors by PET, as was recurrent ovarian cancer in 12 patients. Out of 14 primary ovarian carcinomas, 2 borderline tumors and 1 well-differentiated adenocarcinoma FIGO stage I were not correctly identified. Considering the tumor type, sensitivity, and specificity were 90%, calculating for the positive and negative predictive value 96% and 75%, respectively, and 90% for the diagnostic accuracy. Those statistical parameters were slightly lower for PET detection of lymph node metastasis and peritoneal carcinomatosis. Although its diagnostic accuracy may vary depending on the clinical application, ¹⁸F-FDG PET is basically a suitable method for detecting ovarian malignancies, particularly in patients with relapsed ovarian carcinoma.     

Oncogene amplification in archival ovarian carcinoma detected by fluorescent differential polymerase chain reaction — a routine analytical approach

For quantitative determination of gene amplification of oncogenes involved in ovarian cancer development we have established a rapid, nonradioactive approach. Determination of c- erb B-2 and c-myc gene amplification in archival ovarian carcinoma specimens was based on differential polymerase chain reaction (dPCR) and fluorescent DNA technique. c- erb B-2 or c-myc sequences were amplified by PCR, in which one of each primer pair was fluorescently labeled, simultaneously with a reference gene (γ- IFN ) as internal single copy gene control. PCR products were separated by polyacrylamide gel electrophoresis with an automated DNA sequencer (A.L.F.™, Pharmacia, Freiburg, Germany) and directly quantified after laser activation and emission scanning using appropriate software (Fragment Manager ™, Pharmacia, Freiburg, Germany). This fluorescent differential PCR (fdPCR) method was used for quantitative determination of c- erb B-2 and c-myc gene amplification in 79 formalin-fixed, paraffin-embedded epithelial ovarian carcinoma tissues and 15 benign ovarian tissues. c- erb B-2 gene amplification was found in 18 (22%) and c-myc gene amplification in 13 (17%) of these carcinomas, but could not be detected in benign ovarian tissues. Single oncogene amplification correlated significantly with higher stage and higher grade ( P <0.05). Patients with either c- erb B-2 or c-myc gene amplification or both had significantly shorter relapse-free survival and overall survival. The fdPCR assay is a valuable tool for determination of oncogene amplification even in archival tumor tissue. More detailed information about individual tumor biology of the primary tumor and metastasis as well as criteria for additional therapeutic decisions may be acquired by this analytical approach.     

脂质体-C-erbB_2反义寡核苷酸对人卵巢上皮癌裸鼠皮下移植瘤的作用

目的：探讨经脂质体—硫代磷酸化修饰的Ｃ－ｅｒｂＢ２反义脱氧寡核苷酸（Ｃ－ｅｒｂＢ２ｓｕｌｆｉｄｅ－ＯＤＮｓ）作用后的卵巢上皮癌细胞在裸鼠皮下的成瘤能力及形态学变化。方法：利用离体途径将Ｃ－ｅｒｂＢ２ｓｕｌｆｉｄｅ－ＯＤＮｓ导入卵巢上皮癌细胞，然后接种于裸鼠皮下，观察肿瘤体积的变化，并计算抑瘤率。用透射电镜观察肿瘤形态变化。结果：经脂质体－Ｃ－ｅｒｂＢ２ｓｕｌｆｉｄｅ－ＯＤＮｓ作用后的卵巢上皮癌细胞在裸鼠皮下成瘤能力降低，最大抑瘤率可达４１．７％。超微结构显示实验组肿瘤细胞异染色质增多，分化增高。结论：Ｃ－ｅｒｂＢ２癌基因的反义调控能降低卵巢上皮癌的成瘤能力，抑制肿瘤生长，在卵巢上皮癌的基因治疗中有一定作用     

Amplification of EMSY, a novel oncogene on 11q13, in high grade ovarian surface epithelial carcinomas

OBJECTIVES: Amplification of the 11q13 locus is commonly observed in a number of human cancers including both breast and ovarian cancer. Cyclin D1 and EMS1 have been implicated as candidate oncogenes involved in the emergence of amplification at this locus. Detailed analysis of the 11q13 amplicon in breast cancer led to the discovery of four regions of amplification suggesting the involvement of other genes. Here, we investigate the role of EMSY, a recently described BRCA2 interacting protein, as a key element of the 11q13 amplicon in ovarian cancer. EMSY maps to 11q13.5 and is amplified in 13% of breast and 17% of ovarian carcinomas. METHODS: EMSY amplification was assessed by fluorescent in-situ hybridization (FISH) in 674 ovarian cancers in a tissue microarray and correlated with histopathological subtype and tumor grade. A detailed map of the 11q13 amplicon in 51 cases of ovarian cancer was obtained using cDNA-array-based comparative genomic hybridization (aCGH). To further characterize the role of EMSY within this amplicon, we evaluated both the amplification profiles and RNA expression levels of EMSY and two other genes from the 11q13 amplicon in an additional series of 22 ovarian carcinomas. RESULTS: EMSY amplification was seen in 52/285 (18%) high grade papillary serous carcinomas, 4/27 (15%) high grade endometrioid carcinomas, 3/38 (8%) clear cell carcinomas, and 3/10 (30%) undifferentiated carcinomas. aCGH mapping of 11q13 in ovarian cancer showed that EMSY localized to the region with the highest frequency of copy number gain. Cyclin D1 and EMS1 showed a lower frequency of copy number gain. A highly significant correlation between EMSY gene amplification and RNA expression was also observed (P = 0.0001). This was a stronger correlation than for other genes at 11q13 including Cyclin D1 and PAK1. CONCLUSIONS: These findings support the role of EMSY as a key oncogene within the 11q13 amplicon in ovarian cancer.     

Investigation of loss of heterozygosity at specific loci on chromosomes 3p, 6q, 11p, 17p and 17q in ovarian cancer

In an attempt to further define the genetic events in the pathogenesis and progression of human ovarian cancer, an analysis of constitutional and ovarian carcinoma DNA samples revealed loss of heterozygosity (LOH) at specific loci on chromosomes 3p (38%), 6q (23%), 11p (33%), 17p (82%) and 17q (62%). In contrast, LOH was not observed in benign or borderline tumors. No significant association could be demonstrated between LOH at the loci studied and tumor stage, histologic subtype, grade or patient outcome. Further analyses of large tumor panels are now required to determine the relationship between LOH at these loci and the clinicopathological behavior of ovarian tumors.     

Comparative genomic hybridization in four angiosarcomas of the female breast

OBJECTIVE: Angiosarcomas represent a heterogeneous group of malignant vascular tumors occurring in different anatomic sites. In the female breast, they account for less than 1% of all malignant tumors and mainly develop as secondary angiosarcomas after prior irradiation. Data on cytogenetic findings in angiosarcomas are scarce and up to now no characteristic primary aberrations have been established. We herein add molecular cytogenetic findings in another 4 angiosarcomas to 11 previously reported cases. METHODS: We investigated four angiosarcomas of the female breast (three primary angiosarcomas and one secondary tumor after irradiation for breast cancer) for DNA copy number changes using comparative genomic hybridization (CGH). RESULTS: All angiosarcomas revealed aberrant karyotypes including multiple DNA copy number changes involving various chromosomes. Recurrent DNA copy number changes that occurred in at least two cases included gains at 1q, 7p, 7q, and 8q, as well as losses at 5q and 16q. CONCLUSIONS: Angiosarcoma of the female breast represents a genetically heterogeneous tumor entity without a readily identifiable pattern of common chromosomal alterations. However, reviewing the cytogenetic literature on angiosarcomas of different sites, gains at 8q and 20p appear to emerge as the most frequent aberrations in at least a subset of these tumors.