Loss of cables, a novel gene on chromosome 18q, in ovarian cancer.

Cables, a cyclin-dependent kinase (cdk) interacting protein, has recently been identified and mapped to human chromosome 18q11. Cables appears to be primarily involved in cell cycle regulation and cell proliferation. Overexpression of Cables in Hela and other cell lines inhibits cell proliferation and tumor formation. We hypothesize that loss of Cables expression is associated with ovarian cancer. To test our hypothesis, we examined Cables expression in the four most common subtypes of ovarian carcinomas: serous, endometrioid, mucinous, and clear cell. In addition, mucinous and serous borderline tumors were also included. Loss of Cables expression was observed at high frequency in ovarian serous (11 of 14 cases, 79%) and endometrioid (5 of 10 cases, 50%) carcinomas. In contrast, strong Cables staining was detected in all clear cell carcinomas (10 cases) and mucinous tumors (5 carcinomas and 5 borderline tumors). The majority of serous borderline tumors (11 of 14 cases, 79%) showed positive Cables staining, with the rest showing focal loss of Cables expression. Furthermore, RT-PCR revealed the lack of Cables mRNA in a human ovarian cancer xenograft. No correlation was noted between loss of Cables and histologic grade, tumor stage, and survival. In conclusion, our results indicate that loss of Cables is common in ovarian serous and endometrioid carcinomas and imply that Cables may be involved in the pathogenesis of these two types of ovarian carcinomas.     

Morphological subtypes of ovarian carcinoma: a review with emphasis on new developments and pathogenesis

Ovarian carcinomas comprise a heterogeneous group of neoplasms, the four most common subtypes being serous, endometrioid, clear cell and mucinous. In recent years, our understanding of the underlying pathogenesis and initiating molecular events in the different tumour subtypes has greatly increased, and although ovarian carcinoma is often considered clinically as one disease, there is now a much greater realisation that the various subtypes have a different natural behaviour and prognosis. At present, adjuvant therapy is mainly dependent upon tumour stage and grade rather than type; however, this is likely to change in the future with the development of new chemotherapeutic agents and targeted therapies and clinical trials are necessary to evaluate the efficacy of different agents in clear cell, mucinous and low grade serous carcinomas, neoplasms which are considered relatively resistant to traditional chemotherapeutic regimes. In this review, the major subtypes of ovarian carcinoma are discussed. It is now firmly established that there are two distinct types of ovarian serous carcinoma, low grade and high grade, the former being much less common and arising in many cases from a serous borderline tumour. Low grade and high grade serous carcinoma represent two distinct tumour types with a different underlying pathogenesis rather than low grade and high grade variants of the same neoplasm. Both are usually advanced stage (stage III or IV) at diagnosis. B-raf and k-ras mutations are important molecular events in low grade serous carcinomas while high grade serous carcinomas are almost always associated with TP53 mutation. There is now emerging and compelling evidence that many high grade serous carcinomas (by far the most common subtype of ovarian carcinoma) actually arise from the epithelium of the distal fallopian tube. Future studies regarding the initiating molecular events in the development of this aggressive neoplasm should concentrate on this site. Primary ovarian mucinous carcinomas are uncommon, almost always unilateral and stage I, and largely of so-called intestinal or enteric type. Most arise in a stepwise manner from a pre-existing mucinous cystadenoma and mucinous borderline tumour. Endometrioid and clear cell carcinomas typically present as low stage neoplasms and in many, or most, cases arise from endometriosis; the former are usually well differentiated and there is now evidence that the majority of neoplasms reported in the past as high grade endometrioid carcinoma are of serous type. WT1 is useful in this regard since it is a relatively specific marker of a serous phenotype. It is recommended that different subtypes of ovarian carcinoma are graded using different systems rather than employing a universal grading system.     

Emi1 protein accumulation implicates misregulation of the anaphase promoting complex/cyclosome pathway in ovarian clear cell carcinoma.

Clear cell carcinoma is a clinically and pathologically distinct entity among surface epithelial ovarian neoplasms, recognized for its resistance to standard platinum-based chemotherapy at advanced stage disease and poor prognosis. Despite advances in our understanding of the biology of other surface epithelial ovarian neoplasms, very little is known about the molecular genetic mechanisms that are involved in clear cell tumorigenesis. Early mitotic inhibitor-1 (Emi1) protein is a key cell cycle regulator, that promotes S-phase and mitotic entry by inhibiting the anaphase promoting complex. In cell culture systems, overexpression of Emi1 leads to tetraploidy and genomic instability, especially in the absence of normal p53 function. We investigated Emi1 protein expression in ovarian neoplasms using a tissue microarray constructed from 339 primary ovarian surface epithelial (serous, endometrioid, clear cell, and mucinous) and peritoneal (serous) neoplasms, stromal and mesenchymal tumors, germ cell tumors, and normal ovarian tissue. Significant overexpression of Emi1 protein was present in 82% (27/33) clear cell carcinoma, including one borderline tumor in a diffuse, granular cytoplasmic and perinuclear staining pattern, independent of patient age, presence of ovarian and/or pelvic endometriosis, and FIGO stage. In contrast, only 10% (17/177) primary ovarian and primary peritoneal serous carcinomas, 0% (0/10) mucinous carcinomas, and 19% (6/32) endometrioid carcinomas exhibited significant Emi1 protein overexpression. Accumulation of Emi1 protein was not linked to Ki-67 labeling index, but was directly correlated with cyclin E and inversely correlated with ER in clear cell carcinoma (P<0.001). Emi1 protein expression was present in mixed endometrioid/clear cell tumors but absent in tumors with mixed serous/clear cell histology. These findings represent a potentially important insight into the molecular pathway underlying ovarian carcinogenesis and provide a possible cell cycle model for the development and progression of ovarian clear cell carcinoma.     

Loss of ARID1A expression is related to shorter progression-free survival and chemoresistance in ovarian clear cell carcinoma

Recently, the ARID1A gene has been identified as a novel tumor suppressor in ovarian clear cell carcinoma. The prognostic significance of the loss of ARID1A expression is not known. The current study was designed to evaluate whether ARID1A was a prognostic factor for progression, survival, and chemoresistance in ovarian clear cell carcinoma. A total of 60 patients, who were surgically treated for primary ovarian clear cell adenocarcinoma, were enrolled. Surgical specimens were examined for ARID1A protein expression by immunohistochemistry. The correlations between the loss of ARID1A expression and clinicopathological characteristics, prognosis, and chemosensitivity were investigated. Loss of ARID1A expression was identified in 9 (15.0%) of 60 ovarian clear cell carcinoma samples. Loss of ARID1A staining intensity (0+) was more frequently found in cells of clear cell carcinomas than in high-grade serous carcinomas (P<0.01). Loss of ARID1A expression was significantly correlated with advanced FIGO stage and high CA125 levels (P=0.02, 0.01). There were no significant correlations between loss of ARID1A expression and patient age, status of residual tumor, Ki-67 labeling index, or the status of endometriosis. Loss of ARID1A correlated with shorter progression-free survival of patients with clear cell carcinomas treated with platinum-based chemotherapy (P<0.01). Loss of ARID1A expression tended to correlate with shorter overall survival in patients with ovarian clear cell carcinomas treated with platinum-based chemotherapy. When data were stratified for the multivariate analysis, only the loss of ARID1A expression remained a significant (P=0.03) predictor of reduced progression-free survival. Of the 60 patients with ovarian clear cell carcinomas, 14 patients had measurable residual tumor after primary cytoreductive surgery. Tumors with loss of ARID1A expression were more likely to be chemoresistant than tumors with positive ARID1A expression (100.0 vs 40.0%, P=0.04). This study demonstrates that loss of ARID1A in ovarian clear cell carcinoma is a negative prognostic factor in patients treated with platinum-based chemotherapy. Measurement of ARID1A expression may be a method to predict resistance to platinum-based chemotherapy in patients with ovarian clear cell carcinoma.     

Association of cortactin, fascin-1 and epidermal growth factor receptor (EGFR) expression in ovarian carcinomas: correlation with clinicopathological parameters

Cortactin, fascin-1 and EGFR are recognized as important factors in tumor progression. We tested the hypothesis that cortactin, fascin-1 and EGFR expression correlates with clinicopathological parameters of the four most common ovarian surface epithelial carcinomas--serous cystadenocarcinoma, mucinous cystadenocarcinoma, endometrioid adenocarcinoma, and clear cell carcinoma. Immunohistochemical analysis of cortactin, fascin-1 and EGFR was performed using tissue microarrays of 172 specimens comprising 69 serous cystadenocarcinomas, 44 mucinous cystadenocarcinomas, 45 endometrioid adenocarcinomas and 14 clear cell carcinomas. All ovarian carcinomas showed significant expression of cortactin, fascin-1 and EGFR in staining intensity, tumor percentages and immunostaining scores. In addition, higher immunostaining scores of fascin-1 correlated with more advanced cancer stages (TNM), poorer histological differentiation and poorer survival rate of mucinous cystadenocarcinoma. Similarly, higher immunostaining scores of cortactin correlated with T stages and histological differentiation of serous cystadenocarcinoma. The immunostaining scores of EGFR did not correlate with TNM stages, tumor differentiation or prognosis in the four ovarian surface epithelial carcinomas. Our findings suggest that cortactin and fascin-1 may serve as good biomarkers in evaluating aggressiveness of ovarian serous and mucinous cystadenocarcinoma. And the pharmacological inhibitors of fascin-1 activity may slow down tumor progression and prolong survival time in patients with mucinous cystadenocarcinoma.     

Microsatellite instability and expression of hMLH1 and hMSH2 proteins in ovarian endometrioid cancer.

Microsatellite instability and loss of heterozygosity has been implicated in ovarian carcinogenesis. The reported frequency of microsatellite instability in human ovarian cancer varies significantly owing to the use of heterogeneous tumor histotypes and various microsatellite markers in different laboratories. In this study, we determined the frequency of microsatellite instability in 74 ovarian endometrioid carcinomas using four microsatellite markers (BAT25, BAT26, D5S346, D17S250), and examined hMLH1 and hMSH2 protein expression. In all, 20% of the tumors were microsatellite instability high (two or more markers showing instability) and 12% were microsatellite instability low (one marker showed instability). Loss of hMLH1 and/or hMSH2 expression was found in nine of 15 microsatellite instability-high tumors. The microsatellite instability-high phenotype tended to occur more frequently in low-grade tumors (P=0.053), but did not correlate with clinical stage. Totally, 38% of cases also displayed loss of heterozygosity at D17S250; this loss of heterozygosity was associated with high clinical stage (P=0.097). Our results indicate that both microsatellite and loss of heterozygosity at D17S250 are involved in the development of ovarian endometrioid carcinoma.     

Overexpression of carbonic anhydrase IX (CAIX) is an independent unfavorable prognostic marker in endometrioid ovarian cancer

Carbonic anhydrase IX (CAIX) is a strictly membranous expressed metalloenzyme involved in cell adhesion, pH homeostasis, and cancer progression. This study was designed to assess the role of CAIX in primary ovarian cancer. Two hundred five well-characterized primary ovarian carcinomas were analyzed on a tissue microarray. CAIX expression was determined by immunohistochemistry using a four-step scoring system. Moderate and strong membranous CAIX expression was found in 37 out of 205 (18%) of all assessable ovarian cancer specimens. High levels of CAIX expression were related to mucinous and endometrioid phenotype of ovarian carcinomas (p < 0.05). There was no association between CAIX overexpression and tumor stage, grading, and mitotic count of ovarian carcinomas (p > 0.05). In univariate Cox regression analysis, advanced tumor stage (p < 0.01), high tumor grade (p = 0.017), high mitotic count (p = 0.025), and high CAIX expression levels (p = 0.031) were correlated to shorter overall patient survival. High pT stage (p = 0.036) and CAIX overexpression were connected to poor clinical outcome in endometrioid ovarian carcinomas. Multivariate Cox regression hazard analysis comprising tumor stage, tumor grade, mitotic count, and CAIX expression revealed pT2/3 stage and CAIX overexpression (scores 2 and 3) as independent prognostic markers in ovarian cancer (p < 0.01, each) as well as in the subgroup of endometrioid carcinomas (p < 0.05, each). In conclusion, CAIX is overexpressed in a substantial proportion of mucinous and endometrioid ovarian carcinomas and connected to poor patient outcome. Our data support the potential therapeutic benefit of newly developed targeting antibodies in advanced ovarian cancer.     

Prognostic relevance of hMLH1, hMSH2, and BAX protein expression in endometrial carcinoma.

Endometrial carcinoma is the most common gynecologic malignancy in perimenopausal and postmenopausal women. A role of mismatch repair genes, like hMLH1 and hMSH2 in their pathogenesis, has been suggested. Loss of their function leads to the accumulation of replication errors (mutator phenotype), which are responsible for further mutations in genes with microsatellite sequences in their coding region, such as Bax. We analyzed the expression of hMLH1, hMSH2, and Bax genes in 89 formalin-fixed paraffin-embedded endometrial carcinomas. The immunostains were scored with regard to percentage of positive tumor cells (0%, <10%, 10 to 50%, >50%), and relative staining intensity (1+, 2+, 3+). The staining results were correlated with clinicopathologic features and survival. Loss of hMSH2 expression (0% positive cells) was observed in 1.1% (1/89) of the tumors; loss of hMLH1 was seen in 12.4% (11/89) of the cases, particularly in endometrioid tumors with mucinous differentation (5/11; 45%; P =.03). No significant association was found between the immunoscores and grade, stage criteria of the International Federation of Obstetrics and Gynecology (FIGO), or age of the patients. Among 11 tumors with loss of Bax expression (12.4%), 4 had also loss of hMLH1 (4/11; 36.4%; P =.017). In multivariate analysis (Cox model), significantly longer survival was found for patients with tumors in FIGO Stage I-II (P <.0001), endometrioid type (P =.001), low grade (P =.001), and absence of hMLH1 expression (P =.027). Our results suggest that loss of function of hMLH1 and Bax occur in a subgroup of endometrial carcinoma. In addition to the classical prognostic factors, absence of hMLH1 expression is associated with better outcome of patients.     

The expression of six biomarkers in the four most common ovarian cancers: correlation with clinicopathological parameters

This study aimed to evaluate the relationship of fascin‐1, matrix metalloproteinase (MMP)‐2, MMP‐9, cortactin, survivin, and epidermal growth factor receptor (EGFR) expression with clinicopathological parameters for the four most common ovarian surface epithelial carcinomas. Six biomarkers were investigated immunohistochemically using tissue microarrays of 185 specimens including 79 serous cystadenocarcinomas, 47 mucinous cystadenocarcinomas, 45 endometrioid adenocarcinomas, and 14 clear cell carcinomas. The four most common ovarian carcinomas showed significant expression of fascin‐1, cortactin, survivin, and EGFR, but not of MMP‐2 and MMP‐9. In addition, higher immunostaining scores for fascin‐1 in mucinous cystadenocarcinomas correlated with T stage, N stage, American Joint Committee on Cancer AJCC clinical stage, and a poorer survival rate; for cortactin in serous cystadenocarcinomas correlated with T stage; for cortactin in clear cell carcinomas correlated with T and clinical AJCC stages; and for survivin in clear cell carcinomas correlated with T stage and AJCC clinical stage. In addition, higher immunostaining scores for fascin‐1, cortactin, and survivin correlated with poorer tumor differentiation in serous, mucinous, and endometrioid adenocarcinomas. Thus, the expression of fascin‐1, cortactin, and survivin may be helpful in evaluating the aggressiveness of ovarian mucinous, serous, and clear cell adenocarcinoma. Additionally, the expression of fascin‐1 may be an independent prognostic risk factor in mucinous cystadenocarcinoma.     

LMX1A as a prognostic marker in ovarian mucinous cystadenocarcinoma

This study aimed to evaluate the relationship of LMX1A and osteopontin (OPN) expression with clinicopathologic parameters for the 4 most common ovarian surface epithelial carcinomas. Both biomarkers were investigated immunohistochemically using tissue microarrays of 249 specimens including 91 serous cystadenocarcinomas, 56 mucinous cystadenocarcinomas, 64 endometrioid adenocarcinomas, 26 clear cell carcinomas, and 12 normal ovarian tissues. All 4 carcinomas showed significant expression of LMX1A and OPN. In addition, higher immunostaining scores and percentage of cells stained for LMX1A in mucinous cystadenocarcinomas correlated with T stage, American Joint Committee on Cancer clinical stage, poorer tumor differentiation, and poorer survival rate. In serous cystadenocarcinoma, higher percentage of staining for OPN and higher intensity or immunostaining scores for LMX1A correlated with poorer tumor differentiation. Thus, the expression of LMX1A may be an independent prognostic risk factor in mucinous cystadenocarcinoma and a helpful marker in evaluating this tumor's aggressiveness.     

Microsatellite instability and alteration of the expression of hMLH1 and hMSH2 in ovarian clear cell carcinoma

Microsatellite instability (MSI) is commonly seen in tumors associated with the hereditary nonpolyposis colorectal cancer syndrome and is caused by defects in the DNA mismatch repair genes. MSI has also been observed in various sporadic cancers, including colorectal, gastric, and endometrial. The role and incidence of MSI in ovarian clear cell carcinoma remain unknown. This study was conducted to evaluate the frequency of MSI in ovarian clear cell carcinomas and to evaluate the sensitivity and specificity of immunohistochemistry in predicting mismatch-repair gene deficiency. A total of 42 ovarian clear cell carcinomas were analyzed for MSI using a panel of 5 microsatellite markers (BAT25, BAT26, D5S346, D2S123, and D17S250). Alterations in the expression of hMLH1 and hMSH2 proteins in these tumors were examined. Of the 42 ovarian clear cell tumors analyzed, 6 demonstrated a high level of MSI (MSI-H), 3 demonstrated a low level of MSI (MSI-L), and the remaining 33 exhibited microsatellite stability (MSS). No correlation was found between MSI level and patient age or tumor stage or size (P >0.05). Loss of expression of either hMLH1 or hMSH2 was observed in 4 of the 6 (67.7%) MSI-H tumors, whereas 34 of the 36 (94.4%) MSI-L or MSS tumors expressed both the hMLH1 and hMSH2 gene products. Our results indicate that MSI-H is involved in the development of a subset of ovarian clear cell carcinomas. A strong correlation exists between alterations in the expression of hMLH1 and hMSH2 and the presence of MSI-H in these tumors. However, immunohistochemical testing alone may miss a small fraction of cases with MSI-H.     

Histological classification of ovarian cancer

The histology of ovarian tumors exhibits a wide variety of histological features. The histological classification of ovarian tumors by the World Health Organization (WHO) is based on histogenetic principles, and this classification categorizes ovarian tumors with regard to their derivation from coelomic surface epithelial cells, germ cells, and mesenchyme (the stroma and the sex cord). Epithelial ovarian tumors, which are the majority of malignant ovarian tumors, are further grouped into histological types as follows: serous, mucinous, endometrioid, clear cell, transitional cell tumors (Brenner tumors), carcinosarcoma, mixed epithelial tumor, undifferentiated carcinoma, and others. Clear cell and endometrioid carcinomas are highly associated with endometriosis. In stage distribution, serous carcinoma is found predominantly is stage III or IV. In contrast, clear cell and endometrioid carcinomas tend to remain confined to the ovary. Clear cell and endometrioid carcinomas may be unique histological types compared with serous carcinomas with respect to stage distribution and association with endometriosis.     

Aberrant expression of MUC4 in ovarian carcinoma: diagnostic significance alone and in combination with MUC1 and MUC16 (CA125).

Mucins are being implicated in diagnosis, prognosis, and as therapeutic targets due to their aberrant expression in a variety of carcinomas. Here, we have analyzed the expression of MUC4 and have compared its potential usefulness in early detection and prognosis of ovarian carcinoma alone and in combination with other mucin antigens, MUC1 and MUC16. Clinical significance of the differential mucin expression was evaluated by grouping the tumor samples in early (stage I and II) and advanced (stage III and IV) stage cases and histological subtypes (serous, mucinous, endometrioid and clear cell). Correlation of these mucins with patient's survival (n=63) was determined by Kaplan-Meier analysis in order to predict their prognostic value. MUC4 showed significant overexpression in tumor cases (P<0.0001) with highest incidence (92.0%) among all three mucins. A significant overexpression of MUC1 (P<0.018) and MUC16 (P<0.0001) was also observed in 83.0 and 79.0% of tumor samples, respectively. Notably, MUC4 expression was significantly higher (P相似文献   

Increasing expression of serine protease matriptase in ovarian tumors: tissue microarray analysis of immunostaining score with clinicopathological parameters.

Matriptase is a type II transmembrane serine protease expressed by cells of surface epithelial origin, including epithelial ovarian tumor cells. Matriptase cleaves and activates proteins implicated in the progression of cancer and represents a potential prognostic and therapeutic target. The aim of this study was to examine the expression of matriptase in ovarian tumors and to assign clinicopathological correlations. Immunohistochemical analysis of matriptase was performed in tissue microarrays of 164 ovarian neoplasms including 84 serous adenocarcinomas, 23 mucinous adenocarcinomas, 10 endometrioid adenocarcinomas, six yolk sac tumors, 12 clear cell carcinomas, six dysgerminomas, eight granulosa cell tumors, four transitional cell carcinomas, five fibromas, and six Brenner tumors. All ovarian tumors except the fibromas and Brenner tumors showed significant expression of matriptase. The matriptase scores were significantly higher in the tumors than in their nontumor counterparts (304+/-26 for serous adenocarcinoma; 361+/-28 for mucinous adenocarcinoma; 254+/-17 for endometrioid adenocarcinoma; 205+/-19 for yolk sac tumor; 162+/-16 for clear cell carcinoma; 109+/-11 for dysgerminoma; 105+/-9 for granulosa cell tumor; and 226+/-18 for transitional cell carcinoma). Matriptase scores in serous adenocarcinoma were correlated with TNM stage and FIGO stage. Our findings demonstrate for the first time that matriptase is overexpressed in many malignant ovarian tumors. It may be a novel biomarker for diagnosis and treatment of malignant ovarian tumors.     

Molecular abnormalities in ovarian carcinoma: clinical,morphological and therapeutic correlates

The histopathological classification of ovarian surface epithelial carcinomas (referred to hereafter as ‘ovarian carcinoma’) has shifted over the past 10 years to reflect more clearly our understanding of molecular events during carcinogenesis. Ovarian carcinoma is no longer viewed as a single entity but as multiple disease processes, with each having different molecular pathways altered during oncogenesis, resulting in differences in clinical and pathological features, such as biomarker expression, pattern of spread and response to chemotherapy. There are five subtypes of ovarian carcinoma that are sufficiently distinct and well‐characterized that they should be considered to be different diseases, i.e. high‐grade serous, clear cell, endometrioid, mucinous and low‐grade serous, from most to least common, respectively. This review summarizes the molecular abnormalities of these five ovarian carcinoma subtypes, relating them to clinical and pathological features.     

Advances in sub-classification of ovarian carcinomas by cell type: an update

The histological classification of ovarian carcinomas has changed in recent decades. The five cell types that comprise the vast majority of cases are: high grade serous, low grade serous, endometrioid, clear cell and mucinous, and the criteria for distinguishing these types have evolved. Clinical, epidemiological, pathological and molecular evidence indicates that these cell types reflect different diseases. In particular, it has become clear that high and low grade serous carcinomas are sufficiently distinctive to warrant separate classification rather than different grades of a single type of carcinoma. High grade serous carcinoma causes the vast majority of ovarian cancer deaths and is the appropriate target for screening studies.     

Ovarian carcinoma: current diagnostic principles

Ovarian cancer is the most common cause of death from a gynecologic cancer. The most common types of ovarian cancer are carcinomas of surface epithelial-stromal origin. Ovarian carcinomas are a heterogeneous group of neoplasms. Based on proposed different pathways of tumorigenesis, these tumors are divided into two broad subgroups (type I and II) with different biologic behaviour, prognosis and response to therapy. Type I tumors include low-grade serous adenocarcinoma, low-grade endometrioid adenocarcinoma, mucinous adenocarcinoma, malignant Brenner tumor and some clear cell carcinomas. These tumors are low-grade neoplasms evolving from a defined precursor lesion. Type II tumors are high-grade neoplasms including undifferentiated carcinoma, high-grade serous adenocarcinoma, high-grade endometrioid adenocarcinoma, malignant mixed Müllerian tumor and probably some clear cell carcinomas. At present, the histological type of ovarian carcinoma has only limited impact on the management of these tumors. However, with progress towards the type-specific treatment of ovarian carcinoma, accurate histopathological diagnosis of ovarian carcinoma becomes increasingly important. In this review we summarize recent advances in the histopathological diagnosis of ovarian carcinoma. Moreover, we mention genetic changes in different types of ovarian carcinoma.     

Expression of MAGE-C1/CT7 and selected cancer/testis antigens in ovarian borderline tumours and primary and recurrent ovarian carcinomas

MAGE-C1/CT7, NY-ESO-1, GAGE and MAGE-A4 are members of the cancer/testis (CT) antigen family, which have been proposed as potential targets for cancer immunotherapy. To determine the prevalence and biologic relevance of the novel CT antigen MAGE-C1/CT7 and other antigens, 36 ovarian borderline tumours (BTs), 230 primary ovarian carcinomas (OCs) and 80 recurrent OCs were immunohistochemically analysed using the monoclonal antibodies CT7-33 (MAGE-C1/CT7), E978 (NY-ESO-1), clone 26 (GAGE) and 57B (MAGE-A4). Positivity of at least one CT antigen was present in 39.5 % (81/205) of primary OC and in 50 % (26/52) of all recurrences. Expression of the novel CT antigen MAGE-C1/CT7 was most commonly seen with positivity in 24.5 % of primary and 35.1 % of recurrent OC. MAGE-A4, GAGE and NY-ESO-1 expressions were seen in 22.7, 13.9 and 7.1 % of primary and 22.6, 17.5 and 8.9 % of recurrent OC, respectively. Analysis of histological subtypes (serous, endometrioid, clear cell, mucinous and transitional) exhibited variable expression with negativity in all mucinous OC. High-grade serous OC revealed CT antigen expression in 5.6 to 28 % with MAGE-C1/CT7 being the most frequent, but without correlation with stage or overall survival. MAGE-C1/CT7 expression and coexpression of CT antigens were significantly correlated with grade of endometrioid OC. None of the BT showed CT antigen expression. No significant correlation was seen with stage, overall survival or response to chemotherapy. In summary, CT antigens are expressed in a certain subset of OC with no expression in BT or OC of mucinous histology. These findings may have implications for the design of polyvalent vaccination strategies for ovarian carcinomas.     

β-Catenin Expression Pattern in Stage I and II Ovarian Carcinomas : Relationship with β-Catenin Gene Mutations, Clinicopathological Features, and Clinical Outcome

The immunohistochemical expression pattern of beta-catenin has been correlated with beta-catenin gene mutations, clinicopathological features, and disease outcome in 69 stage I and II ovarian carcinomas. beta-Catenin expression was localized in the nuclei, in addition to the cytoplasm and membrane, in 11 tumors (16%): nine endometrioid carcinomas with widespread nuclear expression and two serous carcinomas with focal nuclear expression. The remaining 58 carcinomas (84%) only had membranous beta-catenin expression. All but one of the endometrioid carcinomas with nuclear beta-catenin expression had considerable squamous metaplasia, and five of these cases had large areas of endometrioid tumor of low malignant potential. In addition, beta-catenin nuclear expression was observed in atypical epithelial cells in endometriotic glands adjacent to an endometrioid carcinoma. Sequencing was performed on 25 tumors and corresponding normal tissue: all 13 endometrioid tumors as well as 12 carcinomas of other histological types (four serous, two clear cell, two mucinous, and two mixed). There were oncogenic mutations in the phosphorylation sequence for GSK-3beta in exon 3 of the beta-catenin gene in seven endometrioid carcinomas with beta-catenin nuclear expression. Three mutations affected codon 32 (D32G, D32Y, and D32Y), one affected codon 33 (S33C), two affected codon 37 (S37C and S37F), and one affected codon 41 (T41A). No mutations were observed in the other 18 carcinomas analyzed, comprising two endometrioid and two serous carcinomas with beta-catenin nuclear expression, and 14 carcinomas of different histological types with only membranous expression. In the univariate and multivariate survival analyses, beta-catenin nuclear expression was selected as an indicator of good prognosis, because no patient whose tumor expressed beta-catenin in the nuclei showed relapses or died, in contrast to the 19 relapses and deaths among patients with tumors that only had beta-catenin membranous expression, including three of the four patients with endometrioid carcinomas. Oncogenic beta-catenin mutation is characteristic of a group of endometrioid carcinomas with a good prognosis, most of which originate from previous benign or borderline lesions. Endometrioid carcinomas with exclusively membranous expression of beta-catenin seem to represent a different subgroup of carcinomas that probably have a worse prognosis. In early-stage ovarian cancer, determination of the beta-catenin expression pattern could prove to be a useful marker for selecting low-risk patients.     

卵巢上皮癌中细胞外信号调节激酶的表达及其与预后的关系

目的: 探讨磷酸化细胞外调节激酶(p-ERK)在卵巢上皮癌组织中的表达及其与肿瘤患者预后之间的关系。方法: 应用Western印迹方法分别测定正常卵巢组织、良性卵巢组织和卵巢上皮癌组织中p-ERK的含量;收集卵巢上皮癌患者的临床资料;应用Kaplan-Meier法和Cox回归对卵巢上皮癌患者进行生存分析。结果: (1)卵巢上皮癌组织中的p-ERK含量明显高于良性卵巢组织和正常卵巢组织(P<0.01),Ⅲ~Ⅳ期卵巢上皮癌组织中p-ERK含量明显高于I~II期(P<0.01),良性卵巢组织中p-ERK含量与正常卵巢组织相比无显著差异(P>0.05);(2)低分化卵巢上皮癌组织中的p-ERK含量高于中、高分化(P<0.01);(3)在不同病理类型卵巢癌中,与浆液性卵巢上皮癌组织相比,未分化腺癌组织中p-ERK含量与其相仿(P>0.05),而黏液性卵巢上皮癌和卵巢子宫内膜样癌组织中p-ERK含量较低(P<0.05);(4)p-ERK含量与生存时间呈负相关,p-ERK含量高的卵巢上皮癌患者生存时间短;(5)卵巢上皮癌患者的生存时间与p-ERK含量、残余灶、肿瘤分期、肿瘤分级以及化疗的疗程有着密切关系(P<0.05),而与肿瘤的病理类型没有相关性(P>0.05)。结论: p-ERK可能是卵巢上皮癌发病机制一个重要的调节激酶;测定p-ERK水平可能对卵巢上皮癌患者预后有预测价值。