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1.
Clin Oncol (R Coll Radiol) ; 35(7): 472-477, 2023 07.
Article in English | MEDLINE | ID: mdl-37173220

ABSTRACT

AIMS: The survival time of patients with recurrent endometrial carcinoma is generally short. However, considerable interindividual variation exists. We developed a risk-scoring model for predicting post-recurrence survival in patients with endometrial carcinoma. MATERIALS AND METHODS: Patients with endometrial carcinoma treated at a single institution between 2007 and 2013 were identified. Pearson chi-squared analyses were used to compute odds ratios for the associations between risk factors and short survival after cancer recurrence. The results for biochemical analyses represented values at diagnosis of disease recurrence or values at initial diagnosis for those patients who had a primary refractory disease. Logistic regression models were constructed for the identification of variables that independently predict short post-recurrence survival. The models were used to assign points based on odds ratios for risk factors and risk scores were derived. RESULTS: In total, 236 patients with recurrent endometrial carcinoma were included in the study. Based on overall survival analysis, 12 months was selected as the cut-off for short post-recurrence survival. Factors associated with short post-recurrence survival were platelet count, serum CA125 concentration and progression-free survival. A risk-scoring model with an area under the receiver operating characteristic curve (AUC) of 0.782 (95% confidence interval 0.713-0.851) was developed in patients without missing data (n = 182). When patients with a primary refractory disease were excluded, age and blood haemoglobin concentration were identified as additional predictors of short post-recurrence survival. For this subpopulation (n = 152), a risk-scoring model with an AUC of 0.821 (95% confidence interval 0.750-0.892) was developed. CONCLUSIONS: We report a risk-scoring model that shows acceptable to excellent accuracy in predicting post-recurrence survival in patients with endometrial carcinoma, with primary refractory diseases included or excluded. This model has potential applications in precision medicine in patients with endometrial carcinoma.


Subject(s)
Endometrial Neoplasms , Female , Humans , Prognosis , Endometrial Neoplasms/pathology , Risk Factors , Survival Analysis , ROC Curve , Retrospective Studies
2.
Clin Genet ; 93(3): 595-602, 2018 03.
Article in English | MEDLINE | ID: mdl-28802053

ABSTRACT

Gene-panel sequencing allows comprehensive analysis of multiple genes simultaneously and is now routinely used in clinical mutation testing of high-risk breast and ovarian cancer patients. However, only BRCA1 and BRCA2 are often analyzed also for large genomic changes. Here, we have analyzed 10 clinically relevant susceptibility genes in 95 breast or ovarian cancer patients with gene-panel sequencing including also copy number variants (CNV) analysis for genomic changes. We identified 12 different pathogenic BRCA1, BRCA2, TP53, PTEN, CHEK2, or RAD51C mutations in 18 of 95 patients (19%). BRCA1/2 mutations were observed in 8 patients (8.4%) and CHEK2 protein-truncating mutations in 7 patients (7.4%). In addition, we identified a novel duplication encompassing most of the RAD51C gene. We further genotyped the duplication in breast or ovarian cancer families (n = 1149), in unselected breast (n = 1729) and ovarian cancer cohorts (n = 553), and in population controls (n = 1273). Seven additional duplication carries were observed among cases but none among controls. The duplication associated with ovarian cancer risk (3/590 of all ovarian cancer patients, 0.5%, P = .032 compared with controls) and was found to represent a large fraction of all identified RAD51C mutations in the Finnish population. Our data emphasizes the importance of comprehensive mutation analysis including CNV detection in all the relevant genes.


Subject(s)
Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , DNA-Binding Proteins/genetics , Gene Duplication , Genetic Association Studies , Genetic Predisposition to Disease , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/genetics , Adult , Aged , Alleles , Biomarkers, Tumor , Exons , Female , Finland , Gene Frequency , Genetic Association Studies/methods , Genetic Testing , Germ-Line Mutation , Hereditary Breast and Ovarian Cancer Syndrome/diagnosis , Hereditary Breast and Ovarian Cancer Syndrome/genetics , High-Throughput Nucleotide Sequencing , Humans , Middle Aged
3.
Br J Cancer ; 107(10): 1761-5, 2012 Nov 06.
Article in English | MEDLINE | ID: mdl-23132392

ABSTRACT

BACKGROUND: Mediator complex participates in transcriptional regulation by connecting regulatory DNA sequences to the RNA polymerase II initiation complex. Recently, we discovered through exome sequencing that as many as 70% of uterine leiomyomas harbour specific mutations in exon 2 of mediator complex subunit 12 (MED12). In this work, we examined the role of MED12 exon 2 mutations in other tumour types. METHODS: The frequency of MED12 exon 2 mutations was analysed in altogether 1158 tumours by direct sequencing. The tumour spectrum included mesenchymal tumours (extrauterine leiomyomas, endometrial polyps, lipomas, uterine leiomyosarcomas, other sarcomas, gastro-intestinal stromal tumours), hormone-dependent tumours (breast and ovarian cancers), haematological malignancies (acute myeloid leukaemias, acute lymphoid leukaemias, myeloproliferative neoplasms), and tumours associated with abnormal Wnt-signalling (colorectal cancers (CRC)). RESULTS: Five somatic alterations were observed: three in uterine leiomyosarcomas (3/41, 7%; Gly44Ser, Ala38_Leu39ins7, Glu35_Leu36delinsVal), and two in CRC (2/392, 0.5%; Gly44Cys, Ala67Val). CONCLUSION: Somatic MED12 exon 2 mutations were observed in uterine leiomyosarcomas, suggesting that a subgroup of these malignant tumours may develop from a leiomyoma precursor. Mutations in CRC samples indicate that MED12 may, albeit rarely, contribute to CRC tumorigenesis.


Subject(s)
Colorectal Neoplasms/genetics , Leiomyosarcoma/genetics , Mediator Complex/genetics , Uterine Neoplasms/genetics , Colorectal Neoplasms/pathology , Exome , Exons , Female , Humans , Leiomyoma/genetics , Leiomyoma/pathology , Leiomyosarcoma/pathology , Mutation , Sequence Analysis, DNA/methods , Uterine Neoplasms/pathology
4.
Br J Cancer ; 105(7): 989-95, 2011 Sep 27.
Article in English | MEDLINE | ID: mdl-21897396

ABSTRACT

BACKGROUND: Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein expressed in several solid cancers. Our purpose was to study its role in serous ovarian cancer patients, and the association to clinicopathological variables and molecular markers. METHODS: We collected retrospectively 562 consecutive serous ovarian cancer patients treated at the Helsinki University Central Hospital. We stained tumour tissue microarrays for CIP2A by immunohistochemistry and constructed survival curves according to the Kaplan-Meier method. Associations to clinicopathological and molecular markers were assessed by the χ(2)-test. RESULTS: We found strong cytoplasmic CIP2A immunoreactivity in 212 (40.4%) specimens, weak positivity in 222 (42.4%) specimens, and negative in 90 (17.2%). Immunopositive CIP2A expression was associated with high grade (P<0.0001), advanced stage (P=0.0005), and aneuploidy (P=0.001, χ(2)-test). Cancerous inhibitor of protein phosphatase 2A overexpression was also associated with EGFR protein expression (P=0.006) and EGFR amplification (P=0.043). Strong cytoplasmic CIP2A immunopositivity predicted poor outcome in ovarian cancer patients (P<0.0001, log-rank test). CONCLUSION: Our results show that CIP2A associates with reduced survival and parameters associated with high grade in ovarian cancer patients, and may thus be one of the factors that identify aggressive subtype (type II) of this disease.


Subject(s)
Autoantigens/metabolism , Biomarkers, Tumor/metabolism , Cystadenocarcinoma, Serous/metabolism , Membrane Proteins/metabolism , Ovarian Neoplasms/metabolism , Cohort Studies , Cytoplasm/metabolism , ErbB Receptors/metabolism , Female , Humans , Immunoblotting , Immunoenzyme Techniques , Intracellular Signaling Peptides and Proteins , Middle Aged , Prognosis , Retrospective Studies , Survival Rate , Tissue Array Analysis
6.
J Pathol ; 211(4): 481-8, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17294421

ABSTRACT

Receptor tyrosine kinases expressed in endothelial cells are potential targets for therapy with specific tyrosine kinase inhibitors. Endothelial cell KIT expression has not been systematically evaluated in human cancer. In the present study, endothelial cell KIT expression was assessed in 345 tumours consisting of 34 different histological types using a tissue microarray technique. Marked KIT expression occurred in the tumour endothelial cells only in primary glioblastomas in the microarray. Moderate to strong KIT and phosphorylated KIT expression was detected in the tumour endothelial cells in six (16%) and seven (19%) of the 37 primary glioblastomas examined, respectively. In whole tissue sections, KIT and phosphorylated KIT were expressed in tumour endothelial cells in 13 (59%) and 11 (50%) of the 22 glioblastomas examined, respectively. RNA in situ hybridization showed KIT mRNA expression in most glioblastomas both in tumour vessel endothelial cells and in perinecrotic palisading glioblastoma cells, whereas little KIT mRNA was found in the endothelial cells of colon or pancreatic carcinomas. Phosphorylated KIT, its ligand stem cell factor, and the downstream signalling molecules phosphorylated Akt and mTOR were often expressed in glioblastoma cells located in the perinecrotic tumour areas that often also contained abundant HIF-1alpha. It is concluded that marked KIT and phosphorylated KIT expression is frequently present in the endothelial cells of glioblastomas, which are known to harbour florid microvascular proliferation with characteristic morphological features. Glioblastomas also express phosphorylated KIT and its activated downstream signalling molecules in the tumour cells. Lower levels of KIT and phosphorylated KIT are present in endothelial cells of other tumour types and in normal tissues. Endothelial cell and tumour cell expression of activated KIT might explain in part the responsiveness of glioblastomas to the combination of imatinib (an inhibitor of KIT) and hydroxyurea.


Subject(s)
Endothelial Cells/chemistry , Glioblastoma/genetics , Neoplasms/genetics , Proto-Oncogene Proteins c-kit/genetics , Adenocarcinoma/chemistry , Adenocarcinoma/genetics , Gene Expression Regulation, Neoplastic/genetics , Glioblastoma/chemistry , Glioblastoma/pathology , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Immunohistochemistry/methods , Necrosis , Neoplasms/chemistry , Neoplasms/pathology , Oligonucleotide Array Sequence Analysis/methods , Oncogene Protein v-akt/genetics , Phosphorylation , Protein Kinases/genetics , Proto-Oncogene Proteins c-kit/analysis , RNA, Messenger/genetics , RNA, Neoplasm/genetics , Stem Cell Factor/genetics , TOR Serine-Threonine Kinases
7.
Br J Cancer ; 91(12): 2048-55, 2004 Dec 13.
Article in English | MEDLINE | ID: mdl-15583695

ABSTRACT

KIT and PDGFRA are receptor tyrosine kinases that can be specifically inactivated by small-molecule tyrosine kinase inhibitors, notably imatinib mesylate. In ovarian carcinoma, expression of KIT and PDGFRA protein has been documented, but the frequency and the molecular background of expression are poorly known. We analysed the expression of KIT and PDGFRA by immunohistochemistry in 522 serous ovarian carcinomas, and mutations of KIT and PDGFRA by denaturing high-performance liquid chromatographyin 125 and 187 serous ovarian carcinomas, respectively. No mutations of KIT or PDGFRA were detected. KIT expression was detected in 12% of carcinomas: low expression in 10% and high expression in 2% of cases. Using normal serous epithelium as a reference, decreased PDGFRA expression was detected in 12% and increased expression in 13% of carcinomas. Both KIT and PDGFRA expression were associated with high tumour grade, high proliferation index and poor patient outcome. By fluorescence in situ hybridisation, no KIT amplification was found in carcinomas with high KIT expression, but two cases showed a relative gain of chromosome 4. In conclusion, no mutations of KIT or PDGFRA were found, but a subset of serous ovarian carcinoma showed overexpression of the proteins, which was associated with aggressive tumour characteristics.


Subject(s)
Biomarkers, Tumor/analysis , Cystadenocarcinoma, Serous/genetics , Ovarian Neoplasms/genetics , Proto-Oncogene Proteins c-kit/genetics , Receptor, Platelet-Derived Growth Factor alpha/genetics , Chromatography, High Pressure Liquid , Cystadenocarcinoma, Serous/metabolism , Cystadenocarcinoma, Serous/pathology , Female , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Middle Aged , Mutation , Neoplasm Staging , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Polymerase Chain Reaction , Prognosis , Protein Array Analysis , Proto-Oncogene Proteins c-kit/metabolism , Receptor, Platelet-Derived Growth Factor alpha/metabolism
8.
Br J Cancer ; 87(10): 1119-27, 2002 Nov 04.
Article in English | MEDLINE | ID: mdl-12402151

ABSTRACT

We observed that the soluble complement regulators factor H and factor H-like protein were abundantly present in ascites samples as well as in primary tumours of patients with ovarian cancer. RT-PCR and immunoblotting analyses showed that the two complement inhibitors were constitutively produced by the ovarian tumour cell lines SK-OV-3 and Caov-3, but not PA-1 or SW626 cells. The amounts of factor H-like protein secreted were equal to those of factor H. This is exceptional, because e.g. in normal human serum the concentration of factor H-like protein is below 1/10th of that of factor H. In ascites samples the mean level of factor H-like protein (130+/-55 microg ml(-1)) was 5.5-fold higher than in normal human serum (24+/-3 microg ml(-1)). Ovarian tumour cells thus preferentially synthesise factor H-like protein, the alternatively spliced short variant of factor H. The tumour cells were found to bind both (125)I-labelled factor H and recombinant factor H-like protein to their surfaces. Surprisingly, the culture supernatants of all of the ovarian tumour cell lines studied, including those of PA-1 and SW626 that did not produce factor H/factor H-like protein, promoted factor I-mediated cleavage of C3b to inactive iC3b. Subsequently, the PA-1 and SW626 cell lines were found to secrete a soluble form of the membrane cofactor protein (CD46). Thus, our studies reveal two novel complement resistance mechanisms of ovarian tumour cells: (i) production of factor H-like protein and factor H and (ii) secretion of soluble membrane cofactor protein. Secretion of soluble complement inhibitors could protect ovarian tumour cells against humoral immune attack and pose an obstacle for therapy with monoclonal antibodies.


Subject(s)
Blood Proteins/biosynthesis , Complement Factor H/biosynthesis , Ovarian Neoplasms/metabolism , Ascitic Fluid/chemistry , Blood Proteins/analysis , Complement C3b/metabolism , Complement C3b Inactivator Proteins , Complement Factor H/analysis , Female , Humans , Immunohistochemistry , Ovarian Neoplasms/chemistry , Tumor Cells, Cultured
9.
Gynecol Oncol ; 82(2): 223-8, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11531271

ABSTRACT

OBJECTIVE: Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary cancer susceptibility disorder associated with a very high risk for carcinoma of the colon and an elevated risk for certain extracolonic cancers including ovarian cancer. Our aim in this study was to describe the clinicopathologic features of ovarian cancer in HNPCC family members. METHODS: . Members of the International Collaborative Group on HNPCC collected retrospective data on 80 ovarian cancer patients who were members of HNPCC families, including 31 known mutation carriers, 35 presumptive carriers (by colorectal/endometrial cancer status), and 14 at-risk family members. RESULTS: Mean age at diagnosis of ovarian cancer was 42.7. Nonepithelial tumors made up only 6.4% of the cancers, and borderline tumors comprised just 4.1% of the epithelial cancers. Among frankly malignant epithelial cases, most cancers were well or moderately differentiated, and 85% were FIGO stage I or II at diagnosis. Synchronous endometrial cancer was reported in 21.5% of cases. CONCLUSIONS: Ovarian cancer in HNPCC differs from ovarian cancer in the general population in several clinically important respects. It occurs at a markedly earlier age. It is more likely to be epithelial. If it is a frankly invasive epithelial cancer, it is more likely to be well or moderately differentiated. HNPCC patients with ovarian cancer are more likely to have a synchronous endometrial cancer than other ovarian cancer patients and are more likely to be diagnosed at an early stage.


Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/pathology , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Adult , Age Factors , Aged , Female , Humans , Male , Middle Aged , Neoplasm Staging , Neoplasms, Multiple Primary/genetics , Neoplasms, Multiple Primary/pathology , Neoplasms, Second Primary/genetics , Neoplasms, Second Primary/pathology , Retrospective Studies
10.
Eur J Hum Genet ; 9(6): 424-30, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11436123

ABSTRACT

Germline mutations of BRCA1 and BRCA2 predispose to hereditary breast-ovarian cancer syndrome. In Finland, 20 different BRCA1/2 mutations have been identified, and 13 of them are founder mutations that account for the vast majority of Finnish BRCA1/2 families. The purpose of our study was to determine the prevalence of BRCA1/2 mutations in unselected Finnish ovarian carcinoma patients and to evaluate the relationship between mutation carrier status and personal/family history of cancer. Two hundred and thirty-three patients were screened for all the 20 BRCA1/2 mutations known in the Finnish population. Additionally, a subgroup of patients with personal history of breast cancer and/or family history of breast and/or ovarian cancer was screened for novel BRCA1/2 mutations. Thirteen patients (5.6%) had mutations: eleven in BRCA1 and two in BRCA2. All the mutation-positive patients were carriers of the previously known Finnish BRCA1/2 mutations, and seven recurrent founder mutations accounted for 12 of the 13 mutations detected. A logistic regression analysis was used to determine the odds of mutation for ovarian carcinoma patients. The most significant predictor of a mutation was the presence of both breast and ovarian cancer in the same woman, but family history of breast cancer was also strongly related to mutation carrier status. Although BRCA1/2 mutation testing is not warranted in the general Finnish ovarian cancer patient population, patients who have also been diagnosed with breast cancer or have family history of breast or breast and ovarian cancer could benefit from referral to genetic counselling and mutation testing.


Subject(s)
BRCA1 Protein/genetics , Carcinoma/genetics , Mutation , Neoplasm Proteins/genetics , Ovarian Neoplasms/genetics , Transcription Factors/genetics , BRCA2 Protein , Cohort Studies , Family Health , Female , Finland , Founder Effect , Humans , Logistic Models , Ovarian Neoplasms/epidemiology
11.
Am J Pathol ; 159(1): 35-42, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11438451

ABSTRACT

The distal half of chromosome arm 18q is frequently lost in ovarian carcinoma. To define the putative tumor suppressor locus/loci more precisely we performed allelic analysis with 27 polymorphic microsatellite markers located at 18q12.3-q23 in 64 serous and 9 mucinous ovarian carcinomas. Fifty-nine percent of the serous carcinomas, but only one (11%) of mucinous carcinomas, showed allelic loss at one or more loci (P = 0.018). In serous carcinomas, deletions were found to be associated with tumor grade and poor survival. The highest frequency of losses was detected at the distal part, 18q22-q23. Two minimal common regions of loss (MCRL) were identified at this region: MCRL1 between D18S465 and D18S61 at 18q22 (3.9 cM) and MCRL2 between D18S462 and D18S70 at 18q23 (5.8 cM). At 18q21.1, proximal to the MCRLs, there are three candidate tumor suppressor genes: SMAD4 (DPC4), SMAD2, and DCC. Their protein expression was studied by immunohistochemistry in normal ovarian tissue and serous carcinomas. Lost or very weak expression of SMAD4, SMAD2 and DCC was found in 28, 28, and 30% of serous carcinomas, respectively. Comparison of allelic loss and protein expression status indicated that none of these genes alone could be the target for the frequent allelic loss at 18q21.1. Together, these genes may account for a substantial proportion of the events, but not all of them. Thus, we propose that the frequent allelic loss at 18q is because of the effect of multiple genes, and there is at least one as yet unidentified tumor suppressor gene at 18q residing distal to SMAD4, SMAD2, and DCC involved in serous ovarian carcinoma.


Subject(s)
Alleles , Carcinoma/genetics , Chromosome Mapping , Chromosomes, Human, Pair 18/genetics , Genes, Tumor Suppressor/genetics , Ovarian Neoplasms/genetics , Tumor Suppressor Proteins , Adenocarcinoma, Mucinous/genetics , Carcinoma/metabolism , Cell Adhesion Molecules/metabolism , DCC Receptor , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Female , Genes, DCC/genetics , Humans , Immunohistochemistry , Loss of Heterozygosity , Ovarian Neoplasms/metabolism , Receptors, Cell Surface , Smad2 Protein , Smad4 Protein , Trans-Activators/genetics , Trans-Activators/metabolism
12.
Cancer Res ; 61(7): 2813-5, 2001 Apr 01.
Article in English | MEDLINE | ID: mdl-11306449

ABSTRACT

Hereditary nonpolyposis colorectal cancer syndrome is associated with an inherited predisposition to primarily colorectal cancer (CRC) and endometrial cancer (EC); however, the biological basis of the organ involvement remains unknown. As an attempt to explore whether the expression levels of MLH1, MSH2, and MSH6 may play a role, we used immunohistochemistry to study 42 ECs and 35 CRCs from patients carrying the same predisposing mutations. Among MSH2 mutation carriers, MLH1 was expressed in both tumor types, whereas MSH2 and, in many cases, also MSH6, were absent. Remarkably, among MLH1 mutation carriers, 54% of ECs (21 of 39), but none of the CRCs (0 of 32), lacked the MSH2 and/or MSH6 protein in addition to lacking MLH1 protein expression. These results demonstrate a marked difference between hereditary nonpolyposis colorectal cancer-related CRCs and ECs and suggest that the development of the latter tumors is selectively associated with the MSH2/MSH6 protein complex deficiency.


Subject(s)
Colonic Neoplasms/metabolism , Colorectal Neoplasms, Hereditary Nonpolyposis/metabolism , DNA-Binding Proteins/biosynthesis , Endometrial Neoplasms/metabolism , Proto-Oncogene Proteins/biosynthesis , Adaptor Proteins, Signal Transducing , Carrier Proteins , Colonic Neoplasms/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA-Binding Proteins/deficiency , Dimerization , Endometrial Neoplasms/genetics , Female , Germ-Line Mutation , Humans , Immunohistochemistry , MutL Protein Homolog 1 , MutS Homolog 2 Protein , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/deficiency , Nuclear Proteins , Proto-Oncogene Proteins/deficiency
13.
Lab Invest ; 81(4): 517-26, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11304571

ABSTRACT

Using comparative genomic hybridization (CGH), we have previously demonstrated frequent loss of 8p, especially its distal part, in ovarian carcinoma. To compare the deletion map of distal 8p in serous and mucinous ovarian carcinomas, we performed allelic analysis with 18 polymorphic microsatellite markers at 8p21-p23. In serous carcinoma, loss of heterozygosity (LOH) was detected in 67% of the samples, and the majority of the carcinomas showed loss of all or most of the informative markers. In contrast, only 21% of mucinous carcinomas showed allelic loss, with only one or two loci showing LOH in each sample. In serous carcinomas, LOH was associated with higher grade tumors. Three distinct minimal common regions of loss could be defined in serous carcinomas (at 8p21.1, 8p22-p23.1, and 8p23.1). Expression of a transcription factor gene, GATA4, located at one of these regions (8p23.1) was studied in serous and mucinous ovarian carcinomas by Northern blotting and immunohistochemical staining of tumor microarray. Expression was found to be lost in most serous carcinomas but retained in the majority of mucinous carcinomas. Our results suggest distinct pathogenetic pathways in serous and mucinous ovarian carcinomas and the presence of more than one tumor suppressor gene at 8p involved in the tumorigenesis of serous carcinoma.


Subject(s)
Adenocarcinoma, Mucinous/genetics , Chromosomes, Human, Pair 8 , Cystadenocarcinoma, Serous/genetics , DNA-Binding Proteins/genetics , Loss of Heterozygosity , Ovarian Neoplasms/genetics , Transcription Factors/genetics , Adenocarcinoma, Mucinous/metabolism , Adenocarcinoma, Mucinous/pathology , Blotting, Northern , Cystadenocarcinoma, Serous/metabolism , Cystadenocarcinoma, Serous/pathology , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/immunology , Female , GATA4 Transcription Factor , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , RNA, Messenger/biosynthesis , Transcription Factors/biosynthesis , Transcription Factors/immunology
14.
J Clin Endocrinol Metab ; 86(4): 1765-8, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11297615

ABSTRACT

Prostaglandins (PGs) have been implicated in regulation of ovarian function. We have previously shown that the expression of cyclooxygenase-2 and the receptor for PGF(2 alpha) are expressed in periovulatory human granulosa cells and upregulated by gonadotropins and cytokines in cultured human ovarian granulosa-luteal (GL) cells. We now show that transcripts for PGE(2) receptor subtypes EP2 and EP4 are expressed in freshly isolated human granulosa cells and in mouse ovaries as detected by Northern blot analysis. However, EP2 and EP4 receptor mRNA levels were low or nondetectable in cultured human GL cells suggesting that these transcripts may be under hormonal and/or cytokine regulation in the ovaries in vivo. Indeed, the proinflammatory cytokine interleukin-1 beta (IL-1 beta) stimulated expression of EP2 and EP4 transcripts in concentration- and time-dependent manner in the GL cells. Furthermore, the transcript for EP2 receptor was localized in the corpus luteum of the mouse ovary by in situ hybridization, and EP2 protein was expressed in human corpus luteum as detected by immunohistochemistry. Our data suggest that IL-1 beta induces expression of EP2 and EP4 receptors in human GL cells, and that EP2 receptor is expressed in both human and murine luteal glands.


Subject(s)
Corpus Luteum/metabolism , Granulosa Cells/metabolism , Receptors, Prostaglandin E/metabolism , Animals , Cells, Cultured , Corpus Luteum/cytology , Female , Humans , Mice , Mice, Inbred Strains , RNA, Messenger/metabolism , Receptors, Prostaglandin E/genetics , Receptors, Prostaglandin E, EP2 Subtype , Receptors, Prostaglandin E, EP4 Subtype
15.
Eur J Hum Genet ; 8(10): 757-63, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11039575

ABSTRACT

In the Finnish breast and ovarian cancer families six BRCA1 and five BRCA2 mutations have been found recurrently. Some of these recurrent mutations have also been seen elsewhere in the world, while others are exclusively of Finnish origin. A haplotype analysis of 26 Finnish families carrying a BRCA1 mutation and 20 families with a BRCA2 mutation indicated that the carriers of each recurrent mutation have common ancestors. The common ancestors were estimated to trace back to 7-36 generations (150-800 years). The time estimates and the geographical clustering of these founder mutations in Finland are in concordance with the population history of this country. Analysis of the cancer phenotypes showed differential ovarian cancer expression in families carrying mutations in the 5' and 3' ends of the BRCA1 gene, and earlier age of ovarian cancer onset in families with BRCA1 mutations compared with families with BRCA2 mutations. The identification of prominent and regional BRCA1 and BRCA2 founder mutations in Finland will have significant impact on diagnostics in Finnish breast and ovarian cancer families. An isolated population with known history and multiple local founder effects in multigenic disease may offer distinct advantages also for mapping novel predisposing genes.


Subject(s)
Breast Neoplasms/genetics , Founder Effect , Genes, BRCA1/genetics , Mutation/genetics , Neoplasm Proteins/genetics , Ovarian Neoplasms/genetics , Transcription Factors/genetics , Adult , Aged , BRCA2 Protein , Breast Neoplasms/pathology , Family , Female , Finland/epidemiology , Genotype , Haplotypes , Humans , Middle Aged , Neoplasm Proteins/metabolism , Ovarian Neoplasms/pathology , Phenotype , Time Factors , Transcription Factors/metabolism
16.
J Clin Endocrinol Metab ; 85(9): 3476-83, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10999851

ABSTRACT

Previous studies have implicated transcription factors GATA-4 and GATA-6 in the regulation of murine ovarian development and function. In rodents, GATA-4 is expressed in granulosa cells of primary and early antral follicles, whereas GATA-6 is expressed in granulosa cells of late antral follicles and luteal glands. Both transcription factors can be detected in lesser amounts in theca cells and interstitial cells. We have now examined the expression of GATA-4 and GATA-6 in human ovaries, human granulosa-luteal (GL) cells and sex cord-derived tumors. We show by in situ hybridization and immunohistochemistry that GATA-4 and GATA-6 messenger RNA (mRNA) and GATA-4 protein are present in granulosa and theca cells in both preantral and antral follicles. Both human ovarian tissue samples and freshly isolated GL cells derived from preovulatory follicles of gonadotropin-treated women express GATA-4, GATA-6, and FOG-2 transcripts, and GATA-6 mRNA expression in GL cell cultures is stimulated by human CG and 8-bromo-cAMP. The vast majority of granulosa and theca cell tumors examined expressed GATA-4 and GATA-6. We also found that mRNA for FOG-2, a recently discovered regulator of GATA-4, is coexpressed with GATA-4 in human ovary samples, normal granulosa cells, and in sex cord-derived tumors. Our results demonstrate that GATA-4, GATA-6, and FOG-2 are expressed in human ovary and in granulosa and theca cell tumors. Our findings support a role for GATA-binding proteins in human ovarian folliculogenesis. Moreover, these data suggest that GATA factors may contribute to the phenotypes of sex cord-derived ovarian tumors.


Subject(s)
DNA-Binding Proteins/genetics , Gene Expression Regulation, Neoplastic/genetics , Ovarian Neoplasms/metabolism , Ovary/metabolism , Sex Cord-Gonadal Stromal Tumors/metabolism , Transcription Factors/genetics , Zinc Fingers , Adult , Aged , Blotting, Southern , Cells, Cultured , Cloning, Molecular , Corpus Luteum/cytology , Corpus Luteum/metabolism , DNA Probes , DNA-Binding Proteins/biosynthesis , Female , GATA4 Transcription Factor , GATA6 Transcription Factor , Granulosa Cells/metabolism , Humans , Immunohistochemistry , In Situ Hybridization , Middle Aged , RNA, Neoplasm/biosynthesis , RNA, Neoplasm/genetics , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors/biosynthesis
17.
J Clin Endocrinol Metab ; 84(8): 2744-50, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10443672

ABSTRACT

Growth differentiation factor 9 (GDF-9) is a transforming growth factor-beta family member that is required for normal folliculogenesis in female mice, but its role as a regulator of human fertility is still unclear. We determined here by in situ hybridization and immunohistochemical analyses the localization of the GDF-9 messenger ribonucleic acid (mRNA) and protein during human folliculogenesis. The GDF-9 transcripts were not detected in primordial follicles, but they are abundantly expressed in primary follicles in frozen sections of ovarian cortical tissue material obtained at laparoscopic surgery. We raised antipeptide antibodies against GDF-9 and showed by immunohistochemical studies on paraffin sections of whole human ovaries that the GDF-9 protein is most abundantly expressed in primary follicles. We recently demonstrated that a novel GDF-9-related factor, GDF-9B, is coexpressed with GDF-9 during murine folliculogenesis. We now isolated human GDF-9B complementary DNA and genomic clones and report the unusually restricted expression pattern of human GDF-9B. The human GDF-9B transcript can be detected only in the gonads by RT-PCR analysis, and in situ hybridization studies indicate that it is not expressed in small primary follicles but, rather, in the oocytes of late primary follicles. Functional studies using the Xenopus laeuis embryo model indicate that unlike the transforming growth factor-beta family members activin and bone morphogenetic protein-4, neither GDF-9 nor GDF-9B affects mesoderm induction, suggesting that they may use signaling pathways distinct from those well defined for activin and bone morphogenetic protein-4. We conclude that 1) both GDF-9 mRNA and protein are abundantly expressed in oocytes of primary follicles in human ovary, suggesting that the GDF-9 transcript is translated at this early stage of folliculogenesis; 2) human GDF-9B is specifically expressed in gonads at low levels; and 3) the expression of GDF-9 mRNA begins slightly earlier than that of GDF-9B in the human oocytes during follicular development. Our results are consistent with the suggestion that GDF-9 and GDF-9B may regulate human folliculogenesis in a manner specific to the ovary.


Subject(s)
Growth Substances/analysis , Intercellular Signaling Peptides and Proteins , Oocytes/chemistry , Ovarian Follicle/physiology , Adult , Animals , Bone Morphogenetic Protein 15 , Female , Growth Differentiation Factor 9 , Growth Substances/genetics , Humans , Mesoderm/physiology , Mice , RNA, Messenger/analysis , Xenopus laevis/embryology
18.
Am J Pathol ; 154(3): 677-81, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10079245

ABSTRACT

Germline mutations of LKB1/Peutz-Jeghers syndrome gene predispose carriers to hamartomatous polyposis of the gastrointestinal tract as well as to cancer of different organ systems. Although Peutz-Jeghers syndrome patients frequently present with neoplasms of the colon, stomach, small intestine, pancreas, breast, ovaries, and cervix, somatic mutations appear to be rare in the sporadic tumor types thus far studied (colorectal, gastric, testicular, and breast cancers). To evaluate whether somatic mutations of LKB1 contribute to the tumorigenesis of yet unstudied tumor types, we screened 14 cell lines and 129 tumor specimens from different cancers for a genetic defect in LKB1. Six melanoma and eight myeloma cell lines were scrutinized for LKB1 somatic mutations by genomic sequencing. No changes were found in the coding LKB1 sequence and exon/intron boundaries. Next, we analyzed 12 pancreatic, 8 gastric, 12 ovarian granulosa cell, 26 cervical, 28 lung, 24 soft tissue, and 19 renal tumors by single-strand conformational polymorphism analysis. Three changes in LKB1 coding nucleotide sequence were identified. One base pair deletion at A957 and G958 substitution by T occurred in a cervical adenocarcinoma sample, resulting in a frameshift and premature stop codon at position 335. Substitution of A581 by T occurred in a lung adenocarcinoma sample, resulting in the change of aspartic acid at position 194 to valine. A loss of another allele was detected in this sample. One silent change, C1257T, was found in a pancreatic carcinoma sample. The changes were not present in the matched normal tissue DNA samples. Our results suggest that mutational inactivation of LKB1 is a rare event in most sporadic tumor types.


Subject(s)
Mutation/genetics , Neoplasms/genetics , Protein Serine-Threonine Kinases/genetics , AMP-Activated Protein Kinase Kinases , Amino Acid Substitution/genetics , Base Sequence/genetics , DNA, Neoplasm/genetics , Humans , Molecular Sequence Data , Polymorphism, Genetic/genetics , Polymorphism, Single-Stranded Conformational , Tumor Cells, Cultured
19.
Cancer Res ; 58(19): 4274-6, 1998 Oct 01.
Article in English | MEDLINE | ID: mdl-9766651

ABSTRACT

Serous carcinomas of the fallopian tube, uterus, and ovary resemble each other both histologically and in clinical behavior. Comparative genomic hybridization was performed on 20 primary fallopian tube carcinoma specimens to find regions of the genome involved in tubal carcinogenesis and to compare the genomic alterations with those previously detected in serous ovarian and uterine carcinomas. The most frequent changes detected in fallopian tube carcinoma were gains at 3q (70%) and 8q (75%), with high-level amplifications in several cases. Other common gains occurred at 1q, 5p, 7q, 12p, and 20q. The most frequent losses were found at 18q, 8p, 4q, and 5q. The frequency and the pattern of chromosomal changes detected in tubal carcinoma were strikingly similar to those observed in serous ovarian and uterine carcinomas, suggesting common molecular pathogenesis.


Subject(s)
Chromosome Aberrations , Chromosome Mapping , Chromosomes, Human , Fallopian Tube Neoplasms/genetics , Ovarian Neoplasms/genetics , Uterine Neoplasms/genetics , Chromosomes, Human, Pair 3 , Chromosomes, Human, Pair 8 , Cystadenoma, Serous/genetics , Cystadenoma, Serous/pathology , Fallopian Tube Neoplasms/pathology , Female , Humans , Neoplasm Staging , Ovarian Neoplasms/pathology , Uterine Neoplasms/pathology
20.
Cancer Res ; 58(13): 2715-9, 1998 Jul 01.
Article in English | MEDLINE | ID: mdl-9661879

ABSTRACT

Germ-line mutations in the BRCA1 and BRCA2 genes confer a predisposition to breast as well as ovarian carcinoma. Except for loss of the respective wild-type allele, somatic genetic changes needed for the progression of inherited ovarian tumors are unknown. A genome-wide search for such alterations was performed by comparative genomic hybridization analysis on BRCA1 and BRCA2 mutation-positive (n = 20) ovarian carcinoma specimens. Comparison with sporadic ovarian carcinomas (n = 20) revealed extensive genetic similarity between the inherited and sporadic carcinomas with the sole exception of a frequent gain of 2q24-q32 in the inherited group, suggesting the presence of an oncogene at 2q24-q32 operating in the absence of BRCA1 function. The overall similarity of gains and losses by comparative genomic hybridization suggests a common main pathway in tumor progression of both inherited and sporadic ovarian carcinomas.


Subject(s)
DNA, Neoplasm/genetics , Genes, Tumor Suppressor/genetics , Nucleic Acid Hybridization/methods , Ovarian Neoplasms/genetics , Adolescent , Adult , Aged , Chromosomes, Human, Pair 2/genetics , Female , Genes, BRCA1/genetics , Humans , Karyotyping , Middle Aged , Point Mutation/genetics
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