1.Different imprinting status of IGF-2 in epithelial ovarian tumors.
Yali, XIONG ; Yongyu, SUN ; Hongfa, LI
Journal of Huazhong University of Science and Technology (Medical Sciences) 2002;22(3):255-6
To explore whether the imprinting status of IGF-2 in the malignant epithelial ovarian tumors is different from that in benign tumors, the target sequences (DNA and RNA) which contain a polymorphism site for ApaI restriction endonuclease digestion were amplified with PCR and RT-PCR methods. Then the PCR/RT-PCR products were digested by ApaI. The IGF-2 transcriptional pattern came out from the results of endonucleases digestion. Among the 36 cases of benign epithelial ovarian tumors, 20 were heterozygous for ApaI locus and all showed genomic imprinting. While in the malignant group, 22 were heterozygous for ApaI locus but six were found to lose imprinting. Significant differences existed between the two groups (P < 0.05). Loss of imprinting of IGF-2 may serve as a marker for differentiating the malignant ovarian cancers from the benign ones. In a new field of molecular genetics, our research provides an experimental basis for genetic diagnosis and treatment of the ovarian cancers.
Cystadenocarcinoma, Serous/*genetics
;
Cystadenoma/genetics
;
*Genomic Imprinting
;
Insulin-Like Growth Factor II/*genetics
;
Ovarian Neoplasms/*genetics
2.Mutations in the D-loop region of mitochondrial DNA in ovarian tumors.
Hong-hui SHI ; Liu VINCENT ; Ngan HEXTAN ; Xiu-yu YANG
Acta Academiae Medicinae Sinicae 2002;24(2):170-173
OBJECTIVETo investigate mutations in the D-loop region of mitochondrial DNA in ovarian tumors.
METHODSThe D-loop region of 25 epithelial ovarian tumors together with the adjacent normal tissues were amplified by PCR and sequenced.
RESULTSAmong the 25 ovarian tumors, 26 mutations were identified with the mutation rate of 32%. 19 mutations were detected in two cases of borderline carcinoma which was a special type of epithelial ovarian carcinoma. There were 6 microsatellite instabilities among the mutations and 11 new polymorphisms which were not reported previously in the GenBank.
CONCLUSIONSThe D-loop region of mitochondrial DNA is a highly polymorphoric and mutable region and the mutation rate is relatively high in patients with ovarian tumors.
Cystadenocarcinoma, Serous ; genetics ; DNA, Mitochondrial ; genetics ; Female ; Humans ; Ovarian Neoplasms ; genetics ; Point Mutation ; Polymorphism, Genetic
3.Key nodes of a microRNA network associated with the integrated mesenchymal subtype of high-grade serous ovarian cancer.
Yan SUN ; Fei GUO ; Marina BAGNOLI ; Feng-Xia XUE ; Bao-Cun SUN ; Ilya SHMULEVICH ; Delia MEZZANZANICA ; Ke-Xin CHEN ; Anil K SOOD ; Da YANG ; Wei ZHANG
Chinese Journal of Cancer 2015;34(1):28-40
Metastasis is the main cause of cancer mortality. One of the initiating events of cancer metastasis of epithelial tumors is epithelial-to-mesenchymal transition (EMT), during which cells dedifferentiate from a relatively rigid cell structure/morphology to a flexible and changeable structure/morphology often associated with mesenchymal cells. The presence of EMT in human epithelial tumors is reflected by the increased expression of genes and levels of proteins that are preferentially present in mesenchymal cells. The combined presence of these genes forms the basis of mesenchymal gene signatures, which are the foundation for classifying a mesenchymal subtype of tumors. Indeed, tumor classification schemes that use clustering analysis of large genomic characterizations, like The Cancer Genome Atlas (TCGA), have defined mesenchymal subtype in a number of cancer types, such as high-grade serous ovarian cancer and glioblastoma. However, recent analyses have shown that gene expression-based classifications of mesenchymal subtypes often do not associate with poor survival. This "paradox" can be ameliorated using integrated analysis that combines multiple data types. We recently found that integrating mRNA and microRNA (miRNA) data revealed an integrated mesenchymal subtype that is consistently associated with poor survival in multiple cohorts of patients with serous ovarian cancer. This network consists of 8 major miRNAs and 214 mRNAs. Among the 8 miRNAs, 4 are known to be regulators of EMT. This review provides a summary of these 8 miRNAs, which were associated with the integrated mesenchymal subtype of serous ovarian cancer.
Cystadenocarcinoma, Serous
;
genetics
;
pathology
;
Epithelial-Mesenchymal Transition
;
Female
;
Humans
;
MicroRNAs
;
physiology
;
Ovarian Neoplasms
;
genetics
;
pathology
4.Hypermethylation of promoter region of RASSF1A gene in ovarian malignant epithelial tumors.
Lin MA ; Jun-hang ZHANG ; Fu-rong LIU ; Xue ZHANG
Chinese Journal of Oncology 2005;27(11):657-659
OBJECTIVETo investigate hypermethylation of promoter region of RASSF1A and its relationship with ovarian malignant epithelial tumors.
METHODSMethylation-specific PCR (MSP) was used to determine the hypermethylation of promoter region of ras association domain family 1 (RASSF1A) gene in 80 cases of ovarian malignant epithelial tumors.
RESULTSNo methylation of promoter region of RASSF1A gene was found in all 80 normal control tissues (0). Of 80 ovarian malignant epithelial tumors 42 were hypermethylated in promoter region of RASSF1A gene (52.5%). There was no statistically significant difference in the frequency of hypermethylation of RASSF1A gene among serious adenocarcinomas, mucinous adenocarcinomas and endometrioid adenocarcinomas (54.2%, 52.4% and 45.5%, respectively; P > 0.05). Hypermethylation of RASSF1A gene happened more often in tumors in stage III and IV (66.7% and 77.8%) than that in stage I and II (21.4% and 16.7%; P < 0.05). It was less frequently observed in well and moderately differentiated tumors (34.5% and 35.0%) than in poorly differentiated tumors (80.6%; P < 0.05).
CONCLUSIONHigh frequency of methylation of RASSF1A promoter exists in ovarian malignant epithelial tumors as a tumor suppressor gene, its suppressor activity may be abrogated by an epigenetic mechanism. Hypermethylation of RASSF1A promoter in patients with epithelial malignant ovarian tumors is related to clinical stage and histopathological grade. It indicates poor prognosis.
Carcinoma, Endometrioid ; genetics ; Cystadenocarcinoma, Mucinous ; genetics ; Cystadenocarcinoma, Serous ; genetics ; DNA Methylation ; Female ; Humans ; Ovarian Neoplasms ; genetics ; Promoter Regions, Genetic ; genetics ; Tumor Suppressor Proteins ; genetics
5.Different imprinting status of IGF-2 in epithelial ovarian tumors.
Yali XIONG ; Yongyu SUN ; Hongfa LI
Journal of Huazhong University of Science and Technology (Medical Sciences) 2002;22(3):255-256
To explore whether the imprinting status of IGF-2 in the malignant epithelial ovarian tumors is different from that in benign tumors, the target sequences (DNA and RNA) which contain a polymorphism site for ApaI restriction endonuclease digestion were amplified with PCR and RT-PCR methods. Then the PCR/RT-PCR products were digested by ApaI. The IGF-2 transcriptional pattern came out from the results of endonucleases digestion. Among the 36 cases of benign epithelial ovarian tumors, 20 were heterozygous for ApaI locus and all showed genomic imprinting. While in the malignant group, 22 were heterozygous for ApaI locus but six were found to lose imprinting. Significant differences existed between the two groups (P < 0.05). Loss of imprinting of IGF-2 may serve as a marker for differentiating the malignant ovarian cancers from the benign ones. In a new field of molecular genetics, our research provides an experimental basis for genetic diagnosis and treatment of the ovarian cancers.
Cystadenocarcinoma, Serous
;
genetics
;
Cystadenoma
;
genetics
;
Female
;
Genomic Imprinting
;
Humans
;
Insulin-Like Growth Factor II
;
genetics
;
Ovarian Neoplasms
;
genetics
6.K-ras mutation analysis in ovarian serous borderline and malignant tumors.
Li MA ; Li-na GUO ; Zhi-yong LIANG ; Xin-yu REN ; Sha-fei WU
Chinese Journal of Pathology 2006;35(12):714-718
OBJECTIVETo investigate the roles of K-ras gene in the tumorigenesis of ovarian serous borderline and malignant tumors.
METHODSFifty one tissue samples of ovarian serous tumors, including 18 conventional serous borderline tumors, 11 micropapillary serous borderline tumors, 12 invasive micropapillary serous carcinomas, and 10 conventional serous carcinomas were investigated for the presence of K-ras mutation. DNA was extracted after microdissection of the tumor tissue, the exon 1 of K-ras gene was amplified by PCR, and the presence of mutation at the codons 12 and 13 was evaluated by direct sequencing analysis.
RESULTSGGT to GTT mutation at codon 12 of the K-ras gene was found in one conventional serous borderline tumors, resulting in valine to glycine substitution. All other 50 cases showed no K-ras mutation. All tumors had a wild-type codon 13.
CONCLUSIONSMutations of K-ras at codons 12 and 13 in ovarian serous tumors are very rare in this series of patients, suggesting a difference present between the Chinese and Caucasian populations. K-ras mutations may play a less important role in the tumorigenesis of ovarian serous tumor of the Chinese patients.
Adolescent ; Adult ; Aged ; Amino Acid Substitution ; Codon ; Cystadenocarcinoma, Serous ; genetics ; Cystadenoma, Serous ; genetics ; Female ; Genes, ras ; genetics ; Humans ; Middle Aged ; Ovarian Neoplasms ; genetics ; Young Adult
7.Pathobiology of ovarian carcinomas.
Mojgan DEVOUASSOUX-SHISHEBORAN ; Catherine GENESTIE
Chinese Journal of Cancer 2015;34(1):50-55
Ovarian tumors comprise a heterogeneous group of lesions, displaying distinct tumor pathology and oncogenic potentiel. These tumors are subdivided into three main categories: epithelial, germ cell, and sex-cord stromal tumors. We report herein the newly described molecular abnormalities in epithelial ovarian cancers (carcinomas). Immunohistochemistry and molecular testing help pathologists to decipher the significant heterogeneity of this disease. Our better understanding of the molecular basis of ovarian carcinomas represents the first step in the development of targeted therapies in the near future.
Carcinoma, Endometrioid
;
pathology
;
Cystadenocarcinoma, Mucinous
;
pathology
;
Cystadenocarcinoma, Serous
;
pathology
;
Female
;
Humans
;
Mixed Tumor, Malignant
;
pathology
;
Neoplasms, Glandular and Epithelial
;
pathology
;
Ovarian Neoplasms
;
genetics
;
pathology
8.Detection of circulating hypermethylated tumor-specific RASSF1A DNA in ovarian cancer patients.
Lin MA ; Fu-rong LIU ; Shu-lan ZHANG
Chinese Journal of Pathology 2005;34(12):785-787
OBJECTIVETo detect hypermethylated tumor-specific RASSF1A DNA in the circulation and its significance in ovarian cancers patients.
METHODSMethylation-specific polymerase chain reaction (MSP) was used to study the hypermethylation of RASSF1A in preoperative serum samples from 51 ovarian cancer patients.
RESULTSThe RASSF1A gene was not methylated in peripheral blood samples from 51 normal patients and 51 patients with benign ovarian tumors. Hypermethylation of RASSF1A gene was found in circulating tumor-specific DNA in 43.1% of patients (22 out of 51 cases) with ovarian cancers (P < 0.05). There was no difference in hypermethylation of RASSF1A gene amongst various ovarian cancer subtypes (P < 0.05). On the other hand, hypermethylation of RASSF1A gene was more frequently encountered in stage III and IV than stage I and II tumors (P < 0.05). It was rarely seen in well and moderately differentiated groups, as compared with poorly differentiated group (P < 0.05).
CONCLUSIONSThere is a higher frequency of RASSF1A hypermethylation in circulating tumor-specific DNA of ovarian cancer patients. RASSF1A has been postulated to play an important role as tumor suppressor gene and can be silenced by promoter hypermethylation. This methylation correlates with clinical stage and histopathologic grade. Such observation may carry diagnostic and prognostic implications when assessing ovarian tumors.
Carcinoma, Endometrioid ; blood ; pathology ; Cystadenocarcinoma, Mucinous ; blood ; pathology ; Cystadenocarcinoma, Serous ; blood ; pathology ; DNA Methylation ; Female ; Humans ; Neoplasm Staging ; Ovarian Neoplasms ; blood ; pathology ; Tumor Suppressor Proteins ; blood ; genetics
9.Mutational Analysis of KRAS, BRAF, and TP53 Genes of Ovarian Serous Carcinomas in Korean Women.
Yun Hyun CHO ; Dae Yeon KIM ; Jong Hyeok KIM ; Yong Man KIM ; Kyu Rae KIM ; Joo Hyun NAM ; Young Tak KIM
Yonsei Medical Journal 2009;50(2):266-272
PURPOSE: To assess the prevalence of KRAS, BRAF, and TP53 mutations in cases of low-grade and high-grade serous carcinomas and to evaluate the clinical outcomes of these morphologically distinct carcinomas. MATERIALS AND METHODS: Patients with primary invasive serous carcinomas were classified according to the universal grading system. Grade 2 serous tumors were excluded. A total of 100 patients were included for clinical evaluation. Thirty-seven patients, including 20 with low-grade and 17 with high-grade carcinomas, were selected for mutational analysis. RESULTS: The low-grade carcinoma group was characterized by young age and premenopausal period compared with the high-grade carcinoma group, but there were no statistically significant differences in stage, metastasis of lymph node and residual disease. There were no statistically significant differences in survival rates, however, the low-grade carcinoma group showed a trend for improved progression-free survival compared with the high-grade carcinoma group of early stage (p = 0.064). Mutations in KRAS and BRAF were found in 6 (30%) and 2 (10%) patients in the low-grade carcinoma group, respectively, however, they were not found in the high-grade carcinoma group. KRAS and BRAF mutations were mutually exclusive, and both mutations were observed in 40% (8/20). The frequency of TP53 mutations in low-grade and high-grade carcinoma groups were found in 20% (4/20) and 70.6% (12/17), respectively (p = 0.009). CONCLUSION: Low-grade serous carcinoma shows mutation pattern different from that with high-grade carcinoma. As there were no significant differences in stage distribution and survival, especially in advanced stage, we suggest that more studies are needed to segregate these patients into distinct disease entities.
Adult
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Cystadenocarcinoma, Serous/*genetics
;
DNA Mutational Analysis
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Female
;
Humans
;
Middle Aged
;
Ovarian Neoplasms/*genetics
;
Proto-Oncogene Proteins/*genetics
;
Proto-Oncogene Proteins B-raf/*genetics
;
ras Proteins/*genetics
10.Shortening of the 3' untranslated region: an important mechanism leading to overexpression of HMGA2 in serous ovarian cancer.
Xiangjun HE ; Jing YANG ; Qi ZHANG ; Heng CUI ; Yujun ZHANG
Chinese Medical Journal 2014;127(3):494-499
BACKGROUNDOncofetal protein high-mobility-group AT-hook protein 2 (HMGA2) is reactivated in serous ovarian cancer (SOC) and its overexpression correlates with poor prognosis. To explore the mechanism, we investigated whether HMGA2 could avoid microRNA regulation due to gene truncation or 3' UTR shortening by alternative polyadenylation.
METHODSReal-time reverse transcription polymerase chain reaction (RT-PCR) was used to evaluate the abundance of different regions of HMGA2 mRNA in 46 SOC samples. Rapid amplification of cDNA 3' ends (3' RACE) and Southern blotting were used to confirm the shortening of 3' untranslated region (UTR). 5' RACE and Southern blotting were used to prove the mRNA decay.
RESULTSNo significant difference in the ratio of the stable coding region to the fragile region was observed between SOC and control normal fallopian tubes, indicating that the HMGA2 gene is not truncated in SOC. Varying degrees of 3' UTR shortening in SOC samples were observed by comparing the abundance of the proximal region and distal region of the HMGA2 3' UTR. The ratio of the proximal to the distal region of the 3' UTR correlated significantly with expression of the HMGA2 coding region in SOC (r = 0.579, P < 0.01). Moreover, although the abundance of the HMGA2 coding region varied, all samples, including the very low expressed samples, exhibit relatively high levels of the proximal 3' UTR region, suggesting a dynamic decay of HMGA2 mRNA from the 5' end. The shortening of 3' UTR and the decay from the 5' end were confirmed by 3' RACE, 5' RACE and subsequent Southern blotting.
CONCLUSIONHeterogeneous 3' UTR lengths render HMGA2 susceptible to different levels of negative regulation by microRNAs, which represents an important mechanism of HMGA2 reactivation in SOC.
3' Untranslated Regions ; genetics ; Cystadenocarcinoma, Serous ; genetics ; metabolism ; Female ; HMGA2 Protein ; genetics ; metabolism ; Humans ; Ovarian Neoplasms ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction