RESUMO
Endometrial cancer in the lower uterine segment (LUS) is associated with Lynch syndrome with MLH1 or MSH2 germline mutation. Here, we report a case of carcinoma of the LUS diagnosed with Lynch syndrome based on MSH6 germline mutation in a 46-year-old woman with abnormal vaginal bleeding. She had had rectal cancer at age 39 with a family history of colon cancer (father, 75 years), pancreatic cancer (paternal grandmother, 74 years), and colon cancer (maternal grandmother, 85 years). Magnetic resonance imaging showed a tumor in the LUS. Endometrial biopsy revealed endometrioid adenocarcinoma G1. As her cancer history met the revised Bethesda criteria, we examined microsatellite instability and the result was negative, but loss of the MSH6 expression was detected by immunohistochemistry. Genetic testing revealed deleterious germline mutation of MSH6, which was compatible with Lynch syndrome. To our knowledge, this is the first case of endometrial carcinoma of the LUS with MSH6 germline mutation.
Assuntos
Carcinoma Endometrioide/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteínas de Ligação a DNA/genética , Neoplasias Uterinas/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-IdadeRESUMO
AIM: Micro ribonucleic acids (miRNAs) play an important pathological role in endometriosis. Leuprolide acetate, an analog of gonadotropin-releasing hormone, is widely used to treat endometriosis; however, the molecular mechanisms involved in endometriotic tissue regression remain unclear. We performed miRNA expression profiling of clinical ovarian endometrioma to obtain insight into the effects of leuprolide acetate treatment. METHODS: We obtained clinical samples from nine normal eutopic endometrium, eight ovarian endometriotic, and 12 leuprolide acetate-treated endometriotic tissues. We compared the miRNA expression profiles of the three groups by performing TaqMan Array MicroRNA Card and bioinformatic analysis. RESULTS: Two miRNAs, miR-939 and miR-154, were upregulated in endometriotic tissue and downregulated in leuprolide acetate-treated endometriotic tissue. Five miRNAs (miR-146a, miR-142-3p, miR-136*, miR-125b-1* and miR-15b*) were unchanged in endometriotic tissue but were upregulated under leuprolide acetate treatment. Ingenuity pathway analysis using predicted target genes for the seven identified miRNAs suggested the involvement of a range of pathways, including axonal guidance, bone morphogenetic protein, phosphatase and tensin homolog and nitric oxide signaling; molecular mechanisms of cancer; and the adipogenesis and signal transducer and activator of transcription 3 (STAT3) pathways. CONCLUSIONS: To our knowledge, this is the first report profiling the miRNAs of endometrioma under leuprolide acetate treatment. The expression of seven miRNAs was modulated, concomitant with the disease state. This result gives new insight into the effects of leuprolide acetate treatment. Further investigation using quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry will allow us to validate the results of this study and to explore new therapeutic targets and biomarkers of endometriosis.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Endometriose/tratamento farmacológico , Endometriose/metabolismo , Leuprolida/uso terapêutico , MicroRNAs/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Adulto , Biomarcadores Tumorais/metabolismo , Endometriose/genética , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Transdução de SinaisRESUMO
AIM: Leuprolide acetate, an analog of gonadotropin-releasing hormone (GnRH), regresses endometriotic tissue and reduces pain, resulting in clinical improvement upon treatment. The molecular mechanisms involved in the regression of endometriotic tissue, however, remain to be elucidated. In this study, we performed genome-wide gene expression profiling of clinical specimens of ovarian endometrioma to obtain insight into the effects of leuprolide acetate treatment. METHODS: We obtained clinical samples from nine normal eutopic endometrium tissues, eight ovarian endometriotic tissues, and 12 leuprolide acetate-treated endometriotic tissues. We compared the gene expression profiles of the three groups using Affymetrix GeneChip Human genome arrays and bioinformatic analysis, including molecular concept analysis. RESULTS: Leuprolide acetate-treated endometriotic tissue showed downregulated genes associated with the biological functions of steroid hormone regulation, cell proliferation, inflammation, and intracellular signaling. These genes included PTGDS, GRP, APLP2, PLTP, and FGFRL1. In contrast, genes upregulated by leuprolide acetate treatment were associated with cell growth inhibition and apoptosis. These genes included CARD11 and USP18. CONCLUSIONS: These preliminary results based on GeneChip analysis suggest that leuprolide acetate treatment induces a modulation of gene expression that allows for cooperative alterations in disease state. This study gives new insight into the effects of leuprolide acetate treatment. Further investigations with quantitative reverse transcription-polymerase chain reaction and immunohistochemistry are needed to validate this study and to explore new therapeutic targets and biomarkers of endometriosis.
Assuntos
Antineoplásicos Hormonais/farmacologia , Endometriose/tratamento farmacológico , Leuprolida/farmacologia , Ovário/efeitos dos fármacos , Ovário/metabolismo , Adulto , Antineoplásicos Hormonais/uso terapêutico , Análise por Conglomerados , Endometriose/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Leuprolida/uso terapêutico , Pessoa de Meia-Idade , Ovário/patologiaRESUMO
The goals of drug repositioning are to find a new pharmacological effect of a drug for which human safety and pharmacokinetics are established and to expand the therapeutic range of the drug to another disease. Such drug discovery can be performed at low cost and in the short term based on the results of previous clinical trials. New drugs for gynecologic tumors may be found by drug repositioning. For example, PPAR ligands may be effective against ovarian cancer, since PPAR activation eliminates COX-2 expression, arrests the cell cycle, and induces apoptosis. Metformin, an antidiabetic drug, is effective for endometrial cancer through inhibition of the PI3K-Akt-mTOR pathway by activating LKB1-AMPK and reduction of insulin and insulin-like growth factor-1 due to AMPK activation. COX-2 inhibitors for cervical cancer may also be examples of drug repositioning. PGE2 is induced in the arachidonate cascade by COX-2. PGE2 maintains high expression of COX-2 and induces angiogenic factors including VEGF and bFGF, causing carcinogenesis. COX-2 inhibitors suppress these actions and inhibit carcinogenesis. Combination therapy using drugs found by drug repositioning and current anticancer drugs may increase efficacy and reduce adverse drug reactions. Thus, drug repositioning may become a key approach for gynecologic cancer in drug discovery.
Assuntos
Reposicionamento de Medicamentos/métodos , Reposicionamento de Medicamentos/tendências , Neoplasias dos Genitais Femininos/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Quimioterapia Combinada/métodos , Feminino , Humanos , Metformina/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Ritonavir/farmacologiaRESUMO
Endometrial cancer is increasing worldwide and the number of patients with this disease is likely to continue to grow, including younger patients. Many endometrial cancers show estrogen-dependent proliferation, but the carcinogenic mechanisms are unknown or not completely explained beyond mutations of single oncogenes and tumor suppressor genes. Possible carcinogenic mechanisms include imbalance between endometrial proliferation by unopposed estrogen and the mismatch repair (MMR) system; hypermethylation of the MMR gene hMLH1; mutation of PTEN, ß-catenin and K-ras genes in type I endometrial cancer and of HER-2/neu and p53 genes in type II endometrial cancer; hypermethylation of SPRY2, RASSF1A, RSK4, CHFR and CDH1; and methylation of tumor suppressor microRNAs, including miR-124, miR-126, miR-137, miR-491, miR-129-2 and miR-152. Thus, it is likely that the carcinogenic mechanisms of endometrial cancer involve both genetic and epigenetic changes. Mutations and methylation of MMR genes induce various oncogenic changes that cause carcinogenesis, and both MMR mutation in germ cells and methylation patterns may be inherited over generations and cause familial tumorigenesis. Determination of the detailed carcinogenic mechanisms will be useful for prevention and diagnosis of endometrial cancer, risk assessment, and development of new treatment strategies targeting MMR genes.
Assuntos
Carcinogênese , Neoplasias do Endométrio/genética , Endométrio/metabolismo , Epigênese Genética , Modelos Biológicos , Mutação , Proteínas de Neoplasias/genética , Proliferação de Células , Transformação Celular Neoplásica , Metilação de DNA , Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Endométrio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , MicroRNAs/metabolismo , Instabilidade de Microssatélites , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismoRESUMO
Cervical cancer is a female-specific disease with a high incidence and mortality. MicroRNAs (miRNAs) are implicated in posttranscriptional regulation of gene expression and in the pathogenic mechanisms of cancer, suggesting their importance in diagnosis and treatment. miRNAs may have roles in the pathogenesis of cervical cancer based on the increases or decreases in several specific miRNAs found in patients with this disease. The miRNAs implicated in cervical cancer are miR-21, miR-126, and miR-143, and clinical application of these miRNAs for diagnosis and treatment is under investigation. Methods for diagnosis of cervical cancer include analysis of changes in the levels of specific miRNAs in serum and determination of aberrant hypermethylation of miRNAs. Supplementation of miR-143 or inhibition of miR-21 activity in vivo may be therapeutic strategy for cervical cancer. Previous approaches to development of siRNA as a drug have provided information for establishment of therapy based on these approaches, and an anti-miR-21 inhibitor has been developed. miRNAs also have effects on drug resistance and may be useful in combination therapy with other drugs.
Assuntos
MicroRNAs/genética , Neoplasias do Colo do Útero/genética , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Viral , Metilação de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Metástase Linfática , MicroRNAs/uso terapêutico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/terapiaRESUMO
MicroRNAs (miRNAs) are small non-coding ribonucleic acids (RNAs) of approximately 22 bp that induce RNA interference with a complementary messenger RNA (mRNA) and act in silencing of mRNA. miRNAs are strongly associated with cancer development and those involved in carcinogenesis are classified into oncogenic miRNAs and tumor suppressor miRNAs (tumor suppressor miRs). Specific miRNAs are expressed in various tissues and changes in regulation of gene expression are thought to cause carcinogenesis. Thus, tissue-specific miRNAs may be biomarkers for cancer diagnosis and prognosis. Approaches to application of miRNAs as cancer therapy are also ongoing, based on the involvement of miRNAs in carcinogenesis. In endometrial cancer, miRNAs are associated with regulation of gene expression, epigenetic dysfunction and carcinogenesis. Thus, miRNAs are likely to have key roles in diagnosis, prognostic prediction, and therapy in endometrial cancer.
Assuntos
Neoplasias do Endométrio/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , RNA Mensageiro/genética , Biomarcadores Tumorais , Transformação Celular Neoplásica , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/patologia , Feminino , Humanos , PrognósticoRESUMO
PURPOSE: Uterine blood flow is required for the maintenance of uterine viability in pregnancy and delivery, but it is unknown how many vessels are necessary for maintenance of uterine viability. The objective of this study was to examine whether unilateral uterine vessels provide sufficient nutrition in pregnancy in a cynomolgus macaque and to evaluate hemodynamics of pregnant uterus by indocyanine green (ICG) fluorescence imaging. METHODS: A cynomolgus macaque with uterine blood flow maintained by the right uterine artery and vein alone was made pregnant. Hemodynamics of the uterus in the third trimester was evaluated by ICG fluorescence imaging. RESULTS: Pregnancy was maintained with the right uterine artery and vein. An appropriate-for-date infant was delivered by Cesarean section. ICG fluorescence imaging showed that the uterine body was imaged from the right side to the center; furthermore, collateral circulation was present from the right uterine artery toward the left uterine artery, with expanded blood flow to the left uterine body. CONCLUSION: Pregnancy and delivery were achieved in a cynomolgus macaque with a unilateral right uterine artery and vein. Blood flow to the side without the artery was complemented by vascularization of collateral circulation to the uterine artery.
Assuntos
Corantes/farmacologia , Verde de Indocianina/química , Imagem Óptica/métodos , Artéria Uterina , Útero/irrigação sanguínea , Animais , Cesárea , Feminino , Hemodinâmica , Humanos , Macaca fascicularis , Gravidez , Terceiro Trimestre da GravidezRESUMO
The recent increase in the frequency of endometrial cancer has emphasized the need for accurate diagnosis and improved treatment. The current diagnosis is still based on conventional pathological indicators, such as clinical stage, tumor differentiation, invasion depth and vascular invasion. However, the genetic mechanisms underlying endometrial cancer have gradually been determined, due to developments in molecular biology, leading to the possibility of new methods of diagnosis and treatment planning. New candidate biomarkers for endometrial cancer include those for molecular epigenetic mutations, such as microRNAs. These biomarkers may permit earlier detection of endometrial cancer and prediction of outcomes and are likely to contribute to future personalized therapy for endometrial cancer.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Metilação de DNA/genética , Neoplasias do Endométrio/patologia , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
Aberrant DNA methylation is widely observed in various types of cancer, and expression of microRNAs (miRNAs/miRs) is suppressed by DNA methylation. The present study explored tumor suppressor miRNAs downregulated by DNA methylation in endometrial cancer cells, as the basis of a novel therapeutic approach for endometrial cancer. Among 821 candidate miRNAs, miR34b was identified as an upregulated miRNA after demethylation treatment in all four endometrial cancer cell lines (HEC108, SNGII, Ishikawa and HHUA) examined. miR34b expression with or without demethylation treatment in cancer cells was confirmed by TaqMan quantitative PCR. MYC and MET, the predicted target genes of miR34b, were downregulated at both the RNA and protein levels following miR34b overexpression. Following miR34b treatment, inhibition of cell growth and invasion, and cell cycle arrest were observed in HEC108 cells. Sensitivity to paclitaxel was increased in cancer cells with miR34b overexpression, compared with untreated cancer cells, but this difference was not identified for cisplatin or doxorubicin. In vivo, combination treatment with miR34b and paclitaxel markedly reduced tumor growth compared with treatment with negative control miRNA and paclitaxel. These data suggest that miR34b enhances paclitaxel sensitivity in endometrial cancer cells, and that miR34b and MET are key targets for treatment of endometrial cancer. The present results may contribute to the development of combination treatment with a demethylation agent, miR34b mimic or MET inhibitor and an anticancer drug.
Assuntos
Neoplasias do Endométrio/tratamento farmacológico , MicroRNAs/fisiologia , Paclitaxel/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Metilação de DNA , Resistencia a Medicamentos Antineoplásicos , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-met/análise , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/fisiologia , Proteínas Proto-Oncogênicas c-myc/análise , Proteínas Proto-Oncogênicas c-myc/fisiologiaRESUMO
Point mutations of KRAS and BRAF genes are thought to be important in carcinogenesis of colon cancer. In particular, gene instability caused by decreased expression of the hMLH1 gene, a DNA mismatch repair (MMR) gene, may be linked to the activating BRAF V600E point mutation in sporadic colon cancer. However, a consensus has not been established regarding the correlation between point mutations of KRAS or BRAF and carcinogenesis in patients with endometrial cancer, which is closely related to colon cancer. Therefore, we analyzed aberrant hypermethylation of the hMLH1 gene, microsatellite instability (MSI), and point mutations of KRAS and BRAF in 44 samples of sporadic endo-metrial cancer, with the aim of examining the mechanism of carcinogenesis in patients with endometrial cancer. Aberrant hMLH1 hypermethylation was found in 17 of the 44 cases (38.6%) and showed a significant positive correlation with MSI (p=0.02). This suggests that an abnormal MMR mechanism plays an important role in carcinogenesis of sporadic endometrial cancer. Point mutation of KRAS was found in 6 of the 44 cases (13.6%), but no BRAF V600E mutation was detected. These data suggest that the BRAF V600E mutation is not the target gene for abnormal MMR in carcinogenesis in patients with sporadic endometrial cancer, unlike in colon cancer. This is supported by the relatively few previous reports indicating a correlation between endometrial cancer and the BRAF V600E mutation. Identification of new candidates for the target gene for abnormal MMR in endometrial cancer requires further work.
Assuntos
Adenocarcinoma/genética , Carcinoma Adenoescamoso/genética , Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio/genética , Mutação Puntual/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenocarcinoma/secundário , Adulto , Idoso , Carcinoma Adenoescamoso/secundário , Metilação de DNA , DNA de Neoplasias/genética , Neoplasias do Endométrio/patologia , Feminino , Humanos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Proteínas ras/genéticaRESUMO
Improvements in epigenetics have resulted in identification of a number of genes with aberrant hypermethylation associated with systematic occurrence of cancer. It is now evident that aberrant hypermethylation inactivates cancer-related genes including those associated with cell cycle control, apoptosis, and DNA repair. An epigenetic analysis of DNA hypermethylation in type I endometrial cancer has led to a proposed mechanism for endometrial carcinogenesis. Reduced DNA mismatch repair due to loss of hMLH1 expression is thought to have a major role in carcinogenesis and these findings open up approaches to prevention, diagnosis, risk assessment, and treatment of type I endometrial cancer. Aberrant DNA hypermethylation can be detected with high sensitivity for identification of cancer cells in sputum, blood and other biopsy materials, including in endometrial cancer specimens. There have been many attempts to use methylation inhibitors as anticancer agents, and epigenetic abnormalities may be useful as biomarkers of anticancer drug sensitivity and to identify biological characteristics of tumor cells for determination of treatment options based on hypermethylation. For example, aberrant hypermethylation of the CHFR gene is correlated with cellular sensitivity to microtubule inhibitors, and this may be useful in treatment of type I endometrial cancer. An ultimate objective of epigenetics is to identify the type of hereditary methylation responsible for cancer, with the goal of improved diagnosis and treatment based on control of methylation.
Assuntos
Metilação de DNA , DNA de Neoplasias/genética , Neoplasias do Endométrio/genética , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Neoplasias/genéticaRESUMO
Some cases of endometrial cancer are associated with a familial tumor and are referred to as hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome). Such tumors are thought to be induced by germline mutation of the DNA mismatch repair (MMR) gene, but many aspects of the pathology of familial endometrial cancer are unclear and no effective screening method has been established. However, the pathology of endometrial cancer with familial tumor has been progressively clarified in recent studies. At present, about 0.5% of all cases of endometrial cancers meet the clinical diagnostic criteria for HNPCC. A recent analysis of the three MMR genes (hMLH1, hMSH2 and hMSH6) revealed germline mutations in 18 of 120 cases (15.0%) of endometrial cancer with familial accumulation of cancer or double cancer, with a frameshift mutation of the hMSH6 gene being the most common. Many cases with mutation did not meet the current clinical diagnostic criteria for HNPCC, indicating that familial endometrial cancer is often not diagnosed as HNPCC. The results suggest that the hMSH6 gene mutation may be important in carcinogenesis in endometrial cancer and germline mutations of the MMR gene may be more prevalent in cases associated with familial accumulation of cancer. An international large-scale muticenter study is required to obtain further information about the pathology of endometrial cancer as a familial tumor.
RESUMO
Though assisted reproduction technology has been developed, a treatment for absolute uterine factor infertility (AUFI), such as defects in the uterus, has not yet been established. Regenerative medicine has been developed and applied clinically over recent years; however, whole solid organs still cannot be produced. Though uterine regeneration has the potential to be a treatment for AUFI, there have been only a few studies on uterine regeneration involving the myometrium in vivo. In the present report, those relevant articles are reviewed. A literature search was conducted in PubMed with a combination of key words, and 10 articles were found, including nine in rat models and one in a mouse model. Of these studies, eight used scaffolds and two were performed without scaffolds. In four of these studies, scaffolds were re-cellularized with various cells. In the remaining four studies, scaffolds were transplanted alone, or other structures were used. Though the methods differed, the injured uterus recovered well, morphologically and functionally, in every study. Only 10 articles were relevant to our investigation, but the results were favorable, if limited to partial regeneration. Recently, uterus transplantation (UTx) has been investigated as a treatment for AUFI. However, UTx has many problems in the medical, ethical and social fields. Though the artificial uterus was also researched and some improvements in this technology were reported, it will take long time for this to reach a clinically applicable stage. Though the results of uterine regeneration studies were promising, these studies were conducted using animal models, so further human studies and trials are needed.
RESUMO
Endometrial polyps are common, yet the molecular mechanisms underlying their formation and progression remain unclear. We examined gene mutations possibly related to the pathogenesis of endometrial polyps, as well as to their clinical features. Four premenopausal patients with endometrial polyps, who were not under drug treatment, were recruited. Whole exomes of endometrial polyps and peripheral blood lymphocytes were analyzed by nextgeneration sequencing, and somatic mutations were derived by subtraction. Then, 35 samples of endometrial polyps and 12 samples of atypical polypoid adenomyoma were newly recruited to validate the identified mutations by polymerase chain reactionreverse sequence specific oligonucleotide method. The mutations were also analyzed in separate stromal and glandular components of the polyps after lasercapture microdissection. Whole exome sequencing revealed that KRAS mutations were the only type of mutation detectable in multiple cases (2/4). Targeted mutation analysis revealed that 16 of 35 samples (45.7%) of endometrial polyps harbored RAS mutations. Mutationpositive cases exhibited a significantly higher number of endometrial polyps (3.25±2.70 vs. 1.74±0.87, P=0.045). Lasercapture microdissection in NRASmutated endometrial polyps revealed that both stromal and glandular components harbored RAS mutations. There was no RAS mutation in 12 samples of atypical polypoid adenomyoma. This is the first report demonstrating that pathogenic RAS mutations are frequent in nontreated endometrial polyps. RAS mutations may have an important role in tumorigenesis and in the formation of multiple endometrial polyps.
Assuntos
Exoma/genética , GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , Mutação , Pólipos/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Doenças Uterinas/genética , Adulto , Feminino , Humanos , Pólipos/patologia , Doenças Uterinas/patologiaRESUMO
[This corrects the article DOI: 10.3892/br.2013.91.].
RESUMO
OBJECTIVE: Lynch syndrome is a cancer predisposition syndrome caused by germline mutation of DNA mismatch repair (MMR) genes. Lynch syndrome only causes about 0.4% of cases of ovarian cancer, which suggests that universal screening may not be cost-efficient. However, the frequency of Lynch syndrome in ovarian cancer is unclear in the Asian population. The goal of the study was to investigate a screening strategy using family history. METHODS: The subjects were 129 patients with ovarian cancer. Clinical and family history were collected using a self-administered questionnaire, and Society of Gynecologic Oncology (SGO) criteria 2007 and PREMM5 were used for risk assessment. Microsatellite instability, immunohistochemistry, and methylation of MMR genes were analyzed. RESULTS: Of the 129 cases, 25 (19.4%) met the SGO criteria, and 4 of these 25 had MSI-high and MMR deficiency. Two cases had loss of MSH2 and MSH6, indicating MSH2 mutation, and the other two had loss of MLH1 and PMS2, including one without MLH1 methylation indicating MLH1 mutation. These results show that screening using family history can detect Lynch syndrome in 12.0% (3/25) of ovarian cancer cases. The 3 cases were positive for PREMM5, but negative for Amsterdam II criteria and revised Bethesda guidelines. Genetic testing in one case with MSH2 and MSH6 deficiency confirmed the diagnosis of Lynch syndrome with MSH2 mutation. CONCLUSION: This is the first study of screening for Lynch syndrome in ovarian cancer using clinical and family history in an Asian population. This approach may be effective for diagnosis in these patients.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Detecção Precoce de Câncer , Neoplasias Ovarianas/genética , Medição de Risco , Adulto , Idoso , Neoplasias Colorretais Hereditárias sem Polipose/etiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , Feminino , Humanos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genéticaRESUMO
Synchronous endometrial and ovarian cancer (SEOC) is a rare entity among gynecological cancers, which exhibits endometrioid histology in its early stages and generally has a good prognosis. However, diagnosis is difficult and recent reports have demonstrated that most clinically diagnosed cases of SEOC have clonally related cancers, indicating metastatic cancer. The association of SEOC with Lynch syndrome is also not clearly understood. We herein present the case of a 41-year-old SEOC patient with MSH2 mutation. The endometrial cancer was an endometrioid adenocarcinoma and the ovarian cancer was mainly endometrioid, but also included a clear cell carcinoma with a borderline clear cell adenofibromatous component, indicating primary ovarian cancer. Both tumors exhibited microsatellite instability (MSI) and loss of expression of MSH2 and MSH6. The patient had a family history of colorectal and gastric cancers. Genetic analysis revealed a germline mutation in exon 6 of MSH2 (c.1042C>T, p.Gln348*) and the patient was diagnosed with Lynch syndrome. This MSH2 mutation has only been registered in one case in the InSiGHT variant databases and has not been reported in a gynecological tumor or SEOC to date. This case is a rare example of a patient with genetically diagnosed Lynch syndrome who also developed SEOC. This synchronous cancer is not common, but it may be caused by Lynch syndrome. Testing for MSI and immunohistochemistry for mismatch repair deficiency is necessary in cases with suspected SEOC.
RESUMO
A relationship between inactivation of mitotic checkpoint genes and sensitivity of cancer cells to anticancer agents has been reported. We investigated the effect of epigenetic inactivation by aberrant hypermethylation of the mitotic checkpoint gene CHFR (checkpoint with forkhead and ring finger) on the sensitivity of cervical cancer cells to taxanes. Methylation-specific PCR (MSP) of cervical smears showed aberrant methylation of CHFR in 12.3% (2/14) of adenocarcinoma specimens. In contrast, aberrant DNA methylation was not detected in normal cervical cells or squamous cell carcinoma cells. Aberrant methylation of CHFR was also analyzed in 6 human cervical carcinoma-derived cell lines and was observed in SKG-IIIb and HeLa cells. These cell lines showed high sensitivity to taxanes, but became taxane-resistant upon treatment with 5-azacytidine. Furthermore, suppression of CHFR expression in siRNA-transfected SKG-IIIa cells caused increased sensitivity to taxanes. In conclusion, aberrant methylation of the CHFR gene may be useful as a molecular marker for selection of therapy for patients with cervical adenocarcinoma with a poor prognosis, and may also suggest a new therapeutic strategy of targeting CHFR in cervical cancer. To our knowledge, this study is the first to examine epigenetic inactivation by aberrant hypermethylation of CHFR in cervical cancer.
Assuntos
Antineoplásicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Proteínas de Ciclo Celular/genética , Epigênese Genética , Inativação Gênica/efeitos dos fármacos , Proteínas de Neoplasias/genética , Taxoides/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma Mucinoso/tratamento farmacológico , Adenocarcinoma Mucinoso/genética , Antimetabólitos Antineoplásicos/farmacologia , Azacitidina/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Metilação de DNA , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Tolerância a Medicamentos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose , Regiões Promotoras Genéticas/genética , RNA Interferente Pequeno/farmacologia , Células Tumorais Cultivadas , Ubiquitina-Proteína LigasesRESUMO
The relationship of aberrant DNA hypermethylation of cell cycle checkpoint genes with the sensitivity of cancer cells to anticancer drugs is a question of current interest. In this study, we investigated the relationship between aberrant hypermethylation of the CHFR (checkpoint with forkhead-associated and ring finger) mitotic checkpoint gene and sensitivity to taxanes in endometrial cancer. Methylation-specific PCR (MSP) indicated aberrant hypermethylation of CHFR in 12.0% (6/50) of endometrial cancer specimens, and suggested that aberrant hypermethylation is significantly more frequent in poorly differentiated adenocarcinoma (G3) (p<0.05). Of six culture cell lines, SNG-II and HEC108 cells showed aberrant hypermethylation and reduced expression of CHFR. These cells had high sensitivity to taxanes but became resistant after demethylation. Cancer specimens with aberrant hypermethylation of CHFR also exhibited high sensitivity to taxanes. To our knowledge, this study is the first to examine aberrant hypermethylation of CHFR in endometrial cancer, and our results suggest that the methylation status of CHFR may be a new molecular index that will allow design of personalized treatment in endometrial cancer. This may be particularly important in poorly differentiated adenocarcinoma (G3), which is known to have a poor prognosis.