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1.
Cancer Sci ; 110(9): 2894-2904, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31348579

RESUMO

Nivolumab is a human monoclonal antibody against the immune checkpoint receptor programmed death-1, inhibiting binding to programmed death-ligand 1 or 2 (PD-L1 or PD-L2). This phase 2 study evaluated the efficacy and safety of nivolumab in patients with advanced/recurrent uterine cervical cancer, uterine corpus cancer, or soft tissue sarcoma (STS). Patients received nivolumab 240 mg at 2-week intervals. Primary endpoint was objective response rate; secondary endpoints included overall survival, progression-free survival, and safety. PD-L1 expression and microsatellite-instability (MSI) status were analyzed as potential efficacy biomarkers. Objective response rate was 25%, 23%, and 0% in patients with cervical cancer (n = 20), corpus cancer (n = 22), and STS (n = 21), respectively. The lower 80% confidence intervals of objective response rates in patients with cervical or corpus cancer exceeded the threshold rate (5%); the primary endpoint was met in cervical and corpus cancer, but not in STS. Median progression-free survival was 5.6, 3.4, and 1.4 months, and 6-month overall survival was 84%, 73%, and 86% in cervical cancer, corpus cancer, and STS, respectively. The objective response rate was higher in patients with cervical cancer with PD-L1-positive (n = 5/15; 33%) versus PD-L1-negative (n = 0/5; 0%) tumors. The two patients with corpus cancer classified as MSI-high responded; the six patients classified as microsatellite stable did not respond. Overall, nivolumab showed acceptable toxicity in all cohorts, with evidence of clinical activity in uterine cervical or corpus cancer, but not in STS. PD-L1 expression in cervical cancer and MSI-high in corpus cancer may predict clinical activity of nivolumab in these cancers.


Assuntos
Antineoplásicos/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Nivolumabe/administração & dosagem , Sarcoma/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antígeno B7-H1/metabolismo , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Japão/epidemiologia , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Intervalo Livre de Progressão , Estudos Prospectivos , Sarcoma/genética , Sarcoma/mortalidade , Sarcoma/patologia , Análise de Sobrevida , Neoplasias Uterinas/genética , Neoplasias Uterinas/mortalidade , Neoplasias Uterinas/patologia , Útero/patologia
2.
Jpn J Clin Oncol ; 49(7): 620-627, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31220306

RESUMO

OBJECTIVE: Recurrent hydatidiform moles are reportedly biparental complete moles and related to mutated NLRP7 and KHDC3L. This study was designed to identify mutations of gene NLRP7 and KHDC3L in biparental complete moles. METHODS: In this study, we have screened NLRP7 and KHDC3L mutations in five patients with recurrent moles and five with sporadic moles. Molar tissues and blood samples were collected from patients and their partners. Genotypes of the molar tissues were determined based on short tandem repeat polymorphism. The coding exons of NLRP7 and KHDC3L were sequenced. RESULTS: Two patients with recurrent moles had biparental complete moles, while all other patients had androgenetic complete moles. Three non-synonymous variants in NLRP7 (c.955 G>A, c.1280 T>C and c.1441 G>A) and one in KHDC3L (c.602 C>G) were identified in patients with recurrent moles. NLRP7 c.1441 G>A and c.1280 T>C were mutations found in the Chinese population, while c.1441 G>A was only detected in patients with biparental complete moles in this study. CONCLUSIONS: Genotyping can be used to differentiate biparental complete moles from androgenetic moles and to predict the risk of recurrent moles in future pregnancies. NLRP7 c.1441 G>A may associate with biparental complete moles. Biparental complete moles exhibit genetic heterogeneity.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Grupo com Ancestrais do Continente Asiático/genética , Mola Hidatiforme/genética , Mutação/genética , Recidiva Local de Neoplasia/genética , Proteínas/genética , Neoplasias Uterinas/genética , Adulto , Sequência de Bases , Feminino , Humanos , Mola Hidatiforme/patologia , Masculino , Repetições de Microssatélites/genética , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Gravidez
3.
Braz J Med Biol Res ; 52(6): e8132, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31141088

RESUMO

The aim of this study was to elucidate the concise effects of a traditional herb pair, Curcumae rhizoma-Sparganii rhizoma (CRSR), on uterine leiomyoma (UL) by analyzing transcriptional profiling. The UL rat model was made by intramuscular injection of progesterone and gavage administration of diethylstilbestrol. From 11 weeks of the establishment of the model, rats of the UL+CRSR group were gavaged daily with CRSR (6.67 g/kg). The serum concentrations of progesterone (P) and estradiol (E2) were determined by radioimmunoassay, the uterine index was measured by caliper measurement, and the pathological status was observed by hematoxylin and eosin stain. Gene expression profiling was checked by NimbleGen Rat Gene Expression Microarrays. The results indicated that the uterine mass of UL+CRSR rats was significantly shrunk and serum P and E2 levels significantly reduced compared to UL animals and nearly to the level of normal rats. Results of microarrays displayed the extensive inhibition of CRSR upon the expression of proliferation and deposition of extracellular matrix (ECM)-related genes, and significantly regulated a wide range of metabolism disorders. Furthermore, CRSR extensively regulated key pathways of the UL process, such as MAPK, PPAR, Notch, and TGF-ß/Smad. Regulation of the crucial pathways for the UL process and ECM metabolism may be the underlying mechanisms of CRSR treatment. Further studies will provide clear clues for effectively treating UL with CRSR.


Assuntos
Curcuma/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Leiomioma/tratamento farmacológico , Extratos Vegetais/farmacologia , Rizoma/química , Neoplasias Uterinas/tratamento farmacológico , Animais , Modelos Animais de Doenças , Feminino , Leiomioma/genética , Leiomioma/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Radioimunoensaio , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição , Neoplasias Uterinas/genética , Neoplasias Uterinas/metabolismo
4.
Diagn Pathol ; 14(1): 32, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31027501

RESUMO

BACKGROUND: Uterine leiomyomas, in contrast to sarcomas, tend to cease growth following menopause. In the setting of a rapidly enlarging uterine mass in a postmenopausal patient, clinical distinction of uterine leiomyoma from sarcoma is difficult and requires pathologic examination. CASE PRESENTATION: A 74-year-old woman presented with postmenopausal bleeding and acute blood loss requiring transfusion. She was found to have a rapidly enlarging uterine mass clinically suspicious for sarcoma. An abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. A 15.5 cm partially necrotic intramural mass was identified in the uterine corpus. The tumor was classified as a cellular leiomyoma. RNA sequencing identified a KAT6B-KANSL1 fusion that was confirmed by RT-PCR and Sanger sequencing. After 6 months of follow-up, the patient remains asymptomatic without evidence of disease. CONCLUSION: Prior studies of uterine leiomyomas have identified KAT6B (previously MORF) rearrangements in uterine leiomyomas, but this case is the first to identify a KAT6B-KANSL1 gene fusion in a uterine leiomyoma. While alterations of MED12 and HMGA2 are most common in uterine leiomyomas, a range of other genetic pathways have been described. Our case contributes to the evolving molecular landscape of uterine leiomyomas.


Assuntos
Histona Acetiltransferases/genética , Leiomioma/genética , Proteínas Nucleares/genética , Neoplasias Uterinas/genética , Idoso , Feminino , Fusão Gênica , Humanos , Leiomioma/diagnóstico por imagem , Leiomioma/patologia , Neoplasias Uterinas/diagnóstico por imagem , Neoplasias Uterinas/patologia
5.
Fertil Steril ; 111(4): 806-815.e1, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30871768

RESUMO

OBJECTIVE: To characterize the effect of ulipristal acetate (UPA) treatment on transforming growth factor (TGF) canonical and noncanonical signaling pathways in uterine leiomyoma tissue and cells. UPA decreased extracellular matrix in surgical specimens; we characterize the mechanism in this study. DESIGN: Laboratory study. SETTING: University. INTERVENTION(S): Exposure of leiomyoma cell lines to UPA. MAIN OUTCOME MEASURE(S): RNAseq was performed on matched myometrium and leiomyoma surgical specimens of placebo- and UPA-treated patients. Changes in gene expression and protein were measured using quantitative polymerase chain reaction and western immunoblot analysis, respectively. RESULT(S): In surgical specimen, mRNA for TGF-ß3 was elevated 3.75-fold and TGFR2 was decreased 0.50-fold in placebo leiomyomas compared with myometrium. Analysis of leiomyomas from UPA-treated women by western blot revealed significant reductions of active TGF-ß3 (0.64 ± 0.12-fold), p-TGFR2 (0.56 ± 0.23-fold), pSmad 2 (0.54 ± 0.04-fold), and pSmad 3 (0.65 ± 0.09-fold) compared with untreated leiomyomas. UPA treatment demonstrated statistically significant reduction in collagen 1, fibronectin, and versican proteins. Notably, there was a statistically significant increase of the extracellular matrix protein fibrillin in leiomyoma treated with UPA (1.48 ± 0.41-fold). Data from in vitro assays with physiologic concentrations of UPA supported the in vivo findings. CONCLUSION(S): TGF-ß pathway is highly up-regulated in leiomyoma and is directly responsible for development of the fibrotic phenotype. UPA attenuates this pathway by reducing TGF-ß3 message and protein expression, resulting in a reduction in TGF-ß canonical signaling. In addition, UPA significantly increased fibrillin protein expression, which can serve to bind inactive TGF-ß complexes. Therefore, UPA inhibits leiomyoma fibrosis by decreasing active TGF-ß3 and diminishing signaling through the canonical pathway. CLINICAL TRIAL REGISTRATION NUMBER: NCT00290251.


Assuntos
Leiomioma/genética , Norpregnadienos/farmacologia , Fator de Crescimento Transformador beta3/genética , Neoplasias Uterinas/genética , Adulto , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leiomioma/metabolismo , Leiomioma/patologia , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator de Crescimento Transformador beta3/metabolismo , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia
6.
Pac Symp Biocomput ; 24: 148-159, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30864318

RESUMO

Natural killer (NK) cells have increasingly become a target of interest for immunotherapies. NK cells express killer immunoglobulin-like receptors (KIRs), which play a vital role in immune response to tumors by detecting cellular abnormalities. The genomic region encoding the 16 KIR genes displays high polymorphic variability in human populations, making it difficult to resolve individual genotypes based on next generation sequencing data. As a result, the impact of polymorphic KIR variation on cancer phenotypes has been understudied. Currently, labor-intensive, experimental techniques are used to determine an individual's KIR gene copy number profile. Here, we develop an algorithm to determine the germline copy number of KIR genes from whole exome sequencing data and apply it to a cohort of nearly 5000 cancer patients. We use a k-mer based approach to capture sequences unique to specific genes, count their occurrences in the set of reads derived from an individual and compare the individual's k-mer distribution to that of the population. Copy number results demonstrate high concordance with population copy number expectations. Our method reveals that the burden of inhibitory KIR genes is associated with survival in two tumor types, highlighting the potential importance of KIR variation in understanding tumor development and response to immunotherapy.


Assuntos
Dosagem de Genes , Neoplasias/genética , Neoplasias/imunologia , Receptores KIR/genética , Algoritmos , Biologia Computacional/métodos , Bases de Dados Genéticas/estatística & dados numéricos , Feminino , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Estimativa de Kaplan-Meier , Células Matadoras Naturais/imunologia , Neoplasias/mortalidade , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/mortalidade , Neoplasias Uterinas/genética , Neoplasias Uterinas/imunologia , Neoplasias Uterinas/mortalidade , Sequenciamento Completo do Exoma
7.
Biomed Pharmacother ; 113: 108760, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30889489

RESUMO

MicroRNAs (miRNAs) are a class of small non-coding RNAs that are closely associated with carcinogenesis. Accumulating data indicate that miR-196b participates in the development of various types of cancers. However, the role of miR-196b in the formation of hydatidiform mole (HM) is still unclear. Our previous studies have demonstrated that miR-196b levels were decreased in JAR and BeWo cells and in HM tissue samples, as demonstrated by RT-PCR analysis. Furthermore, we discovered that overexpression of miR-196b in JAR and BeWo cells inhibited cellular proliferation, migration and invasion, as shown by Cell counting kit-8 (CCK-8) and transwell assays, respectively. Subsequently, we explored the interaction of miR-196b with its target gene in human choriocarcinoma cell lines. MAP3K1 is a target gene predicted by bioinformatic analysis that was previously shown to exhibit reduced expression levels following treatment with miR-196b in JAR and BeWo cells. We demonstrated that MAP3K1 was a direct target of miR-196b using the dual-luciferase reporter assay in Hela cells. In summary, the present study demonstrated that miR-196b suppressed proliferation, migration and invasion of human choriocarcinoma cells by inhibiting its transcriptional target MAP3K1. miR-196b and MAP3K1 may be considered potential targets for the clinical treatment of HM.


Assuntos
Coriocarcinoma/genética , Mola Hidatiforme/genética , MAP Quinase Quinase Quinase 1/genética , MicroRNAs/genética , Neoplasias Uterinas/genética , Adulto , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Coriocarcinoma/patologia , Feminino , Células HeLa , Humanos , Mola Hidatiforme/patologia , Invasividade Neoplásica/genética , Gravidez , Neoplasias Uterinas/patologia , Adulto Jovem
8.
Nat Chem Biol ; 15(4): 391-400, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718813

RESUMO

Hereditary cancer disorders often provide an important window into novel mechanisms supporting tumor growth. Understanding these mechanisms thus represents a vital goal. Toward this goal, here we report a chemoproteomic map of fumarate, a covalent oncometabolite whose accumulation marks the genetic cancer syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC). We applied a fumarate-competitive chemoproteomic probe in concert with LC-MS/MS to discover new cysteines sensitive to fumarate hydratase (FH) mutation in HLRCC cell models. Analysis of this dataset revealed an unexpected influence of local environment and pH on fumarate reactivity, and enabled the characterization of a novel FH-regulated cysteine residue that lies at a key protein-protein interface in the SWI-SNF tumor-suppressor complex. Our studies provide a powerful resource for understanding the covalent imprint of fumarate on the proteome and lay the foundation for future efforts to exploit this distinct aspect of oncometabolism for cancer diagnosis and therapy.


Assuntos
Fumaratos/metabolismo , Leiomiomatose/metabolismo , Síndromes Neoplásicas Hereditárias/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Uterinas/metabolismo , Linhagem Celular Tumoral , Cromatografia Líquida/métodos , Cisteína , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio , Leiomiomatose/genética , Modelos Biológicos , Síndromes Neoplásicas Hereditárias/genética , Proteômica , Transdução de Sinais , Neoplasias Cutâneas/genética , Espectrometria de Massas em Tandem/métodos , Neoplasias Uterinas/genética
9.
Surg Pathol Clin ; 12(1): 107-137, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30709439

RESUMO

Mesenchymal tumors of the uterus comprise a heterogeneous group of neoplasms of varied biologic potential. In addition to being host to several anatomically unique entities, the uterus may contain mesenchymal neoplasms typically found elsewhere in the body. Although smooth muscle neoplasms are common, other mesenchymal neoplasms in this location are relatively rare. Many of these neoplasms exhibit morphologic overlap. In addition to a careful histomorphologic review, definitive classification frequently depends on the judicious application of ancillary immunohistochemical and molecular testing. The intent of this review is to offer a basic approach to the classification of primary uterine mesenchymal neoplasms.


Assuntos
Músculo Liso/patologia , Tumor de Músculo Liso/classificação , Tumor de Músculo Liso/patologia , Neoplasias Uterinas/classificação , Neoplasias Uterinas/patologia , Útero/patologia , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Prognóstico , Tumor de Músculo Liso/genética , Neoplasias Uterinas/genética
10.
Clin Respir J ; 13(2): 105-113, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30597752

RESUMO

OBJECTIVES: Lung metastasizing leiomyomatosis (LML) is an infrequently diagnosed pathology developed after sexual maturation, commonly preceded by uterine myomas. Symptoms can include difficulties to breathe, cough, dyspnea and pain, because of mechanical obstruction exerted by expanding local growing leiomyomas. Lung leiomyomas are normally detected by imaging studies, but nowadays the precise diagnosis demands histological characterization of biopsies obtained from the affected tissues. The purpose of the present study was to determine the presence of genomic alterations in circulating cells of LML. METHODS: Immunohistochemical characterization of a lung biopsy extracted by thoracoscopy was performed. Pathologic proliferative smooth muscle cells were observed in a major lung metastasizing nodule, with a growing pattern similar to a uterine myoma. The presence of cellular linages different to smooth muscle cells was discarded by testing the presence of a battery of molecular markers. Also, a normal karyotype was determine by GTG-banding cytogenetic study, but a high density microarray analysis revealed six submicroscopic chromosomal regions displaying genomic abnormalities: microduplications were detected on chromosomes 4, 14, 17 and 22; and microdeletions on chromosomes 8 and 10. CONCLUSION: This study remarks the relevance of submicroscopic chromosomal analysis of unusual pathologic conditions such as Benign Metastasizing Leiomyomatosis. This propitiate a better understanding of the molecular basis on the development of the pathology, in order to reckon on minimally invasive diagnostic methods, and to design appropriate treatments.


Assuntos
Variações do Número de Cópias de DNA/genética , Genômica/métodos , Leiomiomatose/genética , Neoplasias Pulmonares/patologia , Adulto , Epigenômica , Feminino , Humanos , Cariótipo , Leiomiomatose/diagnóstico por imagem , Leiomiomatose/patologia , Leiomiomatose/cirurgia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Mioma/complicações , Mioma/patologia , Mioma/cirurgia , Metástase Neoplásica/patologia , Neoplasias/etiologia , Neoplasias/genética , Neoplasias/patologia , Células Neoplásicas Circulantes/metabolismo , Fatores de Risco , Toracoscopia/métodos , Tomografia Computadorizada por Raios X/métodos , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Neoplasias Uterinas/secundário
11.
Gynecol Oncol ; 152(3): 612-617, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30612783

RESUMO

OBJECTIVE: We explored the germline mutation spectrum and prevalence among 1650 women with breast and uterine cancer (BUC) who underwent multi-gene hereditary cancer panel testing at a single commercial laboratory. METHODS: The combined frequency of mutations in 23 BC and/or UC genes was compared between BUC cases and control groups with (1) no personal cancer history; (2) BC only; and (3) UC only using logistic regression. RESULTS: Fourteen percent (n = 231) of BUC cases tested positive for mutations in BC and/or UC genes and were significantly more likely to test positive than individuals with BC only (P < 0.001), UC only (P < 0.01), or unaffected controls (P < 0.001). Analysis of gene-specific mutation frequencies revealed that MSH6, CHEK2, BRCA1, BRCA2, ATM, PMS2, PALB2 and MSH2 were most frequently mutated among BUC cases. Compared to BC only, BRCA1, MLH1, MSH2, MSH6, PMS2 and PTEN mutations were more frequent among BUC; however, only ATM mutations were more frequent among BUC compared to UC only. All of the more commonly mutated genes have published management guidelines to guide clinical care. Of patients with a single mutation in a gene with established testing criteria (n = 152), only 81.6% met their respective criteria, and 65.8% met criteria for multiple syndromes. CONCLUSIONS: Women with BUC are more likely to carry hereditary cancer gene mutations than women with breast or uterine cancer alone, potentially warranting expanded genetic testing for these women. Most mutations found via multi-gene panel testing in women with BUC have accompanying published management guidelines and significant implications for clinical care.


Assuntos
Neoplasias da Mama/genética , Mutação em Linhagem Germinativa , Neoplasias Uterinas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença , Testes Genéticos , Humanos , Pessoa de Meia-Idade
12.
Proc Natl Acad Sci U S A ; 116(9): 3873-3882, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30651315

RESUMO

SMAD2 and SMAD3 are downstream proteins in the transforming growth factor-ß (TGF ß) signaling pathway that translocate signals from the cell membrane to the nucleus, bind DNA, and control the expression of target genes. While SMAD2/3 have important roles in the ovary, we do not fully understand the roles of SMAD2/3 in the uterus and their implications in the reproductive system. To avoid deleterious effects of global deletion, and given previous data showing redundant function of Smad2 and Smad3, a double-conditional knockout was generated using progesterone receptor-cre (Smad2/3 cKO) mice. Smad2/3 cKO mice were infertile due to endometrial hyperproliferation observed as early as 6 weeks of postnatal life. Endometrial hyperplasia worsened with age, and all Smad2/3 cKO mice ultimately developed bulky endometrioid-type uterine cancers with 100% mortality by 8 months of age. The phenotype was hormone-dependent and could be prevented with removal of the ovaries at 6 weeks of age but not at 12 weeks. Uterine tumor epithelium was associated with decreased expression of steroid biosynthesis genes, increased expression of inflammatory response genes, and abnormal expression of cell cycle checkpoint genes. Our results indicate the crucial role of SMAD2/3 in maintaining normal endometrial function and confirm the hormone-dependent nature of SMAD2/3 in the uterus. The hyperproliferation of the endometrium affected both implantation and maintenance of pregnancy. Our findings generate a mouse model to study the roles of SMAD2/3 in the uterus and serve to provide insight into the mechanism by which the endometrium can escape the plethora of growth regulatory proteins.


Assuntos
Infertilidade/genética , Proteína Smad2/genética , Proteína Smad3/genética , Neoplasias Uterinas/genética , Animais , Carcinogênese/genética , Proliferação de Células/genética , Endométrio/metabolismo , Endométrio/patologia , Feminino , Regulação da Expressão Gênica/genética , Humanos , Infertilidade/patologia , Camundongos , Camundongos Knockout , Gravidez , Receptores de Progesterona/genética , Neoplasias Uterinas/patologia , Útero/metabolismo , Útero/patologia
13.
Oncogene ; 38(15): 2722-2735, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30538295

RESUMO

Progesterone and its receptor, PR, are essential for uterine leiomyoma (LM, a.k.a., fibroid) tumorigenesis, but the underlying cellular and molecular mechanisms remain unclear. The receptor activator of NF-κB (RANKL) was recently identified as a novel progesterone/PR-responsive gene that plays an important role in promoting LM growth. Here, we used RANKL as a representative gene to investigate how steroid hormone, genetic, and epigenetic signals are integrated to regulate LM stem cell (LSC) function. We demonstrated that RANKL specifically upregulates LSC proliferation through activation of Cyclin D1. RANKL gene transcription was robustly induced by the progesterone agonist R5020, leading to a dramatically higher RANKL expression in LM compared to adjacent myometrial (MM) tissue. MethylCap-Seq revealed a differentially methylated region (DMR) adjacent to the distal PR-binding site (PRBS) 87 kb upstream of the RANKL transcription start site. Hypermethylation of the DMR inhibited recruitment of PR to the adjacent PRBS. Luciferase assays indicated that the DMR and distal PRBS constitute a novel RANKL distal regulatory element that actively regulates RANKL expression. Furthermore, MED12 physically interacts with PR in LM tissue. The interaction between MED12 and PR, binding of PR and MED12 to PRBS, and RANKL gene expression are significantly higher in LM containing a distinct MED12 mutation (G44D) than in LM with wild-type MED12. In summary, our findings suggest that DNA methylation and MED12 mutation together constitute a complex regulatory network that affects progesterone/PR-mediated RANKL gene expression, with an important role in activating stem cell proliferation and fibroid tumor development.


Assuntos
Proliferação de Células/genética , Metilação de DNA/genética , Leiomioma/genética , Complexo Mediador/genética , Ligante RANK/genética , Receptores de Progesterona/genética , Células-Tronco/patologia , Neoplasias Uterinas/genética , Adulto , Proliferação de Células/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Leiomioma/tratamento farmacológico , Pessoa de Meia-Idade , Progesterona/genética , Promegestona/farmacologia , Sítio de Iniciação de Transcrição/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos , Ativação Transcricional/genética , Neoplasias Uterinas/tratamento farmacológico
14.
Fertil Steril ; 111(1): 178-185, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30554729

RESUMO

OBJECTIVE: To determine factors that impact erythropoietin (EPO) production in leiomyomas. We have previously implicated EPO production in promoting the growth of some leiomyomas. DESIGN: The relationship between EPO messenger RNA (mRNA) expression and MED12 gene mutations or mRNA expression levels of high-mobility group AT-hook (HMGA) 1 and HMGA2 were analyzed. Effects of 10-8 M 17ß-E2 on EPO mRNA expression were evaluated using leiomyoma cells grown in primary cultures. SETTING: Graduate school of medicine. PATIENT(S): Patients with leiomyoma. INTERVENTION(S): We used tissue samples and clinical data of 108 patients with leiomyomas to analyze the relation between EPO mRNA expression and MED12 mutation. Tissue samples from another 10 patients with leiomyomas were collected for in vitro experimentation using primary cultures of leiomyoma and myometrial cells. MAIN OUTCOME MEASURE(S): Relations between EPO mRNA expression, MED12 exon 2 mutation, and HMGA1/HMGA2 mRNA expression levels in leiomyoma samplings, in addition to effects of estrogen (E) on EPO mRNA expression in cultures of leiomyoma cells. RESULT(S): The EPO mRNA level was threefold higher in leiomyomas with wild-type (vs. mutated) MED12 genes. There was no correlation between EPO and HMGA1 or HMGA2 mRNA expression levels. In wild-type MED12 leiomyomas only, E2 treatment produced a twofold increase in EPO mRNA expression, whereas mutated MED12 leiomyomas were unaffected. CONCLUSION(S): The EPO mRNA expression increased significantly after E2 treatment only in leiomyomas lacking MED12 mutations. In conjunction with prior evidence linking EPO mRNA expression levels and tumor size, E2-stimulated EPO mRNA expression may explain the marked growth disparities seen in these tumors.


Assuntos
Biomarcadores Tumorais/biossíntese , Eritropoetina/biossíntese , Leiomioma/metabolismo , Complexo Mediador/biossíntese , RNA Mensageiro/biossíntese , Neoplasias Uterinas/metabolismo , Adulto , Biomarcadores Tumorais/genética , Eritropoetina/genética , Estradiol/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Leiomioma/genética , Leiomioma/patologia , Complexo Mediador/genética , Pessoa de Meia-Idade , Mutação/efeitos dos fármacos , Mutação/genética , RNA Mensageiro/genética , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/fisiologia , Células Tumorais Cultivadas , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia
15.
Gynecol Oncol ; 151(2): 243-249, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30194005

RESUMO

OBJECTIVE: Uterine carcinosarcoma (UCS) is a rare and aggressive form of uterine cancer. It is bi-phasic, exhibiting histological features of both malignant epithelial (carcinoma) and mesenchymal (sarcoma) elements, reflected in ambiguity in accepted treatment guidelines. We sought to study the genomic and transcriptomic profiles of these elements individually to gain further insights into the development of these tumors. METHODS: We macro-dissected carcinomatous, sarcomatous, and normal tissues from formalin fixed paraffin embedded uterine samples of 10 UCS patients. Single nucleotide polymorphism microarrays, targeted DNA sequencing and whole-transcriptome RNA-sequencing were performed. Somatic chromosomal alterations (SCAs), point mutation and gene expression profiles were compared between carcinomatous and sarcomatous components. RESULTS: In addition to TP53, other recurrently mutated genes harboring putative driver or loss-of-function mutations included PTEN, FBXW7, FGFR2, KRAS, PIK3CA and CTNNB1, genes known to be involved in UCS. Intra-patient somatic mutation and SCA profiles were highly similar between paired carcinoma and sarcoma samples. An epithelial-mesenchymal transition (EMT) signature tended to differentiate components, with EMT-like status more common in advanced-stage patients exhibiting higher inter-component SCA heterogeneity. CONCLUSIONS: From DNA analysis, our results indicate a monoclonal disease origin for this cohort. Yet expression-derived EMT statuses of the carcinomatous and sarcomatous components were often discrepant, and advanced cases displayed greater genomic heterogeneity. Therefore, separately-profiled components of UCS tumors may better inform disease progression or potential.


Assuntos
Carcinossarcoma/patologia , Neoplasias Uterinas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinossarcoma/genética , Transição Epitelial-Mesenquimal , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias Uterinas/genética
16.
Zhonghua Bing Li Xue Za Zhi ; 47(8): 609-615, 2018 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-30107666

RESUMO

Objective: To investigate the value of short tandem repeat (STR) genotyping in the diagnostic workup of molar and non-molar gestations with correlation of histological characteristics. Methods: Six hundred and fifty-six cases were selected based on clinically suspected hydropic abortion and/or molar pregnancy from July 2015 to September 2017 at Beijing Obstetrics and Gynecology Hospital. DNA was extracted from dissected chorionic villi and paired maternal endometrial FFPE tissue samples by Simplex OUP™ FFPE DNA Tissue Kit. STR genotyping was performed by PowerPlex 16 HS system. Results: DNA genotyping was informative in 649 of 656 cases, leading to identification of 215 hydatidiform mole gestations and 434 non-molar gestations. Most of non-molar gestations (375 cases, 86.4%) were diploid hydropic abortion. Various trisomy syndromes were found (53 cases, 12.2%), including trisomy 2, 3, 4, 7, 8, 13, 16 and 21. Only 2(0.5%) digynic triploid gestations were detected. Moreover, 4 cases (0.9%) of uniparental disomies (homologous or heterologous) were found. There were 196 cases with histologic diagnostic suspicious of hydatidiform moles were accurate sub-classified. Among them, 59 cases hydatidiform moles were under-diagnosed as diploid hydropic abortions, and 28 cases diploid hydropic abortions were over-diagnosed as hydatidiform moles.Compared with partial moles(PHM), there were no specific histomorphological features between the various types of non-molar gestations and partial moles for definitive diagnostic separation. There was no significant difference in the expression of p57(kip2) among PHM, trisomy and diploid hydropic abortions group (P=0.247). Conclusions: STR genotyping can distinguish non-molar gestations from early hydatidiform moles, and efficiently avoid misdiagnosis based only on histological evaluation. Therefore, using STR genotyping, not only can the overdiagnosis of non-molar pregnancy be avoided, but also individualized management can be offered to patients including monitoring of serum hCG.


Assuntos
Mola Hidatiforme/genética , Repetições de Microssatélites/genética , Neoplasias Uterinas/genética , Aborto Espontâneo/genética , Vilosidades Coriônicas , Diploide , Feminino , Genótipo , Humanos , Mola Hidatiforme/diagnóstico , Gravidez , Triploidia , Trissomia , Neoplasias Uterinas/diagnóstico
17.
Genome Biol ; 19(1): 106, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-30086769

RESUMO

BACKGROUND: CTCF binding to DNA helps partition the mammalian genome into discrete structural and regulatory domains. Complete removal of CTCF from mammalian cells causes catastrophic genome dysregulation, likely due to widespread collapse of 3D chromatin looping and alterations to inter- and intra-TAD interactions within the nucleus. In contrast, Ctcf hemizygous mice with lifelong reduction of CTCF expression are viable, albeit with increased cancer incidence. Here, we exploit chronic Ctcf hemizygosity to reveal its homeostatic roles in maintaining genome function and integrity. RESULTS: We find that Ctcf hemizygous cells show modest but robust changes in almost a thousand sites of genomic CTCF occupancy; these are enriched for lower affinity binding events with weaker evolutionary conservation across the mouse lineage. Furthermore, we observe dysregulation of the expression of several hundred genes, which are concentrated in cancer-related pathways, and are caused by changes in transcriptional regulation. Chromatin structure is preserved but some loop interactions are destabilized; these are often found around differentially expressed genes and their enhancers. Importantly, the transcriptional alterations identified in vitro are recapitulated in mouse tumors and also in human cancers. CONCLUSIONS: This multi-dimensional genomic and epigenomic profiling of a Ctcf hemizygous mouse model system shows that chronic depletion of CTCF dysregulates steady-state gene expression by subtly altering transcriptional regulation, changes which can also be observed in primary tumors.


Assuntos
Neoplasias da Mama/genética , Fator de Ligação a CCCTC/genética , Cromatina/química , DNA de Neoplasias/genética , Regulação Neoplásica da Expressão Gênica , Genoma , Neoplasias Hepáticas Experimentais/genética , Neoplasias Uterinas/genética , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Fator de Ligação a CCCTC/deficiência , Linhagem Celular , Cromatina/metabolismo , DNA de Neoplasias/metabolismo , Elementos Facilitadores Genéticos , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Hemizigoto , Homeostase , Humanos , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ligação Proteica , Transdução de Sinais , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia
18.
Virchows Arch ; 473(5): 583-590, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30116888

RESUMO

We examined the value of targeted molecular screening for the identification of uterine anaplastic lymphoma kinase (ALK)-rearranged mesenchymal tumors, including ALK immunohistochemistry followed by molecular genetic testing, in all uterine leiomyosarcomas and STUMPs (smooth muscle tumors of uncertain malignant potential). All leiomyosarcoma and STUMP cases diagnosed in a 10-year period (2006-2016) at Charles University Faculty of Medicine in Pilsen were retrieved and reviewed. Of 23 cases, one case (LMS [leiomyosarcoma]) was positive for ALK rearrangement, namely, PPP1CB-ALK fusion gene. No specific histologic features (i.e., lymphocytic infiltrate and stromal edema) were observed in this case. This suggests that inflammatory myofibroblastic tumor (IMT)-like histologic features may not be an initial reliable screening tool in identifying uterine IMT cases. Thus, we proposed a two-step IHC and molecular genetic testing (as a reflex test) for IMT in all uterine LMS and STUMP cases. This will enhance the proper detection of such tumors at the population level and ultimately offer patients available targeted therapies.


Assuntos
Biomarcadores Tumorais/genética , Rearranjo Gênico , Testes Genéticos/métodos , Leiomiossarcoma/genética , Receptores Proteína Tirosina Quinases/genética , Tumor de Músculo Liso/genética , Neoplasias Uterinas/genética , Quinase do Linfoma Anaplásico , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Leiomiossarcoma/diagnóstico , Leiomiossarcoma/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Estudos Retrospectivos , Tumor de Músculo Liso/diagnóstico , Tumor de Músculo Liso/metabolismo , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/metabolismo
19.
Clin. transl. oncol. (Print) ; 20(8): 1080-1086, ago. 2018. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-173692

RESUMO

Purpose: Pulmonary benign metastasizing leiomyoma (PBML), a rare condition of smooth muscle tumor, originates from women with a history of uterine leiomyoma (LM). Numerous genetic studies of uterine LM have been reported; however, there are few cytogenetic and molecular descriptions of PBML. Therefore, molecular subtyping is necessary to understand the pathogenesis of metastasizing sites. Methods: Driver gene exon-capture sequencing was performed on one patient’s peripheral blood, paraffin samples from primary uterine LM, and lung metastasizing leiomyoma 8 years later. Results: The results showed that the same missense mutations of BLMH, LRP2, MED12, SMAD2, and UGT1A8 were concurrently mutated in the primary uterine LM and the PBML. Moreover, a splice mutation of PTEN (c.492+1G>A) was uniquely identified in the lung metastasis of the patient. Conclusion: This study indicates that the metastatic lung lesions were derived from the same malignant cell clone of uterine LMs and later acquired the novel driver mutations in the evolution of the tumor. In addition, driver gene sequencing can discriminate somatic driver mutations as biological indicators of potential malignant leiomyoma and can identify pathogenic variation driver mutations, which could be used for individualized therapy


No disponible


Assuntos
Humanos , Feminino , Leiomioma/patologia , Neoplasias Uterinas/patologia , Metástase Neoplásica/patologia , Neoplasias Pulmonares/patologia , Neoplasias Uterinas/genética , Leiomioma/genética , Neoplasias Pulmonares/secundário , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Marcadores Genéticos
20.
Gynecol Oncol ; 150(3): 562-568, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30017537

RESUMO

OBJECTIVE: Around 70% of uterine leiomyomas show MED12 mutations while overexpression of HMGA2 mRNA is also highly frequent in fibroids. However, previous studies suggested that alterations in both genes are mutually exclusive. In the present study, we searched for mutation in MED12 and analyzed the expression of HMGA2 in 20 uterine leiomyomas and their matched myometrium. METHODS: Normal and tumor tissue obtained from premenopausal women who underwent hysterectomy were collected after surgery and DNA, RNA and proteins were isolated and analyzed for MED12 mutations using Sanger sequencing, HMGA2 mRNA expression by quantitative PCR and HMGA2 protein detection by western blot and immunohistochemistry. RESULTS: 75% of the tumors displayed MED12 mutation while 65% of them showed overexpression of HMGA2 mRNA in leiomyomata compared to myometrial tissues (p = 0,0008). Interestingly, 50% of the tumors showed mutations in MED12 and overexpression of HMGA2 mRNA simultaneously, suggesting that alterations in both genes are relatively frequent in uterine leiomyomas. CONCLUSIONS: Contrary to the present findings, former studies showed that mutations in MED12 and overexpression of HMGA2 are mutually exclusive. Here, we observed that overexpression of HMGA2 mRNA in tumors measured by quantitative PCR and compared to myometrium is a common phenomenon in fibroids and is frequently associated with MED12 mutations. In addition, the common clonal origin of tumors overexpressing HMGA2 mRNA and its expression in few myometrial tissue points to HMGA2 up-regulation as an early event in leiomyoma tumorigenesis.


Assuntos
Proteína HMGA2/genética , Leiomioma/genética , Complexo Mediador/genética , RNA Mensageiro/metabolismo , Neoplasias Uterinas/genética , Adulto , Feminino , Expressão Gênica , Proteína HMGA2/metabolismo , Humanos , Leiomioma/metabolismo , Complexo Mediador/metabolismo , Pessoa de Meia-Idade , Mutação , Miométrio/metabolismo , Pré-Menopausa , Neoplasias Uterinas/metabolismo
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