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1.
PLoS One ; 15(7): e0236402, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32701999

RESUMO

BACKGROUND: Endometrial cancer (EC) mortality is particularly high among non-Hispanic Blacks and is twice that of non-Hispanic Whites. However, comparisons of EC survival outcomes by race/ethnicity are often confounded by histology and grade. Here, we analyze EC survival disparities in multiracial Florida with a focus on EC types (1 and 2) and subtypes, defined according to histology and grade. METHODS: All 27,809 cases of EC diagnosed during 2005-2016 were obtained from the Florida Cancer Registry. Age-standardized, 5-year cause-specific survival by race/ethnicity and histological type were calculated. Fine and Gray competing risk regression was used to estimate sub-distribution hazard ratios (sHRs) for associations between risk of death due to EC and potential predictive factors such as histology/grade, age, stage at diagnosis, and insurance. RESULTS: Type 2 EC accounted for only 38.7% of all incident EC-cases but 74.6% of all EC-deaths. Blacks were disproportionately affected by type 2 EC (57.6%) compared to Whites, Hispanics, and Asians (35.6%, 37.7%, and 43.0%, respectively). Age-adjusted 5-year survival for types 1 and 2 were 85.3% and 51.6%, respectively; however, there was wide variation within type 2 subtypes, ranging from 60.2% for mixed cell EC to as low as 30.1% for carcinosarcoma. In the multivariable model, Blacks with type 2 EC had a 23% higher risk of death due to EC (sHR: 1.23, 95%CI: 1.12-1.36) compared to Whites. CONCLUSIONS: Population-based analyses should consider the histological heterogeneity of EC because the less common type 2 EC drives racial/ethnic survival disparities in EC. Black women have a higher proportion of more aggressive histological types and an overall higher risk of death due to EC than Whites. To the extent that some of these histological types may be considered different diseases and require specific treatment approaches, further research on etiology and prognosis for detailed type 2 EC subtypes is warranted.


Assuntos
Sobreviventes de Câncer , Neoplasias do Endométrio/epidemiologia , Endométrio/patologia , Neoplasias Uterinas/epidemiologia , Adolescente , Adulto , Afro-Americanos/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Intervalo Livre de Doença , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Florida/epidemiologia , Disparidades nos Níveis de Saúde , Hispano-Americanos/genética , Humanos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Adulto Jovem
3.
Am J Surg Pathol ; 44(6): 849-858, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32205485

RESUMO

Diagnosis of first-trimester partial mole is challenging as the key morphologic features may not be well-developed and may overlap with those of a nonmolar gestation harboring a cytogenetic disorder or degenerative changes. Genotype testing has emerged as the reference tool to distinguish partial mole (diandric triploid genotype) from its nonmolar mimics. However, observer variation in defining the minimum threshold of how much morphologic alteration is required to trigger genotype testing may result in a subset of partial moles that go undetected. We hypothesized that the results of fetal aneuploidy testing performed for prenatal screening or evaluation of miscarriage may assist with triggering molecular testing in the evaluation of products of conception, specifically if fetal triploidy is detected. Gestations with fetal triploidy are either a partial mole (diandric triploidy) or are nonmolar (digynic triploidy). The aims of this study were to define the prevalence of partial mole in 20 products of conception specimens with known fetal triploidy by performing genotype testing and then to determine how well established morphologic criteria for partial mole correlate with the genotype results in this setting. Genotype testing demonstrated that 65% (13/20) were a partial mole and the remainder were nonmolar digynic triploid gestations. Most partial moles were under 9 weeks gestational age and, as expected, lacked classic well-developed morphologic features. Nearly a third (4/13) of the partial moles were originally interpreted as normal or nonmolar gestations with minimal abnormalities that did not merit molecular testing to exclude a partial mole. Even with the retrospective systematic morphologic review, only 23% (3/13) exhibited the combination of chorionic villous enlargement of ≥2.5 mm and cisterns, which has been previously established as the morphologic criteria with the highest predictive value for a molecularly defined partial mole. The other 77% exhibited focal, limited, variable degrees and extent of villous morphologic alterations. We conclude that, given the high prevalence of partial mole among products of conception with known fetal triploidy and the low prevalence of diagnostic morphologic findings in such specimens, reflex genotype testing should be performed in all such cases, regardless of whether or not the morphologic features are suspicious for a partial mole. This reflex testing strategy mitigates against the subjectivity of determining whether subtle villous abnormalities are significant enough to merit pursuing genotype testing. The success of this strategy depends on the clinician documenting the fetal triploidy result at the time of submitting the products of conception specimen and therefore clinician education is needed. Finally, it remains to be determined whether the risk for postmolar gestational trophoblastic disease is the same in diandric triploid gestations that exhibit classic morphologic features as in those that exhibit minimal or negligible villous morphologic abnormalities.


Assuntos
Mola Hidatiforme/diagnóstico , Mola Hidatiforme/genética , Triploidia , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética , Vilosidades Coriônicas/patologia , Feminino , Testes Genéticos/métodos , Genótipo , Humanos , Mola Hidatiforme/epidemiologia , Gravidez , Prevalência , Estudos Retrospectivos , Neoplasias Uterinas/epidemiologia
4.
Nat Commun ; 11(1): 1019, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32094355

RESUMO

Uterine leiomyomas (fibroids) are a major source of gynecologic morbidity in reproductive age women and are characterized by the excessive deposition of a disorganized extracellular matrix, resulting in rigid benign tumors. Although down regulation of the transcription factor AP-1 is highly prevalent in leiomyomas, the functional consequence of AP-1 loss on gene transcription in uterine fibroids remains poorly understood. Using high-resolution ChIP-sequencing, promoter capture Hi-C, and RNA-sequencing of matched normal and leiomyoma tissues, here we show that modified enhancer architecture is a major driver of transcriptional dysregulation in MED12 mutant uterine leiomyomas. Furthermore, modifications in enhancer architecture are driven by the depletion of AP-1 occupancy on chromatin. Silencing of AP-1 subunits in primary myometrium cells leads to transcriptional dysregulation of extracellular matrix associated genes and partly recapitulates transcriptional and epigenetic changes observed in leiomyomas. These findings establish AP-1 driven aberrant enhancer regulation as an important mechanism of leiomyoma disease pathogenesis.


Assuntos
Cromatina/genética , Regulação Neoplásica da Expressão Gênica , Leiomioma/genética , Complexo Mediador/genética , Neoplasias Uterinas/genética , Adulto , Substituição de Aminoácidos , Células Cultivadas , Sequenciamento de Cromatina por Imunoprecipitação , Quinase 8 Dependente de Ciclina/metabolismo , Elementos Facilitadores Genéticos/genética , Epigênese Genética , Éxons/genética , Feminino , Predisposição Genética para Doença , Humanos , Histerectomia , Leiomioma/patologia , Leiomioma/cirurgia , Complexo Mediador/metabolismo , Pessoa de Meia-Idade , Mutação , Miométrio/citologia , Miométrio/patologia , Miométrio/cirurgia , Cultura Primária de Células , RNA-Seq , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Transcrição Genética , Neoplasias Uterinas/patologia , Neoplasias Uterinas/cirurgia
5.
Indian J Pathol Microbiol ; 63(1): 49-52, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32031122

RESUMO

Background: Alpha-methylacyl-coenzyme A racemase (AMACR, P504S) is a commonly used marker in immunohistochemical diagnosis of prostate cancer. Recent studies identified P504S markers of the clear cell histotype in the ovary and/or endometrium. Gastric-type adenocarcinoma (GAS) is difficult to diagnose histologically, particularly when there is crossover with clear cell carcinoma (CCC). However, the significance of P504S for differentially diagnosing GAS and CCC is unclear. Aim: To evaluate P504S as a potential diagnostic marker of GAS and CCC. Settings and Design: We analyzed P504S expression in 48 cervical carcinomas (32 GAS and 16 CCC), as well as the expression of other markers including hepatocyte nuclear factor-1 beta (HNF-1ß) and NapsinA. Material and Methods: The expression differences of HNF-1ß, NapsinA, and P504S in GAS and CCC were detected by immunohistochemistry. Immunohistochemical histoscores based on the intensity and extent of staining were calculated. Results: The positive rates of HNF-1ß in GAS and CCC were 90.32% and 75%, respectively. (χ2 = 2.251, P = 0.663). The positive rates of NapsinA in GAS and CCC were 19.36% and 81.25%, respectively. (χ2 = 47.332, P < 0.01). The positive rates of P504S in GAS and CCC were 16.13% and 81.25%, respectively. (χ2 = 41.420, P < 0.01). HNF-1ß was frequently expressed in GAS and CCC, while NapsinA and P504S were frequently expressed in CCC, and reduced or lost in GAS. Conclusion: NapsinA and P504S can be used to differentiate between GAS and CCC.


Assuntos
Adenocarcinoma de Células Claras/genética , Racemases e Epimerases/genética , Neoplasias do Colo do Útero/genética , Neoplasias Uterinas/genética , Adenocarcinoma de Células Claras/enzimologia , Adulto , Biomarcadores Tumorais , Diagnóstico Diferencial , Feminino , Fator 1-beta Nuclear de Hepatócito/genética , Humanos , Imuno-Histoquímica , Neoplasias Gástricas/genética , Neoplasias do Colo do Útero/enzimologia , Neoplasias Uterinas/enzimologia , Útero/patologia , Vagina/patologia
6.
Sci Rep ; 10(1): 1197, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31988393

RESUMO

Uterine leiomyoma is one of the most common gynaecologic benign tumours, but its genetic basis remains largely unknown. Six previous GWAS identified 33 genetic factors in total. Here, we performed a two-staged GWAS using 13,746 cases and 70,316 controls from the Japanese population, followed by a replication analysis using 3,483 cases and 4,795 controls. The analysis identified 9 significant loci, including a novel locus on 12q23.2 (rs17033114, P = 6.12 × 10-25 with an OR of 1.177 (1.141-1.213), LINC00485). Subgroup analysis indicated that 5 loci (3q26.2, 5p15.33, 10q24.33, 11p15.5, 13q14.11) exhibited a statistically significant effect among multiple leiomyomas, and 2 loci (3q26.2, 10q24.33) exhibited a significant effect among submucous leiomyomas. Pleiotropic analysis indicated that all 9 loci were associated with at least one proliferative disease, suggesting the role of these loci in the common neoplastic pathway. Furthermore, the risk T allele of rs2251795 (3q26.2) was associated with longer telomere length in both normal and tumour tissues. Our findings elucidated the significance of genetic factors in the pathogenesis of leiomyoma.


Assuntos
Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Leiomioma/genética , Neoplasias Uterinas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Coortes , Feminino , Genótipo , Humanos , Japão , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único/genética , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , Homeostase do Telômero/genética
7.
Gynecol Oncol ; 157(1): 106-114, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31954538

RESUMO

OBJECTIVE: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and SMARCA4-deficient undifferentiated uterine sarcoma (SMARCA4-DUS) are rare and aggressive tumors, primarily affecting pre- and perimenopausal women. Inactivating SMARCA4 mutations are thought to be the driving molecular events in the majority of these tumors. Here, we report the clinical course of a family with germline SMARCA4 mutation and compare large cohorts of these rare tumor types. METHODS: We extracted clinico-pathological medical record data for the family with germline SMARCA4 mutation. Clinico-genomic data from SCCOHT and SMARCA4-DUS cohorts were retrospectively extracted from the archives of a large CLIA-certified reference molecular laboratory. RESULTS: We identified a single family with an inherited germline SMARCA4 mutation, in which two different family members developed either SCCOHT or SMARCA4-DUS, both of whom died within one year of diagnosis, despite aggressive surgical, chemotherapy and immunotherapy treatment. Retrospective comparative analysis of large SCCOHT (n = 48) and SMARCA4-DUS (n = 17) cohorts revealed that SCCOHT patients were younger (median age: 28.5 vs. 49.0) and more likely to have germline SMARCA4 alterations (37.5% vs. 11.8%) than SMARCA4-DUS patients. CONCLUSIONS: Growing understanding of the role SMARCA4 plays in the pathogenesis of these rare cancers may inform recommended genetic testing and counseling in families with these tumor types.


Assuntos
Carcinoma de Células Pequenas/genética , DNA Helicases/genética , Mutação em Linhagem Germinativa , Hipercalcemia/genética , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Sarcoma/genética , Fatores de Transcrição/genética , Neoplasias Uterinas/genética , Adulto , Carcinoma de Células Pequenas/patologia , Carcinoma de Células Pequenas/terapia , Diferenciação Celular/fisiologia , Estudos de Coortes , DNA Helicases/deficiência , Feminino , Humanos , Hipercalcemia/patologia , Hipercalcemia/terapia , Pessoa de Meia-Idade , Proteínas Nucleares/deficiência , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Prognóstico , Estudos Retrospectivos , Sarcoma/patologia , Sarcoma/terapia , Fatores de Transcrição/deficiência , Neoplasias Uterinas/patologia , Neoplasias Uterinas/terapia
8.
Am J Surg Pathol ; 44(6): 782-792, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31934920

RESUMO

Immunohistochemistry (IHC) for mismatch repair (MMR) proteins is recommended in endometrial carcinomas as a screening test for Lynch syndrome, and mismatch repair deficiency (MMRd) is reported in ∼30% of cases. However, few studies have evaluated the rate of MMR loss in uterine carcinosarcomas. A 5-year retrospective database search of uterine carcinosarcomas was performed at 3 academic institutions. The histologic diagnoses, type of carcinoma present, and MMR IHC interpretations were confirmed by a gynecologic pathologist. One hundred three cases of uterine carcinosarcomas with available MMR IHC results were identified. Ninety-nine cases (96%) showed intact expression and 4 cases (4%) showed loss of MLH1/PMS2. All MMRd carcinosarcomas identified in this series had an endometrioid carcinomatous component and wild-type p53 expression. In contrast, the majority of MMR intact carcinosarcomas had a serous morphology and aberrant p53 expression. Three additional cases initially diagnosed as carcinosarcoma also revealed MMRd; however, given the lack of clear mesenchymal differentiation, these cases were reclassified as dedifferentiated endometrial carcinomas and were subsequently excluded from the carcinosarcoma category. No cases of Lynch syndrome were identified among carcinosarcoma patients, as all 4 MMRd cases were due to somatic MLH1 hypermethylation. In summary, we found that the rate of MMRd is markedly lower in uterine carcinosarcoma when compared with endometrial carcinoma. In the setting of MMR loss, a diagnosis of dedifferentiated carcinoma should be considered as almost half of the MMRd tumors which were called carcinosarcomas initially were reclassified as dedifferentiated on review. However, given the interobserver variability in the classification of carcinosarcoma versus dedifferentiated carcinoma a universal screening approach that includes uterine carcinosarcoma is still recommended.


Assuntos
Neoplasias Encefálicas/patologia , Carcinossarcoma/genética , Neoplasias Colorretais/patologia , Síndromes Neoplásicas Hereditárias/patologia , Neoplasias Uterinas/genética , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/genética , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA/genética , Feminino , Humanos , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/genética , Estudos Retrospectivos
9.
Am J Obstet Gynecol ; 222(1): 64.e1-64.e16, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31351063

RESUMO

BACKGROUND: Multidrug resistance is a major concern in uterine leiomyosarcoma treatment. Development of effective chemotherapies and management of drug resistance in patients is necessary. The copper efflux transporter adenosine triphosphatase copper transporting beta is a member of the P-type adenosine triphosphatase family and is also known as a strong platinum efflux transporter. Various reports have shown the association between adenosine triphosphatase copper transporting beta and platinum resistance; however, suitable inhibitors or methods for inhibiting platinum efflux via adenosine triphosphatase copper transporting beta are not developed. OBJECTIVE: Our study focused on platinum resistance in uterine leiomyosarcoma. The role of adenosine triphosphatase copper transporting beta in uterine leiomyosarcoma resistance to platinum drugs was investigated both in vitro and in vivo. STUDY DESIGN: Adenosine triphosphatase copper transporting beta expression was investigated by Western blotting and the efficacy of copper sulfate pretreatment and cisplatin administration in adenosine triphosphatase copper transporting beta-expressing cells was investigated both in vitro and in vivo. RESULTS: Western blot analysis of SK-LMS-1 cells (uterine leiomyosarcoma cell line) revealed strong adenosine triphosphatase copper transporting beta expression. A permanent SK-LMS-ATPase copper transporting beta-suppressed cell line (SK-LMS-7B cells) was generated, and cisplatin exhibited a significant antitumor effect in SK-LMS-7B cells, both in vitro (SK-LMS-1 cells, half-maximal inhibitory concentration, 17.2 µM; SK-LMS-7B cells, half-maximal inhibitory concentration, 4.2 µM, P < .01) and in xenografts compared with that in SK-LMS-1 cells (5.8% vs 62.8%, P < .01). Copper sulfate was identified as a preferential inhibitor of platinum efflux via adenosine triphosphatase copper transporting beta. In SK-LMS-1 cells pretreated with 15 µM copper sulfate for 3 hours, the cisplatin half-maximal inhibitory concentration decreased significantly compared with that in untreated cells and resulted in significantly increased intracellular platinum accumulation (1.9 pg/cell vs 8.6 pg/cell, P < .01). The combination of copper sulfate pretreatment with cisplatin administration was also effective in vivo and caused cisplatin to exhibit significantly increased antitumor effects in mice with SK-LMS-1 xenografts (3.1% vs 62.7%, P < .01). CONCLUSION: Our study demonstrates that adenosine triphosphatase copper transporting beta is overexpressed in uterine leiomyosarcoma cells and that copper sulfate, which acts as an inhibitor of platinum efflux via adenosine triphosphatase copper transporting beta, may be a therapeutic agent in the treatment of uterine leiomyosarcoma.


Assuntos
Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Sulfato de Cobre/farmacologia , ATPases Transportadoras de Cobre/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leiomiossarcoma/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , ATPases Transportadoras de Cobre/antagonistas & inibidores , ATPases Transportadoras de Cobre/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Leiomiossarcoma/genética , Leiomiossarcoma/metabolismo , Camundongos , Transplante de Neoplasias , Transplante Heterólogo , Neoplasias Uterinas/genética , Neoplasias Uterinas/metabolismo
10.
J Cancer Res Clin Oncol ; 146(1): 97-104, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31768620

RESUMO

PURPOSE: Uterine neoplasms comprise a broad spectrum of lesions, some of which may pose a diagnostic challenge even to experienced pathologists. Recently, genome-wide DNA methylation-based classification of central nervous system tumors has been shown to increase diagnostic precision in clinical practice when combined with standard histopathology. In this study, we describe DNA methylation patterns of a diverse set of uterine neoplasms and test the applicability of array-based DNA methylation profiling. METHODS: A multicenter cohort including prototypical epithelial and mesenchymal uterine neoplasms was collected. Tumors were subject to pathology review and array-based DNA methylation profiling (Illumina Infinium HumanMethylation450 or EPIC [850k] BeadChip). Methylation data were analyzed by unsupervised hierarchical clustering and t-SNE analysis. RESULTS: After sample retrieval and pathology review the study cohort consisted of 49 endometrial carcinomas (EC), 5 carcinosarcomas (MMMT), 8 uterine leiomyomas (ULMO), 7 uterine leiomyosarcomas (ULMS), 15 uterine tumor resembling ovarian sex cord tumors (UTROSCT), 17 low-grade endometrial stromal sarcomas (LGESS) and 9 high-grade endometrial stromal sarcomas (HGESS). Analysis of methylation data identified distinct methylation clusters, which correlated with established diagnostic categories of uterine neoplasms. MMMT clustered together with EC, while ULMO, ULMS and UTROSCT each formed distinct clusters. The LGESS cluster differed from that of HGESS, and within the branch of HGESS, we observed a notable subgrouping of YWHAE- and BCOR-rearranged tumors. CONCLUSION: Herein, we describe distinct DNA methylation signatures in uterine neoplasms and show that array-based DNA methylation analysis holds promise as an ancillary tool to further characterize uterine neoplasms, especially in cases which are diagnostically challenging by conventional techniques.


Assuntos
Metilação de DNA , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética , Diferenciação Celular/genética , Estudos de Coortes , Feminino , Humanos , Neoplasias Uterinas/classificação , Neoplasias Uterinas/patologia
11.
Int J Gynecol Pathol ; 39(1): 1-7, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30394942

RESUMO

The use of p57 immunohistochemistry (IHC) can distinguish complete mole (CM) from partial mole (PM) and nonmolar abortus (NMA). Molecular genotyping (MG) is the gold standard method for the definitive diagnosis of PM and NMA. However, MG is expensive and not always available. Some data suggest Ki-67 IHC may be helpful in distinguishing NMAs from PMs and could be a substitute for MG. In this study, we examined the utility of p57 and Ki-67 IHC stains in the diagnosis of placental molar disease. The study cohort consisted of 60 cases of products of conception (20 CMs, 20 PMs, and 20 NMAs). All CM cases showed absent (<10%) p57 IHC in chorionic villi. All PM and NMA cases had been subjected to MG and showed diandric triploid or biparental inheritance, respectively. Ki-67 and p57 IHC staining was done on formalin-fixed paraffin-embedded sections from all 60 cases. Both IHC stains were interpreted blinded to the diagnosis. On rereview, we recorded the percentage of cells with nuclear p57 staining in villous cytotrophoblast and stromal cells. Ki-67 proliferative index (%) was determined by manual count of at least 500 villous cytotrophoblastic cells in areas with highest Ki-67 reactivity. Any intensity of nuclear staining was considered positive. The utility of p57 IHC is mainly to exclude or confirm CM. Although there is a significantly higher Ki-67 expression in CMs in comparison to PMs and NMAs, this did not add diagnostic utility. PMs tend to have higher Ki-67 expression than NMAs; however, the difference is not statistically significant. Our data suggest that the use of p57 and Ki-67 IHC cannot reliably distinguish PM from NMAs.


Assuntos
Mola Hidatiforme/diagnóstico , Antígeno Ki-67/metabolismo , Doenças Placentárias/diagnóstico , Neoplasias Uterinas/diagnóstico , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Feminino , Técnicas de Genotipagem , Humanos , Mola Hidatiforme/genética , Mola Hidatiforme/patologia , Imuno-Histoquímica , Doenças Placentárias/genética , Doenças Placentárias/patologia , Gravidez , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia
12.
Int J Gynecol Pathol ; 39(1): 8-18, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30480644

RESUMO

Epithelioid trophoblastic tumor is a malignancy derived from the chorionic laeve-type intermediate trophoblast with sufficient rarity that the vast majority of literature on the topic exists in the form of case reports and small series. Classically, it is regarded as a well-circumscribed tumor with an expansile growth pattern that occurs in reproductive-aged women, usually after a normal pregnancy. However, we recently encountered a case of epithelioid trophoblastic tumor with aggressive spread throughout the abdomen and pelvis in a 68-yr-old female presenting 30 yr after her last delivery. Although to our knowledge this is the first report in a postmenopausal patient to be confirmed by molecular analysis of short tandem repeats, there are multiple similar case reports spanning a variety of clinical settings that deviate from the original description. We therefore sought to synthesize the clinicopathologic data among the available reports in the English literature, with emphasis on pathologic findings. While the overarching themes are largely unchanged, this series of 77 patients reveals a broader spectrum of disease and highlights frequent misdiagnosis. Here we present a clinicopathologic update on this rare entity, with emphasis on a practical approach to diagnosis.


Assuntos
Células Epitelioides/patologia , Neoplasias Trofoblásticas/diagnóstico , Neoplasias Trofoblásticas/patologia , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/patologia , Adolescente , Adulto , Idoso , Feminino , Técnicas de Genotipagem , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Pós-Menopausa , Gravidez , Doenças Raras/diagnóstico , Doenças Raras/genética , Doenças Raras/patologia , Fatores de Tempo , Neoplasias Trofoblásticas/genética , Neoplasias Uterinas/genética , Adulto Jovem
13.
Histopathology ; 76(1): 64-75, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31846533

RESUMO

Almost all uterine mesenchymal tumours have been historically classified as either smooth muscle or endometrial stromal neoplasms. Recent application of molecular techniques has identified numerous lesions with distinctive genetic abnormalities and clinicopathological characteristics. Newly discovered uterine sarcoma subtypes include high-grade endometrial stromal sarcomas with BCOR genetic abnormalities, fibrosarcoma-like uterine sarcomas with NTRK rearrangements and COL1A-PDGFRB fusions, as well as undifferentiated uterine sarcomas with SMARCA4 mutations. Novel PLAG1 and PGR fusions have been identified in subsets of myxoid and epithelioid leiomyosarcomas. Some uterine tumours resembling ovarian sex-cord tumour harbour GREB1 and ESR1 rearrangements. Histological and immunophenotypical features as well as underlying genetic abnormalities defining these lesions are discussed.


Assuntos
Leiomiossarcoma/patologia , Sarcoma do Estroma Endometrial/patologia , Neoplasias Uterinas/patologia , Útero/patologia , Feminino , Rearranjo Gênico , Humanos , Leiomiossarcoma/genética , Fusão Oncogênica , Sarcoma do Estroma Endometrial/genética , Neoplasias Uterinas/genética
14.
Am J Obstet Gynecol ; 222(6): 596.e1-596.e9, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31874141

RESUMO

BACKGROUND: Uterine leiomyomas (fibroids) are smooth muscle neoplasms of the myometrial layer of the uterus and are the most common benign tumors in women. Although their etiology is still unclear, progenitor cells seem to be implicated. OBJECTIVE: To identify the dysregulated pathways involved in leiomyoma onset by microRNA profiling of progenitor cells isolated from normal myometrium and leiomyoma tissue. MATERIALS AND METHODS: Pairs of normal myometrium and uterine fibroid specimens were collected from 12 myomectomy patients. Myometrial progenitor cells and leiomyoma progenitor cells were isolated and characterized for stemness. After total RNA extraction and profiling of their 2646 microRNAs, DIANA-miRPath analysis was applied to find any dysregulated pathways. RESULTS: Only 30 microRNAs showed a significant differential regulation between myometrial progenitor cells and leiomyoma progenitor cells. Removal of those that had values close to the cut-off or that were not consistent among triplicates left 15 microRNAs, of which 7 were downregulated and 8 were upregulated in leiomyoma progenitor cells compared to myometrial progenitor cells. According to DIANA-miRPath analysis, the 7 downregulated microRNAs (hsa-miR-146b-5p; hsa-miR-335-3p; hsa-miR-335-5p; hsa-miR-135b-5p; hsa-miR-10a-3p; hsa-miR-10a-5p; hsa-miR-200a-3p) are all related to 3 pathways, "ECM-receptor interaction" (33 targeted genes), "Adherens junction" (33 targeted genes), and "Hippo signaling" (69 targeted genes), whereas the 8 upregulated miRNAs (hsa-miR-146a-5p; hsa-miR-576-3p; hsa-miR-122-5p; hsa-miR-1246; hsa-miR-595; hsa-miR-658; hsa-miR-4284; hsa-miR-924) are related to 4 pathways, "PI3K-Akt signaling pathway" (71 targeted genes), "Pathways in Cancer" (80 targeted genes), "Cell Cycle" (37 targeted genes), and "Regulation of actin cytoskeleton" (41 targeted genes). CONCLUSION: The findings that only 15 of 2646 microRNAs are differentially regulated in normal myometrium and leiomyoma and that they are involved in 7 dysregulated pathways provides interesting insights into the development of uterine fibroids, and lends support to the hypothesis that leiomyoma onset is the result of alterations affecting progenitor cells.


Assuntos
Regulação Neoplásica da Expressão Gênica , Leiomioma/genética , MicroRNAs/genética , Miométrio/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco/metabolismo , Neoplasias Uterinas/genética , Citoesqueleto de Actina/genética , Junções Aderentes/genética , Adulto , Ciclo Celular/genética , Regulação para Baixo , Grupo com Ancestrais do Continente Europeu/genética , Matriz Extracelular/genética , Feminino , Humanos , Leiomioma/metabolismo , Leiomioma/cirurgia , Miométrio/citologia , Transdução de Sinais/genética , Regulação para Cima , Miomectomia Uterina , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/cirurgia
15.
Artigo em Inglês | MEDLINE | ID: mdl-31851527

RESUMO

R-spondin3 (RSPO3), an activator of Wnt/ß-catenin signaling, plays a key role in tumorigenesis of various cancers, but its role in choriocarcinoma remains unknown. To investigate the effect of RSPO3 on the tumor growth of choriocarcinoma JEG-3 cells, the expression of RSPO3 in human term placenta was detected, and a stable RSPO3-overexpressing JEG-3 cell line was established via lentivirus-mediated transduction. The expression of biomarkers involved in tumorigenicity was detected in the RSPO3-overexpressing JEG-3 cells, and cell proliferation, invasion, migration, and apoptosis were investigated. Moreover, soft agar clonogenic assays and xenograft tumorigenicity assays were performed to assess the effect of RSPO3 on tumor growth in vitro and in vivo. The results showed that RSPO3 was widely expressed in human term placenta and overexpression of RSPO3 promoted the proliferation and inhibited the migration, invasion, and apoptosis of the JEG-3 cells. Meanwhile, RSPO3 overexpression promoted tumor growth both in vivo and in vitro. Further investigation showed that the phosphorylation levels of Akt, phosphatidylinositol 3-kinase (PI3K), and ERK as well the expression of ß-catenin and proliferating cell nuclear antigen (PCNA) were increased in the RSPO3-overexpressing JEG-3 cells and tumor xenograft. Taken together, these data indicate that RSPO3 promotes the tumor growth of choriocarcinoma via Akt/PI3K/ERK signaling, which supports RSPO3 as an oncogenic driver promoting the progression of choriocarcinoma.


Assuntos
Coriocarcinoma/metabolismo , Coriocarcinoma/patologia , Trombospondinas/biossíntese , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia , Adulto , Animais , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Coriocarcinoma/genética , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Gravidez , Trombospondinas/genética , Neoplasias Uterinas/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
16.
Am J Surg Pathol ; 44(1): 30-42, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31464709

RESUMO

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare mesenchymal neoplasm, of uncertain biological potential, that was recently reported to exhibit recurrent gene fusions involving NCOA2-3. The purpose of this study was to, using a larger sample size, better characterize the histopathologic and molecular diversity of UTROSCT. Twenty-six cases of UTROSCT from 5 institutions were selected for further study. Fluorescence in situ hybridization for NCOA1, NCOA2, NCOA3, ESR1 and GREB1, and targeted RNA sequencing was performed on 17 and 8 UTROSCTs, respectively. Eight cases underwent massively parallel sequencing to detect single nucleotide variants (SNV), copy number variations, and structural variants using a targeted hybrid-capture based assay. NCOA1-3 rearrangement was identified in 81.8% (18/22) of cases. The most common fusion was ESR1-NCOA3, occurring in 40.9% (9/22). GREB1-NCOA1 (n=4), ESR1-NCOA2 (n=3), and GREB1-NCOA2 (n=1) rearrangements were also identified. No recurrent SNVs were identified and no tumor had SNVs in FOXL2, DICER1, STK11, or AKT1, which can be seen in ovarian sex cord-stromal tumors. Copy number variations were infrequent. Clinical follow-up was available for 11 cases with a mean follow-up interval of 94.4 (range, 1 to 319) months. Only one case had a recurrence 66 months after the initial diagnosis and this was the single case with a GREB1-NCOA2 fusion. This study reports the morphologic spectrum of UTROSCT and confirms the recently reported recurrent NCOA2-3 gene fusions, in addition to identifying novel rearrangements involving NCOA1 in these tumors.


Assuntos
Rearranjo Gênico , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Adulto , Idoso , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Recidiva Local de Neoplasia , Coativador 1 de Receptor Nuclear/genética , Coativador 2 de Receptor Nuclear/genética , Coativador 3 de Receptor Nuclear/genética , Fusão Oncogênica
17.
Int J Mol Sci ; 20(24)2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31817606

RESUMO

We review recent studies dealing with the molecular genetics and basic results of omics analysis of uterine leiomyoma (LM)-a common benign muscle tumor of the uterus. Whole genome studies of LM resulted in the discovery of many new gene nets and biological pathways, including its origin, transcriptomic, and epigenetic profiles, as well as the impact of the inter-cell matrix in LM growth and involvement of microRNA in its regulation. New data on somatic cell mutations ultimately involved in the origin, distribution and growth of LM are reviewed. Putative identification of LM progenitor SC (stem cells) giving rise to maternal fibroid nodes and junctional zones provide a new clue for hypotheses on the pathogenomics of LM. The reviewed data are consistent with at least two different but probably intimately interacted molecular mechanisms of LM. One of them (the genetic hypothesis) is focused primarily on the MED12 gene mutations and suggests its onset in the side population of embryonic myoblasts of the female reproductive system, which later gave rise to multiple small and medium fibroids. The single and usually large-size fibroids are induced by predominantly epigenetic disorders in LM SC, provoked by enhanced expression of the HMGA2 gene caused by its hypomethylation and epigenetic deregulation enhanced by hypoxia, muscle tension, or chromosome instability/aberrations. The pathogenomics of both genetic and epigenetic programs of LM with many peculiarities at the beginning later became rather similar and partly overlapped due to the proximity of their gene nets and epigenetic landscape. Pathogenomic studies of LM open ways for elaboration of novel strategies of prevention and treatment of this common disease.


Assuntos
Leiomioma/metabolismo , Neoplasias Uterinas/metabolismo , Útero/metabolismo , Animais , Feminino , Humanos , Leiomioma/genética , Mutação/genética , Neoplasias Uterinas/genética , Útero/patologia
18.
Fertil Steril ; 112(6): 1180-1189, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31843095

RESUMO

OBJECTIVE: To determine the expression of miR-29c and its target gene transforming growth factor-ß3 (TGF-ß3) in leiomyoma and the mechanisms of their reciprocal regulation. DESIGN: Experimental study. SETTING: Academic research laboratory. PATIENT(S): Women undergoing hysterectomy for leiomyoma. INTERVENTION(S): Overexpression and underexpression of miR-29c; blockade of DNA methyltransferase 1 (DNMT1). MAIN OUTCOME MEASURE(S): The miR-29c and its target gene TGF-ß3 in leiomyoma and the effects of TGF-ß3 and blockade of DNMT1 on miR-29c expression. RESULT(S): Leiomyoma expressed significantly lower levels of miR-29c, but higher expression of TGF-ß3 compared with matched myometrium. The expression of TGF-ß3 and miR-29c were independent of race/ethnicity. Using 3' untranslated region luciferase reporter assay we confirmed that TGF-ß3 is a direct target of miR-29c in leiomyoma smooth muscle cells (LSMCs). Gain-of-function of miR-29c in LSMCs inhibited the expression of TGF-ß3 at protein and messenger RNA levels, whereas loss-of-function of miR-29c had the opposite effect. Treatment of LSMCs with TGF-ß3 inhibited the expression of miR-29c, whereas it stimulated DNMT1 expression. Knockdown of DNMT1 through transfection with small interfering RNA significantly decreased the expression of TGF-ß3, and induced miR-29c expression. Knockdown of DNMT1 also attenuated the inhibitory effect of TGF-ß3 on miR-29c expression. Furthermore, we demonstrated that TGF-ß3 increased the methylation level of miR-29c promoter in LSMCs. CONCLUSION(S): There is an inverse relationship in the expression of TGF-ß3 and miR-29c in leiomyoma. The TGF-ß3 is a direct target of miR-29c and inhibits the expression of miR-29c through an epigenetic mechanism. The cross-talk between miR-29c and TGF-ß3 provides a feed forward mechanism of fibrosis in leiomyoma.


Assuntos
DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA , Epigênese Genética , Leiomioma/enzimologia , MicroRNAs/metabolismo , Fator de Crescimento Transformador beta3/metabolismo , Neoplasias Uterinas/enzimologia , Adulto , DNA (Citosina-5-)-Metiltransferase 1/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Leiomioma/genética , Leiomioma/patologia , Leiomioma/cirurgia , MicroRNAs/genética , Pessoa de Meia-Idade , Transdução de Sinais , Fator de Crescimento Transformador beta3/genética , Células Tumorais Cultivadas , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Neoplasias Uterinas/cirurgia
19.
Genome Med ; 11(1): 84, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847873

RESUMO

BACKGROUND: Maternal effect mutations in the components of the subcortical maternal complex (SCMC) of the human oocyte can cause early embryonic failure, gestational abnormalities and recurrent pregnancy loss. Enigmatically, they are also associated with DNA methylation abnormalities at imprinted genes in conceptuses: in the devastating gestational abnormality biparental complete hydatidiform mole (BiCHM) or in multi-locus imprinting disease (MLID). However, the developmental timing, genomic extent and mechanistic basis of these imprinting defects are unknown. The rarity of these disorders and the possibility that methylation defects originate in oocytes have made these questions very challenging to address. METHODS: Single-cell bisulphite sequencing (scBS-seq) was used to assess methylation in oocytes from a patient with BiCHM identified to be homozygous for an inactivating mutation in the human SCMC component KHDC3L. Genome-wide methylation analysis of a preimplantation embryo and molar tissue from the same patient was also performed. RESULTS: High-coverage scBS-seq libraries were obtained from five KHDC3Lc.1A>G oocytes, which revealed a genome-wide deficit of DNA methylation compared with normal human oocytes. Importantly, germline differentially methylated regions (gDMRs) of imprinted genes were affected similarly to other sequence features that normally become methylated in oocytes, indicating no selectivity towards imprinted genes. A range of methylation losses was observed across genomic features, including gDMRs, indicating variable sensitivity to defects in the SCMC. Genome-wide analysis of a pre-implantation embryo and molar tissue from the same patient showed that following fertilisation methylation defects at imprinted genes persist, while most non-imprinted regions of the genome recover near-normal methylation post-implantation. CONCLUSIONS: We show for the first time that the integrity of the SCMC is essential for de novo methylation in the female germline. These findings have important implications for understanding the role of the SCMC in DNA methylation and for the origin of imprinting defects, for counselling affected families, and will help inform future therapeutic approaches.


Assuntos
Blastocisto/metabolismo , Metilação de DNA , Mola Hidatiforme/patologia , Oócitos/metabolismo , Proteínas/genética , Neoplasias Uterinas/patologia , Adulto , Feminino , Humanos , Mola Hidatiforme/genética , Recidiva Local de Neoplasia , Placenta/metabolismo , Polimorfismo de Nucleotídeo Único , Gravidez , Análise de Sequência de DNA , Análise de Célula Única , Neoplasias Uterinas/genética
20.
Proc Natl Acad Sci U S A ; 116(51): 25880-25890, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31772025

RESUMO

Uterine carcinosarcoma is an aggressive variant of endometrial carcinoma characterized by unusual histologic features including discrete malignant epithelial and mesenchymal components (carcinoma and sarcoma). Recent studies have confirmed a monoclonal origin, and comprehensive genomic characterizations have identified mutations such as Tp53 and Pten However, the biological origins and specific combination of driver events underpinning uterine carcinosarcoma have remained mysterious. Here, we explored the role of the tumor suppressor Fbxw7 in endometrial cancer through defined genetic model systems. Inactivation of Fbxw7 and Pten resulted in the formation of precancerous lesions (endometrioid intraepithelial neoplasia) and well-differentiated endometrioid adenocarcinomas. Surprisingly, all adenocarcinomas eventually developed into definitive uterine carcinosarcomas with carcinomatous and sarcomatous elements including heterologous differentiation, yielding a faithful genetically engineered model of this cancer type. Genomic analysis showed that most tumors spontaneously acquired Trp53 mutations, pointing to a triad of pathways (p53, PI3K, and Fbxw7) as the critical combination underpinning uterine carcinosarcoma, and to Fbxw7 as a key driver of this enigmatic endometrial cancer type. Lineage tracing provided formal genetic proof that the uterine carcinosarcoma cell of origin is an endometrial epithelial cell that subsequently undergoes a prominent epithelial-mesenchymal transition underlying the attainment of a highly invasive phenotype specifically driven by Fbxw7.


Assuntos
Neoplasias do Endométrio/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Proteína 7 com Repetições F-Box-WD/genética , Proteína 7 com Repetições F-Box-WD/metabolismo , Neoplasias Uterinas/metabolismo , Animais , Movimento Celular , Proliferação de Células , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Endométrio/patologia , Células Epiteliais , Feminino , Humanos , Camundongos , Mutação , PTEN Fosfo-Hidrolase/metabolismo , Fenótipo , Proteína Supressora de Tumor p53/metabolismo , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia
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