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1.
Gynecol Oncol ; 155(2): 318-323, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31495455

RESUMO

BACKGROUND: Numerous studies have investigated the association between hormone receptor expression and clinical outcome in ovarian carcinoma (OC); however, these have largely focussed on serous OCs, with few studies reporting specifically on endometrioid OCs (EnOC). Where analyses have been stratified by histotype, expression has been assessed using the percentage of positive tumor cells, without accounting for nuclear expression intensity. METHODS: Here we assess the expression levels of progesterone receptor (PR), estrogen receptor alpha (ER) and androgen receptor (AR) using histoscore - a nuclear scoring method incorporating both proportion of positive cells and the intensity of nuclear staining - across a cohort of 107 WT1 negative EnOCs. RESULTS: Hierarchical clustering by PR, ER and AR histoscores identified four EnOC subgroups (PR+/ER+, PR+/ER-, PR-/ER+ and PR-/ER-). EnOC patients in the PR+/ER+ and PR+/ER- groups displayed favorable outcome (multivariable HR for disease-specific survival 0.05 [0.01-0.35] and 0.05 [0.00-0.51]) compared to the PR-/ER+ group. Ten-year survival for stage II PRhigh and PRlow cases was 94.1% and 42.4%. ERhigh EnOC patients (PR+/ER+, PR-/ER+) had higher body mass index compared to ERlow cases (P = 0.015) and high grade serous OC patients (P < 0.001). CONCLUSION: These data demonstrate that endometrioid OC cases with high PR expression display markedly favorable outcome. Stage II EnOCs with high PR expression represent potential candidates for de-escalation of first-line therapy. Future work should seek to characterise the sensitivity of PR and ER positive EnOCs to endocrine therapy.


Assuntos
Carcinoma Endometrioide/mortalidade , Receptor alfa de Estrogênio/metabolismo , Neoplasias Ovarianas/mortalidade , Receptores Androgênicos/metabolismo , Receptores de Progesterona/metabolismo , Índice de Massa Corporal , Carcinoma Endometrioide/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/metabolismo , Estudos Retrospectivos
2.
BMC Cancer ; 19(1): 810, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412816

RESUMO

BACKGROUND: Endometrial cancer is the most common gynecological cancer. G-protein coupled receptor 64 (GPR64) belongs to a family of adhesion GPCRs and plays an important role in male fertility. However, the function of GPR64 has not been studied in endometrial cancer. Our objective is to investigate the role of GPR64 in endometrial cancer. METHODS: We examined the levels of GPR64 in human endometrioid endometrial carcinoma by immunohistochemistry analysis. To determine a tumor suppressor role of GPR64 in endometrial cancer, we used a siRNA loss of function approach in human endometrial adenocarcinoma cell lines. RESULTS: GPR64 levels were remarkably lower in 10 of 21 (47.62%) of endometrial carcinoma samples compared to control. Depletion of GPR64 by siRNA transfection revealed an increase of colony formation ability, cell proliferation, cell migration, and invasion activity in Ishikawa and HEC1A cells. The expression of Connexin 43 (Cx43), a member of the large family of gap junction proteins, was reduced through activation of AMP-activated protein kinase (AMPK) in Ishikawa cells with GPR64-deficicy. CONCLUSIONS: These results suggest that GPR64 plays an important tumor suppressor role in endometrial cancer.


Assuntos
Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/patologia , Receptores Acoplados a Proteínas-G/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Conexina 43/metabolismo , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Fosforilação , RNA Interferente Pequeno , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/genética
3.
Int J Clin Oncol ; 24(11): 1419-1428, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31197557

RESUMO

BACKGROUND: To evaluate the expression of programmed cell death-ligand 1 (PD-L1) and CD8 in high-grade endometrial carcinomas and relate it to several clinicopathological parameters. METHODS: One hundred and one (101) patients with high-grade endometrial carcinomas who were completely surgically staged were included in this study. PD-L1 and CD8 + expression was evaluated by immunohistochemistry. RESULTS: In our cohort, 47 women (46.5%) had endometrioid carcinomas and 54 patients (53.5%) were diagnosed with non-endometrioid cancers. In endometrioid carcinomas, there was a significantly higher rate of positivity for PD-L1 expression (p = 0.042) and of intraepithelial CD8 + cell counts (p = 0.004) as opposed to non-endometrioid cancers. There were no significant relationships with any of the other clinicopathological features under study. Univariate and multivariate analysis revealed that only high intraepithelial CD8 + counts (p = 0.01) was associated with longer progression-free survival. Tumors positive for PD-L1 and high intraepithelial CD8 expression were mainly of endometrioid histology, whilst PD-L1-positive/CD8 low and PD-L1-negative/CD8 low tumors were mostly non-endometrioid carcinomas (p = 0.01). PD-L1 negative/CD8 high tumors had the longest progression-free survival (p = 0.032). CONCLUSIONS: In grade 3 endometrial carcinomas, both of endometrioid and non-endometrioid type, high intraepithelial CD8 + counts represent an independent favorable prognostic factor and when related to PD-L1-negative tumors, a longer progression-free survival can be predicted. Immunotherapy could probably be considered for PD-L1-positive/CD8 + high tumors, which were mostly of endometrioid histology.


Assuntos
Antígeno B7-H1/metabolismo , Antígenos CD8/metabolismo , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Idoso , Apoptose , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/patologia , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/terapia , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/terapia , Feminino , Humanos , Imuno-Histoquímica , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida
4.
Genes (Basel) ; 10(5)2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096664

RESUMO

Endometrioid endometrial carcinomas (EEC) are the most common malignant gynecologic tumors. Despite the increase in EEC molecular knowledge, the identification of new biomarkers involved in disease's development and/or progression would represent an improvement in its course. High-mobility group A protein (HMGA) family members are frequently overexpressed in a wide range of malignancies, correlating with a poor prognosis. Thus, the aim of this study was to analyze HMGA1 and HMGA2 expression pattern and their potential role as EEC biomarkers. HMGA1 and HMGA2 expression was initially evaluated in a series of 46 EEC tumors (stages IA to IV), and the findings were then validated in The Cancer Genome Atlas (TCGA) EEC cohort, comprising 381 EEC tumors (stages IA to IV). Our results reveal that HMGA1 and HMGA2 mRNA and protein are overexpressed in ECC, but only HMGA1 expression is associated with increased histological grade and tumor size. Moreover, HMGA1 but not HMGA2 overexpression was identified as a negative prognostic factor to EEC patients. Finally, a positive correlation between expression of HMGA1 pseudogenes-HMGA1-P6 and HMGA1-P7-and HMGA1 itself was detected, suggesting HMGA1 pseudogenes may play a role in HMGA1 expression regulation in EEC. Thus, these results indicate that HMGA1 overexpression possesses a potential role as a prognostic biomarker for EEC.


Assuntos
Carcinoma Endometrioide/genética , Neoplasias do Endométrio/genética , Proteína HMGA1a/genética , Proteína HMGA2/genética , Adulto , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Carcinoma Endometrioide/metabolismo , Neoplasias do Endométrio/metabolismo , Feminino , Proteína HMGA1a/biossíntese , Proteína HMGA2/biossíntese , Humanos , Pessoa de Meia-Idade , Prognóstico , Transcriptoma
5.
Gynecol Oncol ; 154(1): 124-130, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31103324

RESUMO

BACKGROUND: Mismatch repair (MMR) deficiency is found in 20 to 40% of endometrial cancers (ECs) and was recently identified as a discerning feature of one of the four prognostic subgroups identified by The Cancer Genome Atlas. There is accumulating evidence that MMR proteins are involved in the DNA repair processes following radiotherapy. We investigated the predictive value of MMR status for response to adjuvant radiotherapy in patients with stage IB/II, grade 3 endometrioid endometrial cancer (EEC). METHODS: A retrospective multicenter cohort study was performed to compare patients with histopathologically confirmed stage IB/II grade 3 EEC with and without adjuvant radiotherapy. Patients were classified according to the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) identifying ECs as either MMR-deficient, POLE, p53abn or p53wt. Multivariable Cox regression analysis explored associations between adjuvant treatment and outcome. RESULTS: A total of 128 patients were analyzed, including 57 patients (43.0%) with MMR-deficient EECs. Baseline characteristics were comparable, except a higher proportion of MMR-deficient EECs were stage II (36.8% vs. 15.5%, p = 0.006). Eighty-two patients (64.1%) received adjuvant radiotherapy (external beam [n = 55], vaginal brachytherapy [n = 27]). In multivariable analysis, adjuvant radiotherapy was associated with improved disease-specific survival in patients with MMR-deficient EECs (hazard ratio 0.19, 95%-CI 0.05-0.77), but not in patients with MMR-proficient EECs (hazard ratio 0.92, 95%-CI 0.37-2.31). CONCLUSION: Adjuvant radiotherapy improved survival in patients with MMR-deficient EECs. MMR status could be used as a predictive biomarker to select patients that benefit most from adjuvant radiotherapy.


Assuntos
Carcinoma Endometrioide/genética , Carcinoma Endometrioide/radioterapia , Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Radioterapia Adjuvante , Estudos Retrospectivos , Taxa de Sobrevida
6.
Mol Med ; 25(1): 11, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30925862

RESUMO

BACKGROUND: Endometrial carcinoma represents one of the most common cancer types of the female reproductive tract. If diagnosed at an early stage, the 5-year survival rate is promising. However, recurrence and chemoresistance remain problematic for at least 15% of the patients. In the present study, we aim to reveal the mechanism by which PGK1 regulates chemoresistance in endometrial carcinoma. METHODS: qPCR was performed to detect expression of PGK1 in clinical tissue samples of endometrial carcinoma. Specific shRNAs were employed to knockdown PGK1 expression in endometrial cancer cell lines. MTT assay was used to evaluate cell viability and cisplatin sensitivity of endometrial carcinoma cell lines. Western blot was performed to assess the effects of PGK1 knockdown on the expression levels of HSP90, DNA repair-associated proteins (c-JUN, FOSL1, and POLD1), and DNA methylation-related enzymes (DNMT1, DNMT3A and DNMT3B). Immunoprecipitation was performed to verify direct binding between PGK1 and HSP90. RESULTS: We first showed that PGK1 expression is elevated in tumor tissues of endometrial cancer, and high PGK1 levels are associated with clinical stages and metastasis. Knockdown of PGK1 inhibits proliferation of endometrial cancer cells, and enhances the inhibitory effect of cisplatin on cell viability. In addition, knockdown of PGK1 down-regulates the expression of DNA repair-related proteins, methylation-related enzymes, and total cellular methylation level. PGK1 was next shown to interact directly with HSP90 and exhibit pro-tumor effects by modulating the ATPase activity of HSP90. CONCLUSIONS: We propose that PGK1 mediates DNA repair and methylation through the HSP90/ERK pathway, and eventually enhances the chemoresistance to cisplatin. The results provide new insights on functions of PGK1 and HSP90, which might make them as promising targets for endometrial cancer chemotherapy.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Endometrioide/genética , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Neoplasias do Endométrio/genética , Proteínas de Choque Térmico HSP90/metabolismo , Fosfoglicerato Quinase/genética , Animais , Carcinoma Endometrioide/metabolismo , Linhagem Celular Tumoral , Metilação de DNA , Reparo do DNA , Neoplasias do Endométrio/metabolismo , Endométrio/metabolismo , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Fosfoglicerato Quinase/metabolismo
7.
Cancer Sci ; 110(5): 1804-1813, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30907484

RESUMO

Endometrioid carcinoma (EC) is one of the most common malignancies of the female genital system. We reported previously that aldehyde dehydrogenase 1 (ALDH1), a predominant isoform of the ALDH family in mammals and a potential marker of normal and malignant stem cells, is related to the tumorigenic potential of EC. We compared the levels of various proteins in human EC cells with high and low ALDH1 expression using shotgun proteomics and found that serum deprivation-response protein (SDPR) was preferentially expressed in cells with high ALDH1 expression. Also known as cavin-2, SDPR is a member of the cavin protein family, which is required for the formation of caveolae. Using SDPR-knockout EC cells generated using the CRISPR/Cas9 system, we revealed that SDPR was correlated with invasion, migration, epithelial-mesenchymal transition, and colony formation, as well as the expression of ALDH1. RNA sequencing showed that integrin-linked kinase (ILK) signaling is involved in the effect of SDPR on ALDH1. Immunohistochemical analysis revealed that the localization of ILK at the cell cortex was disrupted by SDPR knockout, potentially interfering with ILK signaling. Moreover, immunohistochemical analysis of clinical samples showed that SDPR is related to histological characteristics associated with invasiveness, such as poor differentiation, lymphatic invasion, and the microcystic, elongated, and fragmented histopathological pattern. This is, to our knowledge, the first report that SDPR is related to tumor progression.


Assuntos
Aldeído Desidrogenase/metabolismo , Carcinoma Endometrioide/metabolismo , Proteínas de Transporte/metabolismo , Neoplasias do Endométrio/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Proteínas de Ligação a Fosfato , Retinal Desidrogenase , Transdução de Sinais
8.
J Ovarian Res ; 12(1): 15, 2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30736825

RESUMO

BACKGROUND: Ovarian cancer is the most lethal of all gynecologic malignancies. The relationship between sexual steroids receptors and ovarian cancer progression has been largely evaluated. The presence of progesterone receptors has been associated with an increase of a disease-free period and overall survival in patients with ovarian carcinoma. In the present study, primary cultures of ovarian carcinoma obtained from 35 patients diagnosed with epithelial ovarian cancer were evaluated for cell survival after treatment with 10- 8 M of 17ß-estradiol, progesterone, testosterone and dihydrotestosterone. RESULTS: The results were analyzed considering histological subtypes: low grade serous, high grade serous, endometrioid and mucinous carcinoma; clear cell carcinoma was not included due to failure in obtaining successful cultures of this subtype. A significant reduction of cell survival was observed after progesterone treatment in endometrioid ovarian carcinoma. Changes were not observed in low grade serous, high grade serous and mucinous carcinoma. The effect of progesterone was related to the presence of progesterone receptor (PR), a 43% reduction in the cell number was observed in PR (+) endometrioid ovarian carcinoma. CONCLUSIONS: This study supports the importance of progesterone and the presence of progesterone receptor in the reduction of ovarian cancer progression in the endometrioid ovarian carcinoma.


Assuntos
Antineoplásicos Hormonais/farmacologia , Carcinoma Endometrioide/patologia , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Ovarianas/patologia , Progesterona/farmacologia , Adulto , Carcinoma Endometrioide/metabolismo , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/metabolismo , Estudos Prospectivos , Receptores de Progesterona/metabolismo , Receptores de Esteroides/metabolismo , Células Tumorais Cultivadas/efeitos dos fármacos
10.
Hum Pathol ; 86: 163-169, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30633927

RESUMO

Ovarian cancer (OC) is the main cause of gynecological cancer-associated mortality. Improving the diagnosis is important for guiding clinical treatment. The present study aimed to investigate the relationship between expression of GATA6, a stem cell factor, and its prognosis in OC. In total, 521 OC cases were included. Immunohistochemistry analysis demonstrated that GATA6 was expressed in both high-grade serous carcinoma as well as non-serous tumors. High grade serous carcinoma showed a higher percentage of GATA6 positive staining. Positive staining of GATA6 showed worse overall survival (OS) in all ovarian cancers or serous and non-serous carcinoma individually. GATA6 was revealed as an independent risk factor for prognosis by multivariate Cox analysis. In all, GATA6 may present as a novel marker for poor prognosis in OC.


Assuntos
Adenocarcinoma Mucinoso/metabolismo , Carcinoma Endometrioide/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Fator de Transcrição GATA6/metabolismo , Neoplasias Ovarianas/metabolismo , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/patologia , Cistadenocarcinoma Seroso/mortalidade , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , Taxa de Sobrevida , Adulto Jovem
11.
Pathol Int ; 69(1): 29-36, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30688413

RESUMO

The clinicopathological and immunohistochemical characteristics of clinically occult extrapulmonary lymphangioleiomyomatosis in lymph nodes (LN-LAM) being dissected during surgical staging of pelvic malignancy have not been well investigated. We assessed samples from nine female patients (median age, 61). None had past or familial history of tuberous sclerosis and had LAM lesions other than LN such as lung. The primary malignancies included four endometrial endometrioid carcinomas, one endometrial carcinosarcoma, three ovarian serous carcinomas and one urothelial carcinoma. Median follow-up was 43 months. The number of affected LNs ranged from 1 to 15 (median, 2) with sizes ranging from 1 to 13 mm (median, 3.0). Six cases had clinically occult LN-LAM only within the pelvic LNs, two only within para-aortic LNs, and one within both pelvic and para-aortic lymph nodes. Immunohistochemically, LAM cells exhibited a strong diffuse positivity for ß-catenin and E-cadherin in all nine cases. Clinically occult LN-LAM mainly affects peri- or post-menopausal women. On rare occasions, occult LN-LAM may manifest as systemic LAM, including in the lung. ß-catenin and E-cadherin carry potential utility as additional diagnostic markers.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/patologia , Linfangioleiomiomatose/patologia , Neoplasias Pélvicas/patologia , Adulto , Idoso , Caderinas/metabolismo , Carcinoma Endometrioide/metabolismo , Neoplasias do Endométrio/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Linfonodos/patologia , Linfangioleiomiomatose/metabolismo , Pessoa de Meia-Idade , Neoplasias Pélvicas/metabolismo , Pelve/patologia , beta Catenina/metabolismo
12.
Diagn Pathol ; 14(1): 7, 2019 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-30684972

RESUMO

BACKGROUND: Currently, ribosome-binding protein 1 (RRBP1) is considered to be a novel oncogene that is overexpressed in colorectal cancer, lung cancer, mammary cancer, esophageal cancer and other carcinomas. However, the relationship between RRBP1 and endometrioid-type endometrial carcinoma (EC) remains unknown. Our purpose is to explore the function of RRBP1 in endometrioid-type endometrial carcinoma. METHODS: We investigated the expression of RRBP1 protein by immunohistochemistry on paraffin-embedded surgical specimens from one hundred thirty patients with endometrioid-type endometrial carcinoma. We also evaluated the differences in RRBP1 expression between endometrial cancer samples (n = 35) and normal endometrial tissues (n = 19) by western blotting. RESULTS: RRBP1 was more highly expressed in endometrial cancer samples than in normal samples (P < 0.05). High levels of expression of RRBP1 were strongly correlated with pathological features, such as the Federation of Gynecology and Obstetrics (FIGO) stage, histological grade, depth of myometrial invasion and lymph node metastasis (P < 0.05). Furthermore, RRBP1 expression was an independent prognostic factor for overall survival (OS) and disease-free survival (DFS) in patients with EC (both P < 0.05). CONCLUSION: This experiment identifies the utility of RRBP1 in predicting EC prognosis, revealing that it may be a potential target for therapeutics of EC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Endometrioide/diagnóstico , Proteínas de Transporte/metabolismo , Neoplasias do Endométrio/diagnóstico , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patologia , Progressão da Doença , Intervalo Livre de Doença , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Endométrio/metabolismo , Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Metástase Linfática , Pessoa de Meia-Idade , Prognóstico
13.
Chin Med J (Engl) ; 132(2): 161-170, 2019 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-30614867

RESUMO

BACKGROUND: DNA methylation is involved in numerous biologic events and associates with transcriptional gene silencing, playing an important role in the pathogenesis of endometrial cancer. ESR1/PGR frequently undergoes de novo methylation and loss expression in a wide variety of tumors, including breast, colon, lung, and brain tumors. However, the mechanisms underlying estrogen and progesterone receptors (ER/PR) loss in endometrial cancer have not been studied extensively. The aims of this study were to determine the expression of DNA (cytosine-5)-methyltransferase 3A/3B (DNMT3A/3B) in endometrial cancer to investigate whether the methylation catalyzed by DNMT3A/3B contributes to low ER/PR expression. METHODS: The clinicopathologic information and RNA-Seq expression data of DNMT3A/3B of 544 endometrial cancers were derived from The Cancer Genome Atlas (TCGA) uterine cancer cohort in May 2018. RNA-Seq level of DNMT3A/3B was compared between these clinicopathologic factors with t-test or one-way analysis of variance. RESULTS: DNMT3A/3B was overexpressed in endometrioid carcinoma (EEC) and was even higher in non-endometrioid carcinoma (NEEC) (DNMT3A, EEC vs. NEEC: 37.6% vs. 69.9%, t = -7.440, P < 0.001; DNMT3B, EEC vs. NEEC: 42.4% vs. 72.8%, t = -6.897, P < 0.001). In EEC, DNMT3A overexpression was significantly correlated with the hypermethylation and low expression of the ESR1 and PGR (P < 0.05). The same trend was observed in the DNMT3B overexpression subgroup. In the ESR1/PGR low-expression subgroups, as much as 83.1% of ESR1 and 59.5% of PGR were hypermethylated, which was significantly greater than the ESR1/PGR high-expression subgroups (31.3% and 11.9%, respectively). However, the above phenomena were absent in NEEC, while DNMT3A/3B overexpression, ESR1/PGR hypermethylation, and low ER/PR expression occurred much more often. In univariate analysis, DNMT3A/3B overexpressions were significantly correlated with worse prognosis. In multivariate analysis, only DNMT3A was an independent predictor of disease-free survival (P < 0.05). CONCLUSIONS: DNMT3A/3B expression increases progressively from EEC to NEEC and is correlated with poor survival. The mechanisms underlying low ER/PR expression might be distinct in EEC vs. NEEC. In EEC, methylation related to DNMT3A/3B overexpression might play a major role in ER/PR downregulation.


Assuntos
Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patologia , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/genética , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Receptor alfa de Estrogênio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/genética , DNA (Citosina-5-)-Metiltransferases/genética , Neoplasias do Endométrio/genética , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Prognóstico
14.
Int J Gynecol Pathol ; 38(1): 44-51, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29210800

RESUMO

Endometrial endometrioid carcinoma is related to estrogen excess and expression of estrogen and progesterone receptors. Epidemiological evidence suggests that exposure to elevated androgens, as in polycystic ovarian syndrome, increases the risk of endometrial cancer. Factors impacting androgen receptor (AR) expression are not well studied. Mismatch repair (MMR) deficiency due to MLH1 gene methylation is one of the most common molecular alterations in endometrial cancer, occurring in 15% to 20% of cases. MLH1 methylation can be associated with decreased expression of other genes, so we examined the effect of MMR status on AR expression. As NF-κB is known to induce AR, this transcription factor was also examined. Three hundred forty-four unselected endometrial carcinomas were evaluated for DNA MMR. Loss of expression of MLH1 with MLH1 methylation was defined as MMR deficient, and positive expression of MMR proteins was defined as MMR intact. A case-control cohort of 96 grade 2 endometrioid carcinomas was studied from this set (47 MMR deficient, 49 MMR intact). Cases were matched for histotype, grade, and age. AR and NF-κB immunohistochemical expression were evaluated by 2 different scoring systems (CAP/ASCO and Allred) used for estrogen receptor. Despite higher levels of NF-κB, MMR deficiency was associated with a significantly lower mean percentage of AR expression. The MMR deficient group had more variable AR expression, with more cases scoring on the lower end of the spectrum. These findings have implications for clinical trials of AR antagonists in gynecologic cancers.


Assuntos
Androgênios/metabolismo , Neoplasias Encefálicas/patologia , Carcinoma Endometrioide/patologia , Neoplasias Colorretais/patologia , Neoplasias do Endométrio/patologia , NF-kappa B/metabolismo , Síndromes Neoplásicas Hereditárias/patologia , Receptores Androgênicos/metabolismo , Idoso , Neoplasias Encefálicas/metabolismo , Carcinoma Endometrioide/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Neoplasias Colorretais/metabolismo , Metilação de DNA , Reparo de Erro de Pareamento de DNA/genética , Neoplasias do Endométrio/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Proteína 1 Homóloga a MutL/metabolismo , Síndromes Neoplásicas Hereditárias/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo
15.
Hum Pathol ; 85: 92-100, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30448219

RESUMO

Synchronous endometrial and ovarian carcinomas) represent 5% to 10% of endometrial or ovarian carcinomas. We assessed genetic alterations (in PTEN, CTNNB1, POLE, etc) and evaluated correlations with patient outcomes to determine the utility of clonality analyses for differentiating between metastases and concurrent primary tumors and for determining whether genetic alterations in synchronous tumors are predictive of biological behavior. Genomic DNA was isolated from formalin-fixed, paraffin-embedded tissues and frozen tissues from patients with synchronous endometrial and ovarian carcinomas. Samples were obtained from the Department of Obstetrics and Gynecology at the Shimane University School of Medicine between 2003 and 2017. Sanger sequencing was used to analyze the mutational status of the coding exons in TP53, PTEN, POLE, PIK3CA, KRAS, and CTNNB1 using previously published primers. All patients lived, and 3 had disease recurrence. The frequencies of somatic mutations in TP53, PTEN, CTNNB1, KRAS, and POLE were 3 (37.5%), 2 (25.0%), 3 (37.5%), 0 (0.0%), and 5 (62.5%) of 8 cases in ovarian tumors and 3 (37.5%), 2 (25.0%), 3 (37.5%), 1 (12.5%), and 5 (62.5%) of 8 cases in endometrial tumors, respectively. The frequencies of POLE and CTNNB1 mutations were higher than those in previous reports. A clonal relationship was determined by genomic analyses in 3 of 6 cases that were initially diagnosed as primary independent tumors. We confirmed that these 3 cases were indicated metastatic tumors because the lesion of mutation was the same. This information, provided by the sequencing-based strategy, could be useful for hypothesizing a patient's prognosis and deciding on treatment.


Assuntos
Carcinoma Endometrioide/genética , DNA Polimerase II/genética , Neoplasias do Endométrio/genética , Mutação , Neoplasias Primárias Múltiplas/genética , Neoplasias Ovarianas/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Adulto , Idoso , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Análise Mutacional de DNA , DNA Polimerase II/metabolismo , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Endométrio/metabolismo , Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Neoplasias Primárias Múltiplas/metabolismo , Neoplasias Primárias Múltiplas/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
16.
Cancer ; 125(3): 398-405, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30561762

RESUMO

BACKGROUND: The objective of this study was to assess the correlation between mismatch repair (MMR) status, disease recurrence patterns, and recurrence-free survival (RFS) in patients with high-intermediate-risk (HIR) endometrioid endometrial cancer (EEC). METHODS: A single-institution chart review for consecutive patients who were diagnosed with ECC between 2007 and 2016 was undertaken. Tumor MMR status was determined for all patients based on reported findings for mutL homolog 1 (MLH1), postmeiotic segregation (PMS2), mutS homolog 2 (MSH2), and MSH6 immunohistochemistry; and defective MMR (dMMR) status was defined as the lack of expression of at least 1 of these proteins. Patients were classified with HIR EEC according to criteria used for Gynecologic Oncology Group study 249. The factors associated with recurrence were assessed by logistic regression. RFS and associated factors were assessed by Kaplan-Meier survival analysis and Cox proportional-hazards models. RESULTS: In total, 197 patients who had HIR EEC (64 with dMMR and 133 with intact MMR [iMMR]) were identified, of whom 32 (16.2%) developed recurrent disease. The median follow-up was 54 months. The recurrence rate for women who had dMMR was 28% compared with 10.5% for those who had iMMR (P = .002), independent of the type of adjuvant therapy they received. The increase in distant recurrences among patients who had dMMR was even more pronounced (14.1% vs 3%; P = .003). The estimated 5-year RFS was 66% for women who had dMMR compared with 89% for those who had iMMR (P = .001). Excluding isolated vaginal recurrences, the difference in 5-year RFS was 73.5% versus 95%, respectively (P = .0004). CONCLUSIONS: Patients who had HIR EEC with dMMR had increased rates of recurrence and decreased RFS compared with those who had HIR EEC with iMMR, despite the receipt of similar adjuvant treatment. The current findings highlight the need for alternative treatment options and the importance of MMR status as a biomarker for patients with HIR EEC.


Assuntos
Biomarcadores Tumorais , Neoplasias Encefálicas/diagnóstico , Carcinoma Endometrioide/diagnóstico , Neoplasias Colorretais/diagnóstico , Neoplasias do Endométrio/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Síndromes Neoplásicas Hereditárias/diagnóstico , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Enzimas Reparadoras do DNA/análise , Enzimas Reparadoras do DNA/metabolismo , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , Recidiva Local de Neoplasia/metabolismo , Síndromes Neoplásicas Hereditárias/metabolismo , Síndromes Neoplásicas Hereditárias/mortalidade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida
17.
Hum Pathol ; 85: 72-81, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30447298

RESUMO

Ovarian clear cell and endometrioid carcinomas (type I) are thought to develop from endometriosis. ARID1A loss of expression is known to be related to the promotion of the endometriosis carcinogenesis. Despite the diverse origins and prognosis of type I and type II carcinomas, surgery followed by platinum-based chemotherapy is the mainstay of treatment for both. Limited knowledge about the expression of targeted therapies' biomarkers prevents the use of such markers as potential guides for tailored treatment. This study aimed to evaluate the expression of ARID1A gene and target therapies biomarkers (VEGF, PD-L1, and PARP-1) in ovarian clear cell and endometrioid carcinomas and endometriosis, and its relationship with prognosis. Forty-six ovarian clear cell and endometrioid carcinomas, and 24 endometriosis foci samples retrieved from the same surgical specimens were studied. ARID1A, VEGF, PD-L1, and PARP-1 immunohistochemistry expression was compared in carcinomas and endometriosis with regard to the clinicopathological features and prognosis. We found that endometriosis was associated with increased rates of diagnosis of cancer in the initial stages (P = .008). Different levels of expression of all biomarkers were detected in clear cell and endometrioid carcinomas and endometriosis. However, only the VEGF expression level showed a significant increase in the carcinoma group when compared with endometriosis (P = .0002). PARP-1 overexpression correlated with worse progression-free survival (P = .03) and overall survival (P = .01). In conclusion, endometriosis and ovarian clear cell and endometrioid carcinomas exhibited ARID1A loss of expression, and VEGF, PD-L1, and PARP-1 expression. PARP-1 overexpression in clear cell and endometrioid carcinomas was associated with early recurrence and worse overall survival.


Assuntos
Adenocarcinoma de Células Claras/metabolismo , Carcinoma Endometrioide/metabolismo , Endometriose/metabolismo , Neoplasias Ovarianas/metabolismo , Ovário/metabolismo , Adenocarcinoma de Células Claras/mortalidade , Adenocarcinoma de Células Claras/patologia , Adulto , Idoso , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/patologia , Endometriose/mortalidade , Endometriose/patologia , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Ovário/patologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Prognóstico , Intervalo Livre de Progressão , Taxa de Sobrevida , Fatores de Transcrição/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
J Gynecol Oncol ; 30(1): e13, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30479097

RESUMO

OBJECTIVES: Although patients with grade I and II endometrioid endometrial adenocarcinoma (EEA) are considered with good prognosis, among them 15%-25% died in 5 years. It is still unknown whether integrating estrogen receptor (ER) and progesterone receptor (PR) into clinical risk stratification can help select high-risk patients with grade I-II EEA. This study was to investigate the prognostic value of ER and PR double negativity (ER/PR loss) in grade I-II EEA, and the association between ER/PR loss and The Cancer Genome Atlas (TCGA) classification. METHODS: ER and PR were assessed by immunohistochemistry on hysterectomy specimens of 903 patients with grade I-II EEA. ER and PR negativity were determined when <1% tumor nuclei were stained. Gene expression data were obtained from the TCGA research network. RESULTS: Compared with ER or PR positive patients (n=868), patients with ER/PR loss (n=35) had deeper myometrial infiltration (p=0.012), severer FIGO stage (p=0.004), and higher rate of pelvic lymph node metastasis (p=0.020). In univariate analysis, ER/PR loss correlated with a shorter progression-free survival (PFS; hazard ratio [HR]=5.25; 95% confidence interval [CI]=2.21-12.52) and overall survival (OS; HR=7.59; 95% CI=2.55-22.60). In multivariate analysis, ER/PR loss independently predicted poor PFS (HR=3.77; 95% CI=1.60-10.14) and OS (HR=5.56; 95% CI=1.37-22.55) for all patients, and poor PFS for patients in stage IA (n=695; HR=5.54; 95% CI=1.28-23.89) and stage II-IV (n=129; HR=5.77; 95% CI=1.57-21.27). No association was found between ER/PR loss and TCGA classification. CONCLUSION: Integrating ER/PR evaluation into clinical risk stratification may improve prognosis for grade I-II EEA patients.


Assuntos
Carcinoma Endometrioide/metabolismo , Neoplasias do Endométrio/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Pessoa de Meia-Idade , Invasividade Neoplásica , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Análise Serial de Tecidos
19.
Cancer Biomark ; 24(2): 223-229, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30594917

RESUMO

BACKGROUND: Endometrioid ovarian carcinoma and clear cell ovarian carcinoma are both classified as endometriosis-associated ovarian cancer (EAOC). Despite the high rates of recurrence and mortality of EAOC, no prognostic biomarkers have been determined. ADP-ribosylation factor-like protein 4C (ARL4C) has been reported to be involved in various tumor progression processes, but its clinical significance for predicting prognosis in EAOC cases has never been studied. OBJECTIVE: The present study aimed to determine the clinical significance of ARL4C expression in EAOC prognosis. METHODS: ARL4C expression was semi-quantitatively evaluated via immunohistochemistry in 61 EAOC patients, and the correlations between ARL4C expression and clinicopathological data and survival were statistically analyzed. RESULTS: Thirty-six (59%) cases had high levels of ARL4C, which was related to worse 5-year overall survival (OS) (log-rank test, p= 0.036). In multivariate Cox proportional hazard model, high ARL4C expression was a significantly independent predictive factor for worse 5-year OS (hazard ratio = 12.048, p= 0.0201) and 5-year PFS (hazard ratio = 8.130, p= 0.0036). CONCLUSIONS: ARL4C is a biomarker for worse prognosis and a novel therapeutic target in EAOC.


Assuntos
Fatores de Ribosilação do ADP/genética , Biomarcadores Tumorais/genética , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fatores de Ribosilação do ADP/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma Endometrioide/metabolismo , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/metabolismo , Prognóstico , Análise de Sobrevida
20.
Int J Gynecol Pathol ; 38(1): 59-65, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29140883

RESUMO

The aim was to investigate MAGE-A4 and MAGE-A1 protein expression in high-grade endometrial cancer and determine its correlation with histologic subtype, FIGO stage, presence of vascular invasion, disease free, and overall survival. Immunohistochemical staining was performed by using 77B (MAGE-A1) and 57B (MAGE-A4) monoclonal antibodies on paraffin-embedded sections from high-grade endometrial cancers diagnosed in University Hospital Split between 1998 and 2011 (n=77). Median follow-up time for survivors was 48 mo. MAGE-A4 was found to be expressed in 33% of endometrioid type endometrial cancers grade 3 and in 27% of serous and clear cell carcinomas. MAGE-A1 was found to be expressed in 93% endometrioid endometrial cancer grade 3 and 86% of serous and clear cell carcinomas. Univariate analysis showed that positive immunohistochemical staining for MAGE-A4 was associated with decreased disease free and overall survival in patients with high-grade endometrial cancer. Multivariate analysis showed an association between MAGE-A4 overexpression and decreased disease free but not overall survival in high-grade endometrial cancer. No correlation was found between MAGE-A1 immunohistochemical expression and patient survival. There was no significant correlation between MAGE-A4 and MAGE-A1 expression and histologic subtype, FIGO stage, lymph node metastasis, muscular infiltration, and lymphovascular invasion. MAGE-A4 immunohistochemical expression is associated with decreased disease free and overall survival in patients with high-grade endometrial cancer. Our findings suggest that MAGE-A1 may be expressed in the epithelial cells of the normal endometrium. MAGE-A1 is highly expressed in high-grade endometrial cancer, with no impact on survival.


Assuntos
Adenocarcinoma de Células Claras/patologia , Antígenos de Neoplasias/metabolismo , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/patologia , Proteínas de Neoplasias/metabolismo , Fragmentos de Peptídeos/metabolismo , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/mortalidade , Anticorpos Monoclonais , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/mortalidade , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/mortalidade , Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Gradação de Tumores , Estudos Retrospectivos , Análise de Sobrevida
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