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1.
J Cancer Res Clin Oncol ; 146(4): 971-983, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31927619

RESUMO

PURPOSE: Endometrial mesonephric-like adenocarcinoma (ML-AC) represents a recently recognized subtype of endometrial adenocarcinoma (AC) associated with a subtle immunophenotype with a characteristic KRAS-mutation. Detailed clinico-pathologic analyses and prognostic data on ML-AC are limited. METHODS: We report a series of four cases with histopathological, immunohistochemical, and molecular analyses. These cases as well as the data of previously published cases were reviewed for clinico-pathologic variables and clinical follow-up information. RESULTS: Forty cases of ML-AC were identified. ML-AC represents about 1% of all endometrial carcinomas. Similar to other types of endometrial AC, vaginal bleeding was the leading presenting symptom, and the mean age was 60.0 years (range 31-91). More than a half of the patients presented with locally advanced disease (≥ FIGO stage II) at time of diagnosis, developed a recurrence or died of the disease within a mean follow-up period of 24.7 months (range 3-144.5 months). The most common site of distant disease was pulmonary involvement. Microscopically, ML-ACs present with mixed morphology and show a co-expression of so-called mesonephric and Müllerian markers, suggesting a Müllerian origin of the tumors. Immunostaining for PD-L1 was negative in all tested cases, using different antibodies against PD-L1. Retained staining for mismatch repair proteins on immunohistochemistry and a POLE-mutation suggest a copy number low phenotype within the molecular classification of endometrial carcinomas. Almost all cases showed a KRAS-mutation at codon 12 (mostly G12V). CONCLUSION: Uterine ML-AC represents a distinct subtype of invasive endometrial AC, associated with KRAS-mutations and characteristic immunohistochemical findings. Clinically, ML-AC may show an aggressive behavior with a high rate of recurrent disease and a substantial risk for distant metastatic disease, especially to the lungs.


Assuntos
Adenocarcinoma/diagnóstico , Neoplasias do Endométrio/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Carcinoma Endometrioide/diagnóstico , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patologia , Diagnóstico Diferencial , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Prognóstico
2.
Gynecol Oncol ; 156(1): 194-202, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31757464

RESUMO

OBJECTIVES: Assess outcomes of a clinical cohort of patients with endometrioid endometrial cancer (EEC) harboring somatic POLE exonuclease domain mutations (EDMs). METHODS: Patients were consented to a protocol of tumor-normal massively parallel sequencing of 410-468 cancer related genes. EECs subjected to sequencing from 2014 to 2018 were reviewed. Tumors with somatic POLE EDMs were identified. EECs were assessed for microsatellite instability (MSI) using MSIsensor and immunohistochemical analysis for mismatch repair (MMR) proteins. RESULTS: Of the 451 EECs sequenced, 23 had a POLE EDM (5%): 20 primary and 3 recurrent tumors sequenced. Nineteen cases (83%) were stage I/II and 4 (17%) were stages III/IV. Thirteen EECs (57%) were of FIGO grades 1/2, 10 (43%) grade 3. All patients were treated with surgery and 17 (89%) received adjuvant therapy. Five (22%) demonstrated loss of DNA MMR protein expression, none were due to Lynch syndrome. MSIsensor scores were conclusive for 21 samples: 19 were microsatellite stable and 2 MSI-high. After median follow-up of 30 months, 4/23 (17%) developed recurrences: 3 with initial grade 3 stage I and 1 with grade 1 stage III disease. One patient with grade 2 stage IV EEC had progressive disease after treatment. CONCLUSIONS: Patients with POLE EDM EEC have been shown to have a favorable prognosis. In this real-world cohort of patients, de novo metastatic disease and recurrences in initially uterine-confined cases were observed. Further research is warranted before incorporating the presence of POLE EDM into decision-making regarding adjuvant therapy.


Assuntos
Carcinoma Endometrioide/genética , DNA Polimerase II/genética , Neoplasias do Endométrio/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Adulto , Idoso , Carcinoma Endometrioide/enzimologia , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/terapia , Estudos de Coortes , Reparo de Erro de Pareamento de DNA , DNA Polimerase II/metabolismo , Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/terapia , Feminino , Humanos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Prognóstico , Estudos Prospectivos
3.
Gynecol Oncol ; 156(2): 393-399, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31882243

RESUMO

OBJECTIVES: Increasing grade of endometrioid endometrial cancer (EEC) is associated with aggressive behavior and poor prognosis. The traditional classification system is limited in its ability to guide treatment planning and prognostication. We identify distinct immune biomarker phenotypes using known markers of immunogenicity to identify patients who may benefit from immune therapy (IT). METHODS: 621 tumors were analyzed by multiplatform profiling. NextGen sequencing was performed on 592 genes. Tumor mutational burden (TMB) was defined as high (H) ≥10mutations/megabase. Microsatellite Instability (MSI) by NGS was ≥46 loci. PD-L1 positivity was ≥2+, >5% by IHC. Chi-square tests were used. RESULTS: Overall, MSI-H was found in 33% of EECs, most frequent in grade 3 (G3), followed by grade 2 (G2) and grade 1 (G1) tumors (G3: 37%, G2: 32%, G1: 22%, p = 0.007). TMB-H was identified in 25% of EECs. TMB-H was most common in G3, followed by G2 and G1 tumors (G3: 34%, G2: 23%, G1: 13%, p = 0.006). Overall, PD-L1 expression was found in 5.5% of EECs. G3 EECs had the most frequent PD-L1 expression, followed by G2 and G1 tumors (G3: 12%, G2: 3.0%, G1: 0.9%, p < 0.0001). We identified POLE mutations in 4.5% (28/618). All POLE mutated tumors harbored TMB-H phenotypes but MSI-H and PD-L1 were only present in 10.7% and 14.8% of tumors respectively, suggesting upregulation of T-cell immune response in only a fraction of POLE mutated EECs. Triple negative (TN) biomarker phenotype (ER-/PR-/Her2-) was evaluated as a potential surrogate marker of tumor immunogenicity. We identified TN phenotype in 4% of G1 EEC compared with 9% in G2 and 33% in G3, suggesting loss of hormone expression and possible greater immunogenicity with increasing tumor grade. CONCLUSIONS: High grade tumors appear to be more immunogenic than low grade tumors and may preferentially benefit from IT.


Assuntos
Antígeno B7-H1/biossíntese , Antígeno B7-H1/imunologia , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/imunologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos
4.
Int J Gynecol Pathol ; 39(1): 36-42, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30676432

RESUMO

Cowden syndrome (CS) is a multiple hamartoma syndrome associated with the development of various tumors, including endometrial cancer. However, the histology of CS-associated endometrial cancer remains to be fully described. To our knowledge, this is the first report of a patient with CS having endometrial endometrioid carcinoma with ovarian metastasis demonstrating morula-like features. A 31-yr-old, nulliparous, Japanese woman presented with abnormal genital bleeding. Endometrial biopsy revealed endometrioid carcinoma with an extensive morular formation, partially resembling atypical polypoid adenomyoma (APAM). Moreover, she had a past history of bilateral breast cancer and a family history of juvenile breast cancer in her mother. Genetic testing revealed they shared the same pathogenic germline PTEN mutation. She underwent an abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph node biopsy. Pathologic examination revealed endometrial endometrioid carcinoma with APAM-like histology. Furthermore, the solid components with morula-like morphology and immunophenotypes showed myometrial invasion and ovarian metastasis (FIGO stage IIIA/pT3aN0M0). The present case highlights the need for careful assessment of myometrial invasion and extrauterine spread for appropriate gynecologic treatment even if endometrial biopsy shows APAM-like histology. Moreover, characterization of CS-associated endometrial cancers is required.


Assuntos
Carcinoma Endometrioide/secundário , Neoplasias do Endométrio/complicações , Neoplasias do Endométrio/patologia , Síndrome do Hamartoma Múltiplo/complicações , Neoplasias Ovarianas/secundário , Adenomioma/genética , Adenomioma/patologia , Adulto , Biópsia , Carcinoma Endometrioide/genética , Neoplasias do Endométrio/genética , Feminino , Mutação em Linhagem Germinativa , Síndrome do Hamartoma Múltiplo/genética , Humanos , Mórula/patologia , Invasividade Neoplásica , Neoplasias Ovarianas/genética , PTEN Fosfo-Hidrolase/genética
5.
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
6.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370215

RESUMO

Dedifferentiated endometrial carcinoma (DDEC) is defined as an undifferentiated carcinoma admixed with differentiated endometrioid carcinoma (Grade 1 or 2). It has poor prognosis compared with Grade 3 endometrioid adenocarcinoma and is often associated with the loss of mismatch repair (MMR) proteins, which is seen in microsatellite instability (MSI)-type endometrial cancer. Recent studies have shown that the effectiveness of immune checkpoint inhibitor therapy is related to MMR deficiency; therefore, we analyzed the immunophenotype (MMR deficient and expression of PD-L1) of 17 DDEC cases. In the undifferentiated component, nine cases (53%) were deficient in MMR proteins and nine cases (53%) expressed PD-L1. PD-L1 expression was significantly associated with MMR deficiency (p = 0.026). In addition, the presence of tumor-infiltrating lymphocytes (CD8+) was significantly associated with MMR deficiency (p = 0.026). In contrast, none of the cases showed PD-L1 expression in the well-differentiated component. Our results show that DDEC could be a target for immune checkpoint inhibitors (anti PD-L1/PD-1 antibodies), especially in the undifferentiated component. As a treatment strategy for DDEC, conventional paclitaxel plus carboplatin and cisplatin plus doxorubicin therapies are effective for those with the well-differentiated component. However, by using immune checkpoint inhibitors in combination with other conventional treatments, it may be possible to control the undifferentiated component and improve prognosis.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Endometrioide/tratamento farmacológico , Carcinoma/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Idoso , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Carboplatina/uso terapêutico , Carcinoma/genética , Carcinoma/imunologia , Carcinoma/patologia , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/imunologia , Carcinoma Endometrioide/patologia , Cisplatino/uso terapêutico , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Doxorrubicina/uso terapêutico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/imunologia , Neoplasias do Endométrio/patologia , Feminino , Expressão Gênica , Humanos , Imunofenotipagem , Linfócitos do Interstício Tumoral , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/uso terapêutico , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia
7.
Anticancer Res ; 39(8): 4143-4147, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366499

RESUMO

BACKGROUND/AIM: Vitamin D analogs have a protective effect on carcinogenesis in humans. Since vitamin D receptor (VDR) is detected in many histotypes of cancer, this study evaluated the role of VDR expression in endometrioid carcinoma. MATERIALS AND METHODS: Tumor samples were collected from 60 patients who had undergone surgery, and the pattern of VDR expression assessed in tissue microarray (TMA) blocks of tumor samples. When VDR expression in the cytoplasm was higher than that in the nucleus, this was noted as 'displacement'. Using statistical analysis, the relationship between VDR expression and clinicopathological factors was evaluated. RESULTS: Immunohistochemical staining of nuclear VDR was as follows: Negative: 32 (53.3%); mild: 13 (21.7%); moderate: 14 (23.3%); strong: 1 (1.7%). For cytoplasmic VDR expression: Negative: 2 (3.3%); mild: 19 (31.7%); moderate: 31 (51.7%); strong: 7 (11.7%). VDR displacement was found in 42 (70%) cores. VDR displacement was significantly positively correlated with endometrioid carcinoma having lower histological grade (1, p=0.03). CONCLUSION: Displacement of VDR was significantly correlated with lower histological grade. Clinicians might be able to predict prognosis and decide therapies related to vitamin D analogs using this remarkable biomarker for endometrial carcinoma.


Assuntos
Carcinogênese/genética , Carcinoma Endometrioide/genética , Prognóstico , Receptores de Calcitriol/genética , Adulto , Idoso , Carcinoma Endometrioide/patologia , Citoplasma/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Análise Serial de Tecidos , Vitamina D/genética
8.
Gynecol Oncol ; 154(3): 516-523, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31340883

RESUMO

OBJECTIVE: Endometrioid ovarian carcinomas (EOCs) comprise 5-10% of all ovarian cancers and commonly co-occur with synchronous endometrioid endometrial cancer (EEC). We sought to examine the molecular characteristics of pure EOCs in patients without concomitant EEC. METHODS: EOCs and matched normal samples were subjected to massively parallel sequencing targeting 341-468 cancer-related genes (n = 8) or whole-genome sequencing (n = 28). Mutational frequencies of EOCs were compared to those of high-grade serous ovarian cancers (HGSOCs; n = 224) and EECs (n = 186) from The Cancer Genome Atlas, and synchronous EOCs (n = 23). RESULTS: EOCs were heterogeneous, frequently harboring KRAS, PIK3CA, PTEN, CTNNB1, ARID1A and TP53 mutations. EOCs were distinct from HGSOCs at the mutational level, less frequently harboring TP53 but more frequently displaying KRAS, PIK3CA, PIK3R1, PTEN and CTNNB1 mutations. Compared to synchronous EOCs and pure EECs, pure EOCs less frequently harbored PTEN, PIK3R1 and ARID1A mutations. Akin to EECs, EOCs could be stratified into the four molecular subtypes: 3% POLE (ultramutated), 19% MSI (hypermutated), 17% copy-number high (serous-like) and 61% copy-number low (endometrioid). In addition to microsatellite instability, a subset of EOCs harbored potentially targetable mutations, including AKT1 and ERBB2 hotspot mutations. EOCs of MSI (hypermutated) subtype uniformly displayed a good outcome. CONCLUSIONS: EOCs are heterogeneous at the genomic level and harbor targetable genetic alterations. Despite the similarities in the repertoire of somatic mutations between pure EOCs, synchronous EOCs and EECs, the frequencies of mutations affecting known driver genes differ. Further studies are required to define the impact of the molecular subtypes on the outcome and treatment of EOC patients.


Assuntos
Carcinoma Endometrioide/classificação , Carcinoma Epitelial do Ovário/classificação , Neoplasias Ovarianas/classificação , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Cistadenocarcinoma Seroso/classificação , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Análise Mutacional de DNA , Feminino , Humanos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Intervalo Livre de Progressão , Estudos Retrospectivos
9.
Exp Oncol ; 41(2): 138-143, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31262163

RESUMO

AIM: To analyze copy number variations of HER-2/neu, c-MYC and CCNE1 oncogenes and their protein expression in endometrioid endometrial carcinomas in relation to the degree of tumor progression and presence of a family history of cancer in cancer patients. MATERIALS AND METHODS: The study was conducted on endometrial cancer (EC) samples from 68 patients with I-II FIGO stages of disease. Copy number analysis of HER-2/neu, c-MYC and CCNE1 genes was performed by quantitative PCR. Protein expression was analyzed using immunohistochemistry. RESULTS: Assessment of copy number variations of HER-2/neu, c-MYC and CCNE1 genes revealed their amplification in the tumors of 18.8, 25.0 and 14.3% of EC patients, respectively. High expression of corresponding proteins was detected in 14.6, 23.5 and 65.6% of patients, respectively. It was established that HER-2/neu gene amplification is more common in the group of tumors of low differentiation grade than in moderate grade EC (35.7 and 5.5% of cases, respectively, p < 0.05). Also, high expression of c-Myc protein was more frequently observed in low differentiated tumors compared to the moderately differentiated EC (36.6 and 13.2% of cases, respectively, p < 0.05). Expression of HER-2/neu and cyclin E proteins was found to be dependent on the depth of tumor invasion into the myometrium. High expression of HER-2/neu protein was observed in 25.0 and 4.1% of EC patients with tumor invasion > ½ and < ½ of the myometrium, respectively, and cyclin E - in 86.7 and 46.6% of cases, respectively, p < 0.05. It was shown that among patients with a family history of cancer, a larger proportion of cases with high expression of c-Myc protein was observed compared to the group of patients with sporadic tumors (43.8 and 17.3%, respectively; p < 0.05). CONCLUSIONS: Amplification of HER-2/neu gene, along with high expression of c-Myc, HER-2/neu and cyclin E proteins, are associated with such indices of tumor progression as a low differentiation grade and deep myometrial invasion, suggesting the potential possibility of including these markers in the panel for determining the molecular EC subtype associated with an aggressive course of the disease. In a certain category of EC patients, there is a relationship between a family history of cancer and high expression of c-Myc protein.


Assuntos
Carcinoma Endometrioide/genética , Ciclina E/genética , Neoplasias do Endométrio/genética , Proteínas Oncogênicas/genética , Proteínas Proto-Oncogênicas c-myc/genética , Receptor ErbB-2/genética , Sequência de Bases , Biomarcadores Tumorais/genética , Carcinoma Endometrioide/patologia , Variações do Número de Cópias de DNA/genética , Neoplasias do Endométrio/patologia , Endométrio/patologia , Feminino , Amplificação de Genes/genética , Humanos , Pessoa de Meia-Idade , Miométrio/patologia , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia
10.
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
11.
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
12.
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
13.
Gynecol Oncol ; 153(3): 517-520, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30910249

RESUMO

OBJECTIVES: Stage I, grade 1 endometrial cancers have low recurrence rates and often do not receive adjuvant therapy. We compared recurrent cases to matched non-recurrent controls to evaluate for molecular markers associated with higher risk of recurrence. METHODS: A case-control study including all cases of recurrent stage I, grade 1 endometrioid endometrial cancer at one institution in a ten-year period. Cases were matched to controls by age, BMI, weight and stage. Molecular testing and immunohistochemistry were performed on archival tumor specimens: microsatellite instability (MSI-H), mismatch repair status, POLE mutational status, and next-generation sequencing. RESULTS: 15 stage I, grade 1 endometrial cancer cases with recurrent disease and available tumor specimens were identified. CTNNB1 and MSI-H were present at significantly higher rates in cases than controls (CTNNB1 60% vs. 28%, OR 3.9, 95%CI 1.1-14.7, p = 0.04 and MSI-H 53% vs. 21%, OR 4.4, 95%CI 1.1-17.0, p = 0.03). POLE mutations were found in 0% of cases vs. 7% of controls (p = 0.54). Among specimens demonstrating microsatellite stability (MSS), 100% of cases vs. 26% of controls had CTNNB1 mutations (p < 0.001). CTNNB1 wild type tumors were MSI-H in 100% of cases vs. 19% of controls (p < 0.001). CONCLUSIONS: Compared to controls, CTNNB1 mutation is present at significantly higher rates in recurrent stage I, grade 1 endometrial cancers and is found most commonly in MSS tumors. MSI-H is also present at significantly higher rates in recurrent cases. These markers may be useful for prognostic risk stratification and adjuvant therapy decision-making in this otherwise low-risk population.


Assuntos
Carcinoma Endometrioide/genética , Neoplasias do Endométrio/genética , Recidiva Local de Neoplasia/genética , beta Catenina/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Endometrioide/patologia , Estudos de Casos e Controles , Classe I de Fosfatidilinositol 3-Quinases/genética , DNA Polimerase II/genética , Neoplasias do Endométrio/patologia , Feminino , Humanos , Proteínas de Membrana/genética , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , PTEN Fosfo-Hidrolase/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteína Supressora de Tumor p53/genética
14.
Ann Diagn Pathol ; 39: 92-104, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30798077

RESUMO

Endometrial carcinoma is the most frequently occurring female genital tract malignancy in developed nations, with a rising annual incidence. Endometrioid endometrial carcinoma (EEC), the most common histological variant, differs in morphologic and molecular characteristics from serous carcinomas but morphological distinction of high-grade EECs from serous carcinomas may prove difficult. Thus, molecular categorization of tumors may allow for better tumor classification with greater insight into the underlying biology of endometrial carcinomas with new therapeutic options. Microsatellite instability (MSI) is a commonly occurring molecular aberration in EECs and has been identified in most Lynch Syndrome (LS) associated tumors. This tumor syndrome predisposes afflicted individuals to a myriad of tumors including endometrial carcinoma. Herein, the molecular signature of endometrial tumors as well as LS, and its clinical manifestations are reviewed. Understanding of the pathogenetic pathways allows for greater comprehension of occurrences at a molecular level which are then appreciated at a cellular and tissue level, by the histopathologist. The molecular classification of endometrial tumors allows for further targeted therapeutic options for affected patients. Screening tests for patients with suspected LS enables surveillance of other tumors in the affected patient and her family with the potential to decrease morbidity and mortality. It is envisioned that this overview will allow for enhanced comprehension of genetic pathways by practicing pathologists, oncologists, gynecologists and other members of the multidisciplinary team, all of whom are involved in the management of the patient with an endometrial malignancy.


Assuntos
Carcinoma Endometrioide/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Cistadenocarcinoma Seroso/genética , Neoplasias do Endométrio/genética , Carcinoma Endometrioide/patologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Cistadenocarcinoma Seroso/patologia , Diagnóstico Diferencial , Detecção Precoce de Câncer , Neoplasias do Endométrio/patologia , Feminino , Humanos , Instabilidade de Microssatélites , Terapia de Alvo Molecular , Proteína 1 Homóloga a MutL/genética , PTEN Fosfo-Hidrolase/genética , Transdução de Sinais
15.
Taiwan J Obstet Gynecol ; 58(1): 164-167, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30638473

RESUMO

OBJECTIVE: We aimed to assess resistin gene polymorphisms, namely 420C > G and 62G > A and their effect on the risk of endometrial cancer (EC). MATERIALS AND METHODS: Between January 2012 and January 2015, of the total of 183 patients diagnosed with EC, 94 patients were enrolled into the study. Patients with diabetes mellitus, hypertension and history of any other cancer were excluded. To identify the importance of nucleotide polymorphism including 420C > G and 62G > A in the resistin gene, 94 healthy volunteers were included as the control group. RESULTS: Among the Resistin 420 gene polymorphism profiles, 420 GC (47.9%) was the most common gene polymorphism in the EC group. Also, the polymorphism of 420 CC (57.7%, p: 0.002) lead the list in the control group followed by the 420GC (37.5%) polymorphism. Resistin 62 gene polymorphism analysis demonstrated that the 62GC polymorphism was significantly more common in the EC group (p < 0.01), while 62 AG (52.9%) was observed most frequently in the control group bringing about a reduction in the risk of EC (p < 0.01, Odds Ratio:0.37). Additionally, the alleles of 420G+ and 62A + were significantly more common in the EC group and the control group, respectively (p:0.02 and p<:0.01). Multivariate regression analysis revealed that the presence of 420G + allele increased the EC risk 1.99 fold while the presence of 62A + allele was shown to decrease the risk of EC (p<:0.01 Odds Ratio:0.038). CONCLUSION: Our study for the first time had demonstrated that Resistin 420G > C and 62G > A gene polymorphisms play a role in EC development.


Assuntos
Carcinoma Endometrioide/genética , Neoplasias do Endométrio/genética , Resistina/genética , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Resistina/sangue
16.
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
17.
Mol Cancer Res ; 17(3): 731-740, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30610106

RESUMO

The molecular events driving low-grade endometrioid endometrial carcinoma (LGEC) development-like in many cancers-are incompletely understood. Hence, here we performed multiregion, comprehensive somatic molecular profiling of routinely processed formalin-fixed, paraffin-embedded (FFPE) material from 13 cases of LGEC totaling 64 minute, spatially defined cell populations ranging from presumed precursor lesions through invasive LGEC. Shared driving PTEN, PIK3R1, or PIK3CA mutations support clonal origin of the samples in each case, except for two cases with two clonally distinct neoplastic populations, consistent with unexpected multiclonality in LGEC development. Although substantial heterogeneity in driving somatic alterations was present across populations in nearly all cases, these alterations were usually clonal in a given population, supporting continued selection and clonal sweeping of driving alterations in populations with both precursor and LGEC histology. Importantly, CTNNB1 mutational status, which has been proposed as both prognostic and predictive in LGEC, was frequently heterogeneous and subclonal, occurring both exclusively in precursor or cancer populations in different cases. Whole-transcriptome profiling of coisolated RNA from 12 lesions (from 5 cases) was robust and confirmed histologic and molecular heterogeneity, including activated Wnt signaling in CTNNB1-mutant versus wild-type populations. Taken together, we demonstrate clinically relevant multiclonality and intratumoral heterogeneity during LGEC development with important implications for diagnosis, prognosis, and therapeutic prediction. More broadly, our methodology is broadly scalable to enable high-throughput genomic and transcriptomic characterization of precursor and invasive cancer populations from routine FFPE specimens. IMPLICATIONS: Multiregion profiling of LGEC populations using a highly scalable approach demonstrates clinically relevant multiclonality and intratumoral heterogeneity.


Assuntos
Carcinoma Endometrioide/genética , Neoplasias do Endométrio/genética , Carcinoma Endometrioide/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe Ia de Fosfatidilinositol 3-Quinase/genética , Neoplasias do Endométrio/patologia , Feminino , Humanos , Mutação , Gradação de Tumores , PTEN Fosfo-Hidrolase/genética , Inclusão em Parafina
18.
Exp Mol Pathol ; 106: 78-88, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30503404

RESUMO

Uterine endometrial carcinoma is one of the common cancers in females. Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are a small subpopulation of cancer cells that are tumorigenic and are resistant to treatments, thus they are focused as treatment targets. However, the heterogeneity of CSCs/CICs is still elusive, and we therefore analyzed CSCs/CICs at the clonal level. We previously established sphere-cultured CSCs/CICs from primary human uterine endometrial carcinoma, and we isolated several clones from CSCs/CICs in this study. Interestingly, we established two types of clones based on the growth pattern. The clones were termed sphere clones (S clones) and leukemia-like clones (LL clones). Functional analysis revealed that S clones are resistant to chemotherapy, whereas LL clones are sensitive to chemotherapy. On the other hand, S clones are less tumorigenic, while LL clones are highly tumorigenic. Transcriptome analysis using serial analysis of gene expression sequencing (SAGE-Seq) revealed distinctive gene expression profiles in S clone cells and LL clone cells. The results indicate that CSCs/CICs are composed of functionally heterogenic subpopulations including highly tumorigenic clones and treatment-resistant clones and that the characteristics of CSCs/CICs might be determined by the characteristics of different clones that compose CSCs/CICs.


Assuntos
Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/patologia , Células-Tronco Neoplásicas/patologia , Animais , Carboplatina/farmacologia , Carcinoma Endometrioide/genética , Células Clonais/patologia , Meios de Cultura , DNA de Neoplasias/genética , Neoplasias do Endométrio/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Paclitaxel/farmacologia , Fenótipo , Análise de Sequência de DNA , Soro , Esferoides Celulares , Células Tumorais Cultivadas
19.
Int J Gynecol Pathol ; 38 Suppl 1: S64-S74, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30550484

RESUMO

In this review, we sought to address 2 important issues in the diagnosis of endometrial carcinoma: how to grade endometrial endometrioid carcinomas and how to incorporate the 4 genomic subcategories of endometrial carcinoma, as identified through The Cancer Genome Atlas, into clinical practice. The current International Federation of Gynecology and Obstetrics grading scheme provides prognostic information that can be used to guide the extent of surgery and use of adjuvant chemotherapy or radiation therapy. We recommend moving toward a binary scheme to grade endometrial endometrioid carcinomas by considering International Federation of Gynecology and Obstetrics defined grades 1 and 2 tumors as "low grade" and grade 3 tumors as "high grade." The current evidence base does not support the use of a 3-tiered grading system, although this is considered standard by International Federation of Gynecology and Obstetrics, the American College of Obstetricians and Gynecologists, and the College of American Pathologists. As for the 4 genomic subtypes of endometrial carcinoma (copy number low/p53 wild-type, copy number high/p53 abnormal, polymerase E mutant, and mismatch repair deficient), which only recently have been identified, there is accumulating evidence showing these categories can be reproducibly diagnosed and accurately assessed based on biopsy/curettage specimens as well as hysterectomy specimens. Furthermore, this subclassification system can be adapted for current clinical practice and is of prognostic significance independent of conventional variables used for risk assessment in patients with endometrial carcinoma (eg, stage). It is too soon to recommend the routine use of genomic classification in this setting; however, with further evidence, this system may become the basis for the subclassification of all endometrial carcinomas, supplanting (partially or completely) histotype, and grade. These recommendations were developed from the International Society of Gynecological Pathologists Endometrial Carcinoma project.


Assuntos
Carcinoma Endometrioide/diagnóstico , Neoplasias do Endométrio/diagnóstico , Carcinoma Endometrioide/classificação , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/classificação , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Genômica , Ginecologia , Humanos , Gradação de Tumores , Estadiamento de Neoplasias , Patologistas , Guias de Prática Clínica como Assunto , Prognóstico , Sociedades Médicas
20.
Mod Pathol ; 32(3): 405-414, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30315273

RESUMO

There is currently no blood-based marker in routine use for endometrial cancer patients. Such a marker could potentially be used for early detection, but it could also help to track tumor recurrence following hysterectomy. This is important, as extra-vaginal recurrence of endometrial endometrioid adenocarcinoma is usually incurable. This proof-of-principle study was designed to determine if tumor-associated mutations could be detected in cell-free DNA from the peripheral blood of early and late stage endometrial endometrioid carcinoma patients. Approximately 90% of endometrioid carcinomas have at least one mutation in the genes CTNNB1, KRAS, PTEN, or PIK3CA. Using a custom panel targeting 30 hotspot amplicons in these four genes, next-generation sequencing was performed on cell-free DNA extracted from plasma obtained from a peripheral blood draw at the time of hysterectomy and the matching tumor DNA from 48 patients with endometrioid endometrial carcinomas. At least one mutation in the tumor was detected in 45/48 (94%) of patients. Fifteen of 45 patients (33%) had a mutation in the plasma that matched a mutation in the tumor. These same mutations were not detected in the matched negative control buffy coat. Presence of a plasma mutation was significantly associated with advanced stage at hysterectomy, deep myometrial invasion, lymphatic/vascular invasion, and primary tumor size. Detecting a plasma-based mutation was independent of the amount of cell-free DNA isolated from the plasma. Overall, 18% of early stage patients had a mutation detected in the plasma. These results demonstrate that mutations in genes relevant to endometrial cancer can be identified in the peripheral blood of patients at the time of surgery. Future studies can help to determine the post-operative time course of mutation clearance from the peripheral blood and if mutation re-emergence is predictive of recurrence.


Assuntos
Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Carcinoma Endometrioide/genética , DNA Tumoral Circulante/genética , Neoplasias do Endométrio/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/sangue , Carcinoma Endometrioide/diagnóstico , DNA Tumoral Circulante/sangue , Neoplasias do Endométrio/sangue , Neoplasias do Endométrio/diagnóstico , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/diagnóstico
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