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1.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(3): 373-378, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31631606

RESUMO

Objective: To establish a radiomic model for predicting lymph node (LN) metastasis in patients with non-small cell lung cancer (NSCLC). Methods: The prediction model was developed using a training cohort comprising 100 patients with clinicopathologically confirmed NSCLC. Data were gathered from January 2014 to December 2015. Radiomic features of NSCLC were obtained from non-contrast and enhancement computed tomography (CT). Lasso-logistic regression models were established for data dimension reduction, feature selection, and radiomics signature building. Consistency coefficient ( ICCs) was used to evaluate the consistency between observer interior and interobserver.The consistency index (C-index)is used to evalutate the prediction of lymph node metastasis by using the radiomics signature, shown with the area under the receiver operating characteristic curve ( AUC).Multivariate logistic regression analyses were performed to develop the prediction model, considering radiomics signature and clinicopathologic risk factors. The radiomics model was validated in a validation cohort comprising 100 consecutive NSCLC patients from January 2016 to December 2017 in terms of its calibration and discrimination. AUC was used to evaluate the predictive effectiveness of the model, and Delong test was used to compare models. Hosmer-Lemeshow good of fit test was used to evaluate the calibration of prediction models.The results were represented by correction curves to compare the consistency between the predicted results of the model and the actual probability of LN metastasis. Results: The consistency between observer interior and interobserver was good, with ICCs higher than 0.75.The radiomics signature, including 22 selected features, was associated with LN metastasis. AUC was 0.781 in training cohort and 0.776 in validation cohort. The individualized prediction model identified radiomics signature, neuron specific enolase (CEA), cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), and carbohydrate antigen 125 (CA125) as independent predictors. The model showed good discrimination, with 0.836 AUC in the training cohort, and 0.821 AUC in the validation cohort. The model in both the training and validation cohorts had good calibration,which demonstrated high consistency with the actual LN metastasis. Conclusion: The radiomics model incorporating radiomics signature and clinical risk factors can be conveniently used to facilitate preoperative individualized prediction of LN metastasis in patients with NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Metástase Linfática/diagnóstico , Antígenos de Neoplasias/genética , Antígeno Ca-125/genética , Humanos , Queratina-19/genética , Modelos Logísticos , Linfonodos , Proteínas de Membrana/genética , Fosfopiruvato Hidratase/genética , Valor Preditivo dos Testes , Estudos Retrospectivos
2.
BMC Cancer ; 19(1): 406, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039761

RESUMO

BACKGROUND: CA125 is a well-established ovarian cancer (OC) serum biomarker. The CA125 heavily glycosylated epitope is carried by the MUC16 mucin, a high molecular weight transmembrane mucin. Upon proteolytic cleavage, the extracellular domain of MUC16 is released from the cell surface into malignant ascites and blood vessels. Previous studies have shown that both tumor and surrounding mesothelial cells may express MUC16. Although little is known about the regulation of MUC16 expression in these cells, recent evidence suggest that inflammatory cytokines may stimulate MUC16 expression. Because malignant ascites is a pro-inflammatory environment, we investigated whether OC ascites stimulate the expression and release of MUC16 by human peritoneal mesothelial cells (HPMCs). METHODS: HPMCs were isolated from peritoneal lavages of women operated for conditions other than cancer. MUC16 protein expression was determined by immunoblot, immunofluorescence or immunohistochemistry depending on the experiments. The release of MUC16 from the cell surface was measured using EIA and MUC16 mRNA expression by ddPCR. RESULTS: We show that high-grade serous ascites from patients with OC (n = 5) enhance MUC16 expression in HPMCs. Malignant ascites, but not benign peritoneal fluids, stimulate the release of MUC16 in HPMCs in a dose-dependent manner, which is abrogated by heat inactivation. Moreover, we establish that ascites-induced MUC16 expression occurs at the post-transcriptional level and demonstrate that ascites-induced MUC16 expression is mediated, at least partially, through an Akt-dependent pathway. A cytokine array identified upregulation of several cytokines and chemokines in ascites that mediate MUC16 upregulation versus those that do not, including CCL7, CCL8, CCL16, CCL20, CXCL1, IL-6, IL-10, HGF and IL-1 R4. However, when individually tested, none of these factors affected MUC16 expression or secretion. Concentrations of CA125 in the serum of a given patient did not correlate with the ability of its corresponding ascites to stimulate MUC16 release in HPMCs. CONCLUSIONS: Collectively, these data indicate that mesothelial cells are an important source of MUC16 in the context of ovarian cancer and malignant ascites is a strong modulator of MUC16 expression in HPMCs and uncover the Akt pathway as a driving factor for upregulation of MUC16. Factors in ascites associated with enhanced MUC16 expression and release remains to be identified.


Assuntos
Ascite/metabolismo , Antígeno Ca-125/genética , Antígeno Ca-125/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Neoplasias Ovarianas/metabolismo , Regulação para Cima , Ascite/genética , Ascite/patologia , Linhagem Celular Tumoral , Citocinas/genética , Células Epiteliais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Gradação de Tumores , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Peritônio/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
3.
Scand J Clin Lab Invest ; 79(1-2): 71-74, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30727773

RESUMO

Tumor markers are noninvasive diagnostic tools for cancer. Their abnormal expression often occurs earlier than clinical symptoms or other detection signals. Appropriate reference intervals (RIs) of tumor markers are important for health evaluation, cancer diagnosis, therapy monitoring and prognosis assessment. In this study, we aimed to establish the RIs of cancer antigen 125 (CA125), CA15-3, CA19-9, CA72-4, alpha fetoprotein (AFP), carcino-embryonic antigen (CEA), neuron-specific enolase (NSE) and cytokeratin 19 fragment antigen 21-1 (CYFRA21-1) in apparently healthy Henan population. A total of 1705 apparently healthy participants (21-89 years) were recruited from five representative geographical regions in Henan province. Nonparametric 95th percentile intervals were used to define the RIs of CA125, CA15-3, CA19-9, CA72-4, AFP, CEA, NSE and CYFRA21-1. The test results of CA125, CA15-3, CA19-9, CA72-4, AFP, CEA, NSE and CYFRA21-1 can traceable to reference measurement procedures. The age- and gender-specific RIs of the tumor markers were established. We established age- and gender-specific RIs for CA125, CA15-3, CA19-9, CA72-4, AFP, CEA, NSE and CYFRA21-1. The newly established RIs should be more suitable for Henan population. It will be valuable for clinicians to make a medical diagnosis, therapeutic management decision and other physiological assessment.


Assuntos
Antígenos de Neoplasias/genética , Antígenos Glicosídicos Associados a Tumores/genética , Biomarcadores Tumorais/genética , Antígeno Ca-125/genética , Antígeno CA-19-9/genética , Antígeno Carcinoembrionário/genética , Queratina-19/genética , Mucina-1/genética , Fosfopiruvato Hidratase/genética , alfa-Fetoproteínas/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/sangue , Antígenos Glicosídicos Associados a Tumores/sangue , Biomarcadores Tumorais/sangue , Antígeno Ca-125/sangue , Antígeno CA-19-9/sangue , Antígeno Carcinoembrionário/sangue , China , Feminino , Voluntários Saudáveis , Humanos , Queratina-19/sangue , Masculino , Pessoa de Meia-Idade , Mucina-1/sangue , Fosfopiruvato Hidratase/sangue , Gravidez , Valores de Referência , Fatores Sexuais , alfa-Fetoproteínas/metabolismo
4.
BMC Cancer ; 19(1): 171, 2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30795761

RESUMO

BACKGROUND: Epithelial ovarian cancer (EOC) remains one of the most lethal gynecologic cancers, and its pathogenetic mechanism remains unclear. Here we show that MUC16 promotes the translocation of p120-catenin (p120ctn) to the cytoplasm and consequently activates ras homolog (Rho) GTPases RhoA/Cdc42 activation to modulate the proliferation and migration abilities of EOC cells. METHODS: We collect 94 ovarian cancer (OC) patients' tissue samples to constitute tissue microarray (TMA) and analyze the MUC16 and p120ctn expression levels. Lentivirus transfection is used to overexpress cytoplasmic tail domain (CTD) of MUC16 and CRISPR/Cas9 genome-editing system is firstly used to knock out MUC16 in EOC cells. The proliferation or migration ability of cells is analyzed by MTS or migration assay. RESULTS: We find that MUC16 and p120ctn are aberrantly overexpressed in 94 clinical OC samples compared with benign ovarian tumors (BOT). MUC16 is a critical inducer of the proliferation and migration of EOC cells and the CTD of MUC16 plays an important role during this process. In addition, we reveal the relationship between MUC16 and p120ctn, which has not previously been studied. We show that MUC16 promotes the translocation of p120ctn to the cytoplasm and consequently activates Rho GTPases to modulate the proliferation and migration abilities of EOC cells. The cell proliferation and migration abilities induced by MUC16 are mediated by p120ctn through RhoA/Cdc42 activation. CONCLUSIONS: The highly expressed MUC16 promotes the translocation of p120ctn to the cytoplasm, where it activates RhoA/Cdc42 to modulate the proliferation and migration abilities of EOC cells. These findings may provide new targets for the treatment of EOC.


Assuntos
Antígeno Ca-125/metabolismo , Carcinoma Epitelial do Ovário/metabolismo , Cateninas/metabolismo , Citoplasma/metabolismo , Proteínas de Membrana/metabolismo , Antígeno Ca-125/genética , Carcinoma Epitelial do Ovário/genética , Movimento Celular , Proliferação de Células , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Feminino , Técnicas de Silenciamento de Genes , Humanos , Proteínas de Membrana/genética , Transporte Proteico , Análise Serial de Tecidos , Células Tumorais Cultivadas , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
5.
Proteomics Clin Appl ; 13(4): e1800155, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30790454

RESUMO

PURPOSE: The relationship of lung adenocarcinoma (LUAD)-specific proteases and the mutant profile of cytoskeletal and extracellular matrix proteins (CECMPs) are examined. EXPERIMENTAL DESIGN: Mutant CECMPs are assessed with an automated application of a protease binding, amino acid-based, scoring database. RESULTS: MUC16 (Human Genome Organization symbol for mucin-16 gene) mutants in particular are, more often than not, resistant to matrix-metalloproteases (MMPs) commonly secreted by LUAD cells, and LUAD cases representing the MUC16, MMP resistant mutants have a worse outcome. Similar results are obtained for MUC16 mutants resistant to cathepsins, also commonly secreted by LUAD cells. Analyses also show that MUC16, MMP resistant peptide mutants have greater binding affinities to HLA-A and HLA-B when compared to MUC16, MMP nonresistant peptide mutants. CONCLUSION: These results provide a potential, novel biomarker for lung cancer progression, in particular, protease resistant MUC16 peptides; and suggest a possible mechanism of immune escape entailing the reduction of mutant peptides available for HLA class I binding.


Assuntos
Bases de Dados de Proteínas , Antígenos HLA-A/metabolismo , Antígenos HLA-B/metabolismo , Mutação , Proteínas de Neoplasias/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Antígeno Ca-125/genética , Antígeno Ca-125/metabolismo , Colagenases/genética , Colagenases/metabolismo , Feminino , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/genética , Peptídeos/genética , Peptídeos/metabolismo
6.
J Int Med Res ; 47(1): 96-104, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30198356

RESUMO

OBJECTIVE: This study was performed to investigate the diagnostic accuracy of frozen section (FS) of mucinous borderline ovarian tumors (mBOTs) and the diagnostic value of various risk factors for misdiagnosis. METHODS: Patients with either an FS or permanent pathologic diagnosis of mBOT were included. Optimum cut-off values for serum tumor markers and maximal tumor diameter were determined, and risk factors for underdiagnosis of mucinous malignant ovarian tumors (mMOTs) were evaluated. The sensitivity, specificity, Youden's index, and diagnostic odds ratio of the risk factors were assessed to determine their diagnostic value for mMOTs. RESULTS: Of 121 included patients, 97 were diagnosed with mBOTs by FS. Relatively abnormal cancer antigen 125 (CA125), carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA) levels; bilateral tumors; and specific pathological features showed significant associations with underdiagnosis of mMOTs in the univariate analysis. The presence of specific pathological features was the only significant risk factor in the multivariate analysis. The CA125, CA19-9, and CEA levels and specific pathological features demonstrated certain diagnostic value in detecting malignant cases among FS-diagnosed mBOTs. CONCLUSIONS: In patients with FS-diagnosed mBOT, significant predictors of malignancy were relatively higher CA125, CA19-9, and CEA levels; bilateral tumors; and tumors with specific pathological features.


Assuntos
Adenocarcinoma Mucinoso/diagnóstico , Antígenos Glicosídicos Associados a Tumores/genética , Biomarcadores Tumorais/genética , Antígeno Ca-125/genética , Antígeno Carcinoembrionário/genética , Erros de Diagnóstico/estatística & dados numéricos , Proteínas de Membrana/genética , Neoplasias Ovarianas/diagnóstico , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/cirurgia , Adulto , Feminino , Secções Congeladas , Expressão Gênica , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Estudos Retrospectivos , Fatores de Risco
7.
Biochem Biophys Res Commun ; 506(4): 780-786, 2018 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-30389134

RESUMO

Mutations in oncogenes or tumor suppressors can reprogram tumor metabolism by controlling multiple metabolic changes including glycolysis, glutaminolysis, increased autophagy, and macropinocytosis. Somatic mutations are essential for the development and growth of gastric cancer (GC), but the precise roles of these mutations in GC glucose metabolism remain largely unknown. In this study, we examined cancer genomes in 375 GC samples and demonstrated several glycolysis-related mutations in GC. Of note, loss-of-function mutation in MUC16 gene was identified. Mutated MUC16 predicted a better prognosis in GC patients. Gene set enrichment analysis suggested that mutated MUC16 status was associated with down-regulation of PI3K/Akt/mTOR signaling and Myc expression. GC cells with MUC16 mutations had reduced glycolytic capacity. Subsequently, genetic silencing of MUC16 in SNU16 and SNU5 cells led to significant reduction in glucose uptake, lactate production, extracellular acidification rate, and colony formation ability, indicating the critical regulatory roles of MUC16 in GC glycolysis and tumorigenesis. Specifically, western blotting showed that MUC16 knockdown inhibited PI3K/Akt/mTOR signaling, and reduced the protein level of Myc, which acts as a key transcription factor in regulating glycolysis. Taken together, our findings identify the MUC16-PI3K/Akt/mTOR-Myc axis as a critical signaling cascade that couples genomic mutations to metabolic reprogramming in GC.


Assuntos
Antígeno Ca-125/genética , Glicólise , Proteínas de Membrana/genética , Mutação/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Inativação Gênica , Humanos , Fenótipo , Prognóstico , Neoplasias Gástricas/patologia , Resultado do Tratamento
8.
Sci Rep ; 8(1): 14725, 2018 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-30282979

RESUMO

New plasma and tissue biomarkers of epithelial ovarian cancer (EOC) could improve early diagnosis and post-diagnosis clinical management. Here we investigated tissue staining and tissue secretion of CLIC1 and CLIC4 across EOC subtypes. CLIC1 and CLIC4 are two promising biomarkers we previously showed were elevated in EOC patient sera. Individually, CLIC1 or CLIC4 stained larger percentages of malignant tumors across all EOC subtypes compared with CA125, particularly early stage and mucinous tumors. CLIC4 also stained benign tumors but staining was limited to nuclei; whereas malignant tumors showed diffuse cellular staining of stromal and tumor cells. Both proteins were shed by all EOC subtypes tumors in short term organ culture at more consistent levels than CA125, supporting their potential as pan-subtype serum and tissue biomarkers. Elevated CLIC4 expression, but not CLIC1 expression, was a negative indicator of patient survival, and CLIC4 knockdown in cultured cells decreased cell proliferation and migration indicating a potential role in tumor progression. These results suggest CLIC1 and CLIC4 are promising serum and tissue biomarkers as well as potential therapeutic targets for all EOC subtypes. This justifies development of high throughput serum/plasma biomarker assays to evaluate utility of a biomarker panel consisting of CLIC1, CLIC4 and CA125.


Assuntos
Antígeno Ca-125/genética , Carcinoma Epitelial do Ovário/genética , Canais de Cloreto/genética , Proteínas de Membrana/genética , Idoso , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Antígeno Ca-125/sangue , Carcinoma Epitelial do Ovário/sangue , Carcinoma Epitelial do Ovário/diagnóstico , Canais de Cloreto/sangue , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Membrana/sangue , Pessoa de Meia-Idade
9.
J Transl Med ; 16(1): 259, 2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-30236127

RESUMO

BACKGROUND: MUC4 is a membrane-bound mucin that promotes carcinogenetic progression and is often proposed as a promising biomarker for various carcinomas. In this manuscript, we analyzed large scale genomic datasets in order to evaluate MUC4 expression, identify genes that are correlated with MUC4 and propose new signatures as a prognostic marker of epithelial cancers. METHODS: Using cBioportal or SurvExpress tools, we studied MUC4 expression in large-scale genomic public datasets of human cancer (the cancer genome atlas, TCGA) and cancer cell line encyclopedia (CCLE). RESULTS: We identified 187 co-expressed genes for which the expression is correlated with MUC4 expression. Gene ontology analysis showed they are notably involved in cell adhesion, cell-cell junctions, glycosylation and cell signaling. In addition, we showed that MUC4 expression is correlated with MUC16 and MUC20, two other membrane-bound mucins. We showed that MUC4 expression is associated with a poorer overall survival in TCGA cancers with different localizations including pancreatic cancer, bladder cancer, colon cancer, lung adenocarcinoma, lung squamous adenocarcinoma, skin cancer and stomach cancer. We showed that the combination of MUC4, MUC16 and MUC20 signature is associated with statistically significant reduced overall survival and increased hazard ratio in pancreatic, colon and stomach cancer. CONCLUSIONS: Altogether, this study provides the link between (i) MUC4 expression and clinical outcome in cancer and (ii) MUC4 expression and correlated genes involved in cell adhesion, cell-cell junctions, glycosylation and cell signaling. We propose the MUC4/MUC16/MUC20high signature as a marker of poor prognostic for pancreatic, colon and stomach cancers.


Assuntos
Antígeno Ca-125/genética , Bases de Dados Genéticas , Genoma Humano , Genômica , Proteínas de Membrana/genética , Mucina-4/genética , Mucinas/genética , Antígeno Ca-125/metabolismo , Linhagem Celular Tumoral , Análise por Conglomerados , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Humanos , Proteínas de Membrana/metabolismo , Mucina-4/metabolismo , Mucinas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Curva ROC , Análise de Sobrevida
10.
JAMA Oncol ; 4(12): 1691-1698, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30098163

RESUMO

Importance: MUC16, which encodes cancer antigen 125 (CA-125), is frequently mutated in gastric cancer (GC); however, its association with tumor mutation load (TML) and outcome in patients with GC has not been established, to date. Objective: To investigate whether MUC16 mutations are associated with TML and prognosis in patients with GC. Design, Setting, and Participants: Statistical analysis of genomic data from 437 GC samples obtained from The Cancer Genome Atlas (TCGA) and 256 samples from an Asian cohort. Both cohorts contained data of patients with GC involved in previous genomic studies. Data were obtained from TCGA on September 3, 2017, and from the Asian cohort on March 5, 2013, and analyzed from September 3 to December 1, 2017. The TCGA cohort was used as a discovery set and the Asian cohort as a validation set. Kaplan-Meier survival analysis and multivariate Cox and logistic regression models were applied. Regression models addressed confounding factors; Bayesian variant nonnegative matrix factorization was used to extract mutational signatures. The MutSigCV algorithm was used to identify significantly mutated genes. Main Outcomes and Measures: Primary outcomes were mutation frequency, overall survival, and TML, calculated using Kaplan-Meier survival analysis, odds ratios (ORs), and significance of signaling pathways. Results: MUC16 was mutated in 168 of 437 (38.4%) of the GC samples from the TCGA cohort and in 57 of 256 (22.3%) from the Asian cohort. In both cohorts, GC samples with MUC16 mutations exhibited significantly greater TML than those without MUC16 mutations (median mutation counts: TCGA cohort, 264 with MUC16 mutation vs 115 without; Asian cohort, 134 with MUC16 mutation vs 74 without; Wilcoxon rank sum test, both P < .001). This association was independent of mutations in POLE and BRCA1/2 and mutational signatures in the TCGA cohort (OR, 1.87; 95% CI, 1.49-2.36; P < .001) and the Asian cohort (OR, 1.69; 95% CI, 1.25-2.29; P < .001). MUC16 mutations were significantly associated with better prognosis in both cohorts (median overall survival, 46.9 [95% CI, 26.4-NA (not available)] vs 26.7 [95% CI, 20.2-43.1] months; log-rank test, P = .007 [TCGA cohort] and not calculable [the median overall survival of patients with GC and MUC16 mutations could not be calculated because more than half the patients in the group were alive] vs 36.8 months; P = .04 [Asian cohort]). The association remained statistically significant after controlling for age, sex, TNM stage, mutations in POLE and BRCA1/2, and mutational signatures (hazard ratio, 0.61 [95% CI, 0.42-0.89]; log rank test, P = .01). Immune response and cell cycle regulation circuits were among the top altered signaling pathways in samples with MUC16 mutations (normalized enrichment score, 1.70 [95% CI, 1.57-1.79] and 2.04 [95% CI, 1.90-2.18]; adjusted P < .001). The prognostic significance of MUC16 mutation identified in the TCGA cohort was validated in the Asian cohort. Conclusions and Relevance: These findings indicate that MUC16 mutations may be associated with higher TML, better survival outcomes, and immune response and cell cycle pathways. These findings may be immediately applicable for guiding immunotherapy treatment for patients with GC.


Assuntos
Adenocarcinoma/genética , Antígeno Ca-125/genética , Proteínas de Membrana/genética , Taxa de Mutação , Neoplasias Gástricas/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia
11.
Expert Opin Ther Targets ; 22(8): 675-686, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29999426

RESUMO

INTRODUCTION: MUC16 is overexpressed in multiple cancers and plays an important role in tumorigenicity and acquired resistance to therapy. Area covered: In this review, we describe the role of MUC16 under normal physiological conditions and during tumorigenesis. First, we provide a summary of research on MUC16 from its discovery as CA125 to present anti-MUC16 therapy trials that are currently in the initial phases of clinical testing. Finally, we discuss the reasons for the limited effectiveness of these therapies and discuss the direction and focus of future research. Expert opinion: Apart from its protective role in normal physiology, MUC16 contributes to disease progression and metastasis in several malignancies. Due to its aberrant overexpression, it is a promising target for diagnosis and therapy. Cleavage and shedding of its extracellular domain is the major barrier for efficient targeting of MUC16-expressing cancers. Concerted efforts should be undertaken to target the noncleaved cell surface retained portion of MUC16. Such efforts should be accompanied by basic research to understand MUC16 cleavage and decipher the functioning of MUC16 cytoplasmic tail. While previous efforts to activate anti-MUC16 immune response using anti-CA125 idiotype antibodies have met with limited success, ideification of neo-antigenic epitopes in MUC16 that correlate with improved survival have raised raised hopes for developing MUC16-targeted immunotherapy.


Assuntos
Antígeno Ca-125/genética , Proteínas de Membrana/genética , Terapia de Alvo Molecular , Neoplasias/terapia , Animais , Antígeno Ca-125/imunologia , Progressão da Doença , Epitopos/imunologia , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoterapia/métodos , Proteínas de Membrana/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Sobrevida
12.
Int J Mol Sci ; 19(7)2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30011875

RESUMO

Optimal research results rely on the selection of cellular models capable of recapitulating the characteristics of primary tumours from which they originate. The expression of mucins (MUC16 and MUC1) and truncated O-glycans (Tn, STn and T) represents a characteristic footprint of serous ovarian carcinomas (SOCs). Therefore, selecting ovarian cancer (OVCA) cell lines that reflect this phenotype is crucial to explore the putative biological role of these biomarkers in the SOC setting. Here, we investigated a panel of OVCA cell lines commonly used as SOC models, and tested whether, when cultured in 2D and 3D conditions, these recapitulate the mucin and O-glycan expression profiles of SOCs. We further explored the role of truncating the O-glycosylation capacity in OVCAR3 cells through knockout of the COSMC chaperone, using in vitro and in vivo assays. We found that the majority of OVCA cell lines of serous origin do not share the mucin and truncated O-glycan footprint of SOCs, although 3D cultures showed a higher resemblance. We also found that genetic truncation of the O-glycosylation capacity of OVCAR3 cells did not enhance oncogenic features either in vitro or in vivo. This study underscores the importance of well-characterized cellular models to study specific features of ovarian cancer.


Assuntos
Antígeno Ca-125/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Proteínas de Membrana/metabolismo , Mucina-1/metabolismo , Neoplasias Ovarianas/metabolismo , Polissacarídeos/metabolismo , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Antígeno Ca-125/genética , Linhagem Celular Tumoral , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Feminino , Perfilação da Expressão Gênica , Glicosilação , Humanos , Proteínas de Membrana/genética , Camundongos Nus , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Mucina-1/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fenótipo , Transplante Heterólogo
13.
J Ovarian Res ; 11(1): 47, 2018 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-29903044

RESUMO

BACKGROUND: The clinical treatment of ovarian cancer with ascites is problematic. The main reasons for treatment failure are the susceptibility to intraperitoneal metastasis and chemotherapeutic drug resistance. The purpose and significance of this study is to evaluate which marker might evaluate treatment efficacy and improve the cure rate. RESULTS: This study compared a no chemotherapy group with a chemotherapy group regarding the determination of carbohydrate antigen 125 and human epididymis protein 4 in ovarian cancer ascitic supernatants and cross-analyzed routine serum carbohydrate antigen 125 levels. The level of human epididymis protein 4 in the ascites of the chemotherapy group was significantly lower than that of the no chemotherapy group (p < 0.001). Moreover, the expression of ascitic human epididymis protein 4 correlated positively with serum carbohydrate antigen 125 levels (p < 0.001). MDR was positive in 13 of the 30 samples (43.33%) in the chemotherapy group with highly expressed CA125. CONCLUSION: The level of human epididymis protein 4 in ovarian cancer ascites may reflect the therapeutic effect of ovarian cancer patients, and a high level of human epididymis protein 4 might predict chemoresistance and the possibility of ascites formation. The determination of the expression of human epididymis protein 4 alone or combined with carbohydrate antigen 125 levels in both serum and ascites in ovarian cancer patients with ascites may have important significance for guiding and improving the treatment regimen.


Assuntos
Ascite/tratamento farmacológico , Antígeno Ca-125/genética , Neoplasias Ovarianas/tratamento farmacológico , Proteínas/genética , Adulto , Idoso , Ascite/complicações , Ascite/genética , Ascite/patologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Antígeno Ca-125/sangue , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Falha de Tratamento
14.
Mikrochim Acta ; 185(7): 331, 2018 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-29915871

RESUMO

The authors describe a method for enhancing the hybridization chain reaction (HCR) by using gold nanoparticles (AuNPs). This can considerably improve the sensitivity of electrochemical immunoassays as demonstrated for the carbohydrate antigen 125 (CA125), a biomarker for ovarian cancer. Compared to previous HCR based assays, the DNA acting as fuel strands were immobilized onto AuNPs, so that dendrimeric like chains were formed on the electrode after HCR. The improved signal is due to the reaction of DNA on the electrode. Specifically, the reaction of the phosphate groups of DNA with molybdate forms redox-active molybdophosphate, and this generates a strong electrochemical current. The immunosensor was prepared by sequential capturing, on the electrode, (a) antibody against CA125, (b) analyte (CA125), and (c) an aptamer against CA125 to form a sandwich structure. The primer on the aptamer sequence initiates HCR by annealing to one strand of DNA on the AuNPs and to another DNA in solution. The increased loading of DNA molecules onto the electrode increases the amount of phosphate groups and subsequently increases the electrical signal. The sensitivity of the assay is found to be significantly improved compared to assays without HCR and when using conventional HCR. The immunosensor was successfully applied to the determination of CA125 in human serum samples. The detection limit (based on an S/N ratio of 3) is 50 µU.mL-1. This indicates that this signal amplification strategy has a large potential in terms of clinical applications. It may be modified such that it also can be applied to the determination of other analytes for which proper aptamers are available. Graphical abstract Gold nanoparticle (AuNP) enhanced hybridization chain reaction is reported to improve the sensitivity of electrochemical immunosensor. Hybridization chain reaction is carried out by annealing of H1 DNA strand immobilized on AuNP to the sticky end primer sequence of the aptamer and H2 strand to the complementary sequence of H1.


Assuntos
Antígeno Ca-125/sangue , Ouro , Nanopartículas Metálicas , Neoplasias Ovarianas/diagnóstico , Biomarcadores Tumorais/sangue , Antígeno Ca-125/genética , Técnicas Eletroquímicas , Feminino , Humanos , Imunoensaio , Hibridização de Ácido Nucleico , Neoplasias Ovarianas/sangue
15.
PLoS One ; 13(5): e0197029, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29738555

RESUMO

Mesothelin is a cell surface protein that is overexpressed in numerous cancers, including breast, ovarian, lung, liver, and pancreatic tumors. Aberrant expression of mesothelin has been shown to promote tumor progression and metastasis through interaction with established tumor biomarker CA125. Therefore, molecules that specifically bind to mesothelin have potential therapeutic and diagnostic applications. However, no mesothelin-targeting molecules are currently approved for routine clinical use. While antibodies that target mesothelin are in development, some clinical applications may require a targeting molecule with an alternative protein fold. For example, non-antibody proteins are more suitable for molecular imaging and may facilitate diverse chemical conjugation strategies to create drug delivery complexes. In this work, we engineered variants of the fibronectin type III domain (Fn3) non-antibody protein scaffold to bind to mesothelin with high affinity, using directed evolution and yeast surface display. Lead engineered Fn3 variants were solubly produced and purified from bacterial culture at high yield. Upon specific binding to mesothelin on human cancer cell lines, the engineered Fn3 proteins internalized and co-localized to early endosomes. To our knowledge, this is the first report of non-antibody proteins engineered to bind mesothelin. The results validate that non-antibody proteins can be engineered to bind to tumor biomarker mesothelin, and encourage the continued development of engineered variants for applications such as targeted diagnostics and therapeutics.


Assuntos
Domínio de Fibronectina Tipo III/genética , Proteínas Ligadas por GPI/genética , Neoplasias/genética , Engenharia de Proteínas/métodos , Anticorpos Monoclonais/farmacologia , Biomarcadores Tumorais/genética , Antígeno Ca-125/genética , Linhagem Celular Tumoral , Proteínas Ligadas por GPI/uso terapêutico , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Proteínas Associadas à Matriz Nuclear/genética , Ligação Proteica
16.
Cancer Biol Ther ; 19(7): 622-630, 2018 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-29652548

RESUMO

The tumor-shed antigen CA125 has recently been found to bind certain monoclonal antibodies (mAbs) and suppress immune-effector mediated killing through perturbation of the Fc domain with CD16a and CD32a Fc-γ activating receptors on immune-effector cells. Amatuximab is a mAb targeting mesothelin whose mechanism of action utilizes in part antibody-dependent cellular cytotoxicity (ADCC). It is being tested for its therapeutic activity in patients with mesothelioma in combination with first line standard-of-care. To determine if CA125 has immunosuppressive effects on amatuximab ADCC and associated clinical outcomes, post hoc subgroup analysis of patients from a Phase 2 study with primary diagnosed stage III/IV unresectable mesothelioma treated with amatuximab plus cisplatin and pemetrexed were conducted. Analysis found patients with baseline CA125 levels no greater than 57 U/m (∼3X the upper limit of normal) had a 2 month improvement in progression free survival (HR = 0.43, p = 0.0062) and a 7 month improvement in overall survival (HR = 0.40, p = 0.0022) as compared to those with CA125 above 57 U/mL. In vitro studies found that CA125 was able to bind amatuximab and perturb ADCC activity via decreased Fc-γ-receptor engagement. These data suggest that clinical trial designs of antibody-based drugs in cancers producing CA125, including mesothelioma, should consider stratifying patients on baseline CA125 levels for mAbs that are experimentally determined to be bound by CA125.


Assuntos
Anticorpos Monoclonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno Ca-125/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Membrana/metabolismo , Mesotelioma/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Idoso , Anticorpos Monoclonais/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno Ca-125/sangue , Antígeno Ca-125/genética , Antígeno Ca-125/imunologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Feminino , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Proteínas de Membrana/sangue , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Mesotelioma/sangue , Mesotelioma/mortalidade , Mesotelioma/patologia , Pessoa de Meia-Idade , Pemetrexede/farmacologia , Pemetrexede/uso terapêutico , Neoplasias Pleurais/sangue , Neoplasias Pleurais/mortalidade , Neoplasias Pleurais/patologia , Intervalo Livre de Progressão , RNA Interferente Pequeno/metabolismo , Receptores de IgG/imunologia , Receptores de IgG/metabolismo
17.
Cancer Epidemiol Biomarkers Prev ; 27(7): 790-804, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29661801

RESUMO

Background: Neoplastic and non-neoplastic events may raise levels of mucins, CA15.3, and CA125, and generate antibodies against them, but their impact on epithelial ovarian cancer (EOC) risk has not been fully defined.Methods: CA15.3, CA125, and IgG1 antibodies against them were measured in 806 women who developed EOC and 1,927 matched controls from the European Prospective Investigation of Nutrition and Cancer. Associations between epidemiologic factors and anti-mucin antibodies were evaluated using generalized linear models; EOC risks associated with anti-mucin antibodies, by themselves or in combination with respective antigens, were evaluated using conditional logistic regression.Results: In controls, lower antibodies against both mucins were associated with current smoking; and, in postmenopausal women, higher levels with longer oral contraceptive use and later-age-at and shorter-interval-since last birth. Lower anti-CA15.3 antibodies were associated with higher body mass and, in premenopausal women, more ovulatory cycles. Higher anti-CA15.3 and anti-CA125 antibodies were associated with higher risk for mucinous EOC occurring ≥ 3 years from enrollment. Long-term risk for serous EOC was reduced in women with low CA125 and high anti-CA125 antibodies relative to women with low concentrations of both.Conclusions: We found general support for the hypothesis that anti-mucin antibody levels correlate with risk factors for EOC. Antibodies alone or in combinations with their antigen may predict longer term risk of specific EOC types.Impact: Anti-CA125 and anti-CA15.3 antibodies alone or in perspective of antigens may be informative in the pathogenesis of EOC subtypes, but less useful for informing risk for all EOC. Cancer Epidemiol Biomarkers Prev; 27(7); 790-804. ©2018 AACR.


Assuntos
Biomarcadores Tumorais/genética , Antígeno Ca-125/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Estudos Prospectivos , Fatores de Risco
18.
Drug Deliv ; 25(1): 797-806, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29542355

RESUMO

Ovarian cancer is the leading cause of cancer death among gynecological malignancies. The high mortality rate has not been significantly reduced despite advances in surgery and chemotherapy. Gene therapy shows therapeutic potential, but several key issues must be resolved before clinical application. To minimize toxicity in noncancerous tissues, tumor-specific ligands are conjugated to vectors to increase the selectivity of drug delivery. The expression pattern of follicle-stimulating hormone (FSH) receptor in normal and cancer tissues provides an opportunity for highly selective drug delivery in ovarian cancer. Furthermore, tumor-specific promoters can conditionally regulate therapeutic gene expression in tumor or normal tissues. The mucin 16 (MUC16) promoter might be a potential tool to drive ovarian cancer-localized gene expression since MUC16/CA125 is overexpressed in most ovarian carcinomas. Here, we screened the possible MUC16 promoter sequences and constructed MUC16 promoter-driven gro-α shRNA plasmid vectors. The vectors were specifically delivered into ovarian cancer cells via FSH peptide-conjugated nanoparticles. The predicted promoter sequence with TAAA repeats showed high transcriptional activity. The nanoparticle complex containing MUC16 promoter-driven gro-α shRNA and FSH peptides had the ability to decrease gro-α protein secretion in ovarian cancer cells and block tumor growth without obvious toxic effects in a nude mouse model bearing ovarian cancer. Our study provides a novel gene delivery system using a MUC16 promoter trigger and FSH peptide-mediated active targeting in ovarian cancer, and this system may be a promising strategy for specific genetic therapeutic delivery.


Assuntos
Subunidade beta do Hormônio Folículoestimulante/administração & dosagem , Proteínas de Membrana/antagonistas & inibidores , Nanopartículas/química , Neoplasias Ovarianas/terapia , Regiões Promotoras Genéticas , RNA Interferente Pequeno/administração & dosagem , Terapêutica com RNAi/métodos , Animais , Antígeno Ca-125/genética , Antígeno Ca-125/metabolismo , Carcinoma/metabolismo , Carcinoma/patologia , Carcinoma/terapia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Quimiocina CXCL1/antagonistas & inibidores , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Biologia Computacional , Feminino , Subunidade beta do Hormônio Folículoestimulante/química , Subunidade beta do Hormônio Folículoestimulante/metabolismo , Subunidade beta do Hormônio Folículoestimulante/uso terapêutico , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia Eletrônica de Transmissão , Nanopartículas/ultraestrutura , Invasividade Neoplásica/prevenção & controle , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Transplante de Neoplasias , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Tamanho da Partícula , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/uso terapêutico , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/uso terapêutico , Propriedades de Superfície , Carga Tumoral
19.
Cancer Lett ; 418: 167-175, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29337110

RESUMO

Pancreatic cancer is the most lethal tumor. CA125 (gene symbol MUC16) is an important serum marker for pancreatic cancer diagnosis and treatment. High serum CA125 is related to metabolic tumor burden and poor prognosis. The circulating Treg subset is another independent prognostic factor for pancreatic cancer. Our unpublished data indicated that the circulating Treg proportion might be related to the serum CA125 level. However, the potential relationship and underlying mechanism of MUC16 and Treg in pancreatic cancer tissues remain unclear. In this study, we found that pancreatic cancer tissues were positive for both MUC16 C terminal (MUC16c) and Foxp3 expression and that their expression was correlated. MUC16c released into the cytoplasm via EGF induction significantly increased IL-6 expression and secretion. The PI3K/AKT pathway may participate in the regulation of IL-6 expression and secretion. By treating CD4+ T cells with IL-6 or co-culturing the cells with pancreatic cancer cells, tumor-derived IL-6 was identified to promote Foxp3 expression and Treg differentiation, which was significantly inhibited by the JAK2 inhibitor AG-490. In sum, our study demonstrated that the relationship between the MUC16c level and Foxp3 expression in the local tumor environment was consistent with that of the serum CA125 level and circulating Treg proportion in the systemic environment. MUC16c promoted Foxp3 expression and tumor-associated Treg enrichment in tumor tissues through tumor-secreted IL-6 activation of the JAK2/STAT3 pathway. These findings may provide deeper insight into potential pancreatic cancer therapy approaches.


Assuntos
Antígeno Ca-125/imunologia , Interleucina-6/imunologia , Proteínas de Membrana/imunologia , Neoplasias Pancreáticas/imunologia , Linfócitos T Reguladores/imunologia , Antígeno Ca-125/genética , Antígeno Ca-125/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Estimativa de Kaplan-Meier , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Transdução de Sinais/imunologia , Linfócitos T Reguladores/metabolismo
20.
Nature ; 551(7681): 512-516, 2017 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-29132146

RESUMO

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies.


Assuntos
Antígenos de Neoplasias/imunologia , Proteínas de Bactérias/imunologia , Sobreviventes de Câncer , Reações Cruzadas/imunologia , Neoplasias Pancreáticas/imunologia , Linfócitos T Citotóxicos/imunologia , Adenocarcinoma/sangue , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Antígenos de Neoplasias/genética , Proteínas de Bactérias/sangue , Proteínas de Bactérias/genética , Antígeno Ca-125/genética , Antígeno Ca-125/imunologia , Simulação por Computador , Reações Cruzadas/genética , Humanos , Imunoterapia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/genética , Prognóstico , Análise de Sobrevida , Linfócitos T Citotóxicos/citologia , Sequenciamento Completo do Exoma
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