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1.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(9): 1044-1052, 2020.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33051417

RESUMO

OBJECTIVES: To analyze the expression level of ubiquitin conjugating enzyme E2C (UBE2C) in lung adenocarcinoma and its clinical significance. METHODS: The differences in mRNA and protein expression levels of UBE2C in normal lung tissues and lung adenocarcinoma (LUAD) tissues were determined with the Cancer Genome Atlas (TCGA), Oncomine, and human protein atlas (HPA) databases. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic value of UBE2C in LUAD. The correlation between UBE2C and LUAD clinicopathological parameters, as well as its relationship with LUAD prognosis was analyzed based on TCGA, International Cancer Genome Consortium (ICGC), and cbioPortal databases. Gene set enrichment analysis (GSEA) was used to analyze the possible pathways of UBE2C in the progression of LUAD. RESULTS: The mRNA expression level of UBE2C was higher in LUAD tissues than in the normal lung tissues (P<0.01) and it was positively correlated with TNM and N stages (both P<0.05). The UBE2C protein expression level was also increased in LUAD tissues than in the normal lung tissues (P<0.01). ROC curve analysis indicated that UBE2C could be used as an auxiliary diagnostic index for LUAD (AUC=0.969, 95% CI 0.953 to 0.984, P<0.01). Survival analysis showed that the overall survival (OS) of UBE2C high expression group was significantly lower than that of low expression group (P<0.05). The OS of LUAD patients with UBE2C change was lower than that of patients without change (P<0.01). UBE2C was highly expressed in the gene set relevant to cell cycle, p53 signaling pathway, DNA mismatch repair, and DNA replication (all P<0.01). CONCLUSIONS: The expression level of UBE2C is significantly up-regulated in LUAD tissues. The high expression or genetic alteration of UBE2C indicates poor prognosis in LUAD patients. UBE2C can be used as a potential molecular diagnostic marker for LUAD and a potential target for LUAD treatment.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Adenocarcinoma/genética , Adenocarcinoma de Pulmão/genética , Humanos , Pulmão , Neoplasias Pulmonares/genética , Prognóstico , Enzimas de Conjugação de Ubiquitina/genética
2.
Medicine (Baltimore) ; 99(41): e22707, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031343

RESUMO

RATIONALE: Anlotinib has been proved to be effective in advanced refractory non-small cell lung cancer. PATIENT CONCERNS: A 47-year-old female non-smoker was admitted due to persistent chest tightness for a month. DIAGNOSES: Epidermal growth factor receptor (EGFR) wild-type advanced primary lung adenocarcinoma without brain or bone metastasis. INTERVENTIONS: The patient failed 2 lines of pemetrexed/docetaxel plus carboplatin and third-line erlotinib. Fourth-line anlotinib was administered thereafter. OUTCOMES: The pulmonary lesions showed partial remission 5 months after anlotinib monotherapy. The patient demonstrated a progression-free survival of more than 7 months and an overall survival of >12 months. The adverse events including hypertension and fatigue were well-tolerated. LESSONS: Salvage anlotinib might be a reasonable choice in EGFR wild-type lung adenocarcinoma after failure of chemotherapy. Further well-designed trials are warranted to verify this occasional finding.


Assuntos
Adenocarcinoma/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Quinolinas/uso terapêutico , Adenocarcinoma/genética , Feminino , Genes erbB-1 , Humanos , Neoplasias Pulmonares/genética , Pessoa de Meia-Idade , Terapia de Salvação
3.
PLoS One ; 15(8): e0238380, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866185

RESUMO

Pancreatic adenocarcinoma is characterized by a complex tumor environment with a wide diversity of infiltrating stromal and immune cell types that impact the tumor response to conventional treatments. However, even in this poorly responsive tumor the extent of T cell infiltration as determined by quantitative immunohistology is a candidate prognostic factor for patient outcome. As such, even more comprehensive immunophenotyping of the tumor environment, such as immune cell type deconvolution via inference models based on gene expression profiling, holds significant promise. We hypothesized that RNA-Seq can provide a comprehensive alternative to quantitative immunohistology for immunophenotyping pancreatic cancer. We performed RNA-Seq on a prospective cohort of pancreatic tumor specimens and compared multiple approaches for gene expression-based immunophenotyping analysis compared to quantitative immunohistology. Our analyses demonstrated that while gene expression analyses provide additional information on the complexity of the tumor immune environment, they are limited in sensitivity by the low overall immune infiltrate in pancreatic cancer. As an alternative approach, we identified a set of genes that were enriched in highly T cell infiltrated pancreatic tumors, and demonstrate that these can identify patients with improved outcome in a reference population. These data demonstrate that the poor immune infiltrate in pancreatic cancer can present problems for analyses that use gene expression-based tools; however, there remains enormous potential in using these approaches to understand the relationships between diverse patterns of infiltrating cells and their impact on patient treatment outcomes.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Linfócitos T/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
4.
Tokai J Exp Clin Med ; 45(3): 113-116, 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-32901897

RESUMO

Mutations in the gene encoding epidermal growth factor receptor (EGFR) are the most frequent driver mutations in lung adenocarcinoma in Japan. Exon 19 deletion and L858R mutation in exon 21 are the most common EGFR mutations. Uncommon mutations, such as G719X, S768I, and L861Q, and compound mutations, combinations of 2 common or uncommon mutations, have also been reported. EGFR tyrosine kinase inhibitors (TKIs) are effective against cancers harboring common mutations; however, their efficacy against cancers with uncommon or compound mutations remains unclear. We report the case of a 67-year-old man with lung adenocarcinoma (clinical stage IIIA [cT1N2M0]), harboring an uncommon compound mutation, G719X and S768I. The cancer progressed within 2 months of initial chemoradiotherapy. Treatment with afatinib (40 mg/day) produced a partial response, which was maintained for 17 months with continued treatment. A literature review revealed that lung cancer with G719X/S768I compound mutation exhibited good response to EGFR-TKIs, even better than that of lung cancers with single uncommon mutations.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Afatinib/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Receptores ErbB/genética , Éxons/genética , Deleção de Genes , Humanos , Masculino , Resultado do Tratamento
5.
Medicine (Baltimore) ; 99(35): e21895, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871920

RESUMO

MicroRNAs (miRNAs) refers to a small, short non-coding RNA of endogenous class. They have shown to have an increasingly altered expression in many types of cancer, including colorectal cancer (CRC).In the present study, miRNA TaqManMGB and qRT-PCR was used to quantify the expression and clinical significance of 3 mature human miRNA in 82 pairs of colorectal adenocarcinoma tissues and normal adjacent tissue samples (NATS) collected from patients of the south-east part of Romania. Differences between CRC and NATS were analyzed using Wilcoxon test, while correlations between miRNAs expression levels and clinicopathological features were examined using non-parametric tests. In addition, the ability of selected miRNAs to function as biomarkers and, as potential indicators in CRC prognosis was also examined.When the miRNA expression was compared in CRC related NATS, miR-143, and miR-145 were significantly underexpressed (4.99 ±â€Š-1.02 vs -5.66 ±â€Š-1.66, P < .001; -4.85 ±â€Š-0.59 vs -9.27 ±â€Š-1.51, P < .001, respectively), while the pattern of miR-92a was significantly overexpressed (-5.55 ±â€Š-2.83 vs -4.92 ±â€Š-2.44, P < .001). Moreover, the expression levels of selected miRNAs were identified to be correlated with gradual increases in fold change expression with the depth of tumor invasion, lymph node invasion, and maximal increases with distant metastasis. Furthermore, the receiver operating characteristic analysis demonstrated that potential diagnostic of miR-143, miR-145, and miR-92a in discriminating CRC from NATS, with the area under the curve of 0.74, 0.85, and 0.84 respectively. The Kaplan-Meier and the log-rank test showed that a high level of miR-92a and low levels of miR-143 and miR-145 predicted poor survival rate in our cohorts.In conclusion, we can summarize that miR-145 and miR-143 are decreased, while miR-92 is increased in CRC compared to NATS, and associated with different stages of CRC pathogenesis. Thus, the expression of selected miRNAs can represent potential diagnostic and prognostic tools in patients with CRC from Romania.


Assuntos
Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/genética , Neoplasias Colorretais/diagnóstico , MicroRNAs/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Idoso , Área Sob a Curva , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Romênia , Transcriptoma
6.
Anticancer Res ; 40(10): 5765-5776, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988904

RESUMO

BACKGROUND/AIM: We evaluated the safety, feasibility, and preliminary efficacy of Wilms tumor gene 1 (WT1) peptide and Mucin 1 (MUC1)-pulsed dendritic cell (DC) (WT1/MUC1-DC) vaccination as an adjuvant immunotherapy for surgically resectable pancreatic ductal adenocarcinoma (PDA) patients. PATIENTS AND METHODS: Eligible patients were administered WT1/MUC1-DC vaccination at least seven times every 2 weeks with concomitant adjuvant chemotherapy after surgical resection of PDA. RESULTS: Ten patients were enrolled and no Grade 2 or higher toxicities were associated with DC vaccination. The estimated overall survival (OS) and relapse-free survival (RFS) at 3-years from the time of surgical resection were 77.8% and 35.0%, respectively. Immunohistochemical analysis suggested a possible relationship between induction of WT1-specific cytotoxic T lymphocyte after DC vaccination and higher infiltration of CD3/CD4/CD8 lymphocytes in tumor tissues. CONCLUSION: WT1/MUC1-DC vaccination in the adjuvant setting was safe and well-tolerated in PDA patients after tumor resection. A large-scale prospective study is warranted to evaluate the clinical benefit of this modality.


Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Mucina-1/genética , Proteínas WT1/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Quimioterapia Adjuvante/métodos , Células Dendríticas/imunologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Humanos , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade , Mucina-1/uso terapêutico , Proteínas WT1/uso terapêutico
7.
Anticancer Res ; 40(10): 5411-5416, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988861

RESUMO

BACKGROUND: Patients with inflammatory bowel disease have markedly increased risk for developing colitis-associated colorectal adenocarcinoma (CAC). There is no established prognostic biomarker for CAC. MATERIALS AND METHODS: A retrospective study was performed on a cohort of 57 CACs. Expression of caudal type homeobox transcription factor 2 (CDX2) and YES-associated protein 1 (YAP1) expression was correlated with clinicodemographic and histopathological features. RESULTS: Neither YAP1 nor CDX2 expression alone was significantly associated with tumor invasion beyond the muscularis propria or lymph node status. However, a subgroup of CAC with double negativity for expression of YAP1 and CDX2 was more frequently found in younger patients, and more frequently associated with higher pathological tumor stage and nodal metastasis. Furthermore, a positive correlation between CDX2 and YAP1 expression was identified in CAC and sporadic colorectal adenocarcinoma. CONCLUSION: Our study demonstrates that double negativity for expression of YAP1 and CDX2 defines a subgroup of CAC with early onset and aggressive clinical features.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Fator de Transcrição CDX2/genética , Colite/genética , Neoplasias Colorretais/genética , Fatores de Transcrição/genética , Adenocarcinoma/complicações , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Biomarcadores Tumorais/genética , Colite/complicações , Colite/patologia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/patologia , Feminino , Humanos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico
8.
APMIS ; 128(11): 563-572, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32794589

RESUMO

Neuroendocrine tumors (NETs) are often diagnosed from the metastases of an unknown primary tumor. Specific immunohistochemical (IHC) markers indicating the location of a primary tumor are needed. The proprotein convertase subtilisin/kexin type 2 (PCSK2) is found in normal neural and neuroendocrine cells, and known to express in NETs. We investigated the tissue microarray (TMA) of 86 primary tumors from 13 different organs and 9 metastatic NETs, including primary tumor-metastasis pairs, for PCSK2 expression with polymer-based IHC. PCSK2 was strongly positive in all small intestine and appendiceal NETs, the so-called midgut NETs, in most pheochromocytomas and paragangliomas, and in some of the typical and atypical pulmonary carcinoid tumors. NETs showing strong positivity were re-evaluated in larger tumor cohorts confirming the primary observation. In the metastases, the expression of PCSK2 mirrored that of the corresponding primary tumors. We found negative or weak staining in NETs from the thymus, gastric mucosa, pancreas, rectum, thyroid, and parathyroid. PCSK2 expression did not correlate with Ki-67 in well-differentiated NETs. Our data suggest that PCSK2 positivity can indicate the location of the primary tumor. Thus, PCSK2 could function in the IHC panel determined from screening metastatic NET biopsies of unknown primary origins.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Carcinoma Neuroendócrino/genética , Neoplasias Gastrointestinais/genética , Neoplasias Pulmonares/genética , Tumores Neuroendócrinos/genética , Paraganglioma/genética , Feocromocitoma/genética , Pró-Proteína Convertase 2/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Biomarcadores Tumorais/genética , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/cirurgia , Cromogranina A/genética , Feminino , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/cirurgia , Expressão Gênica , Humanos , Imuno-Histoquímica , Antígeno Ki-67/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Metástase Linfática , Masculino , Estadiamento de Neoplasias , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/cirurgia , Paraganglioma/diagnóstico , Paraganglioma/patologia , Paraganglioma/cirurgia , Feocromocitoma/diagnóstico , Feocromocitoma/patologia , Feocromocitoma/cirurgia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia
9.
PLoS One ; 15(8): e0236580, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756609

RESUMO

Lung cancer is generally treated with conventional therapies, including chemotherapy and radiation. These methods, however, are not specific to cancer cells and instead attack every cell present, including normal cells. Personalized therapies provide more efficient treatment options as they target the individual's genetic makeup. The goal of this study was to identify the frequency of causal genetic mutations across a variety of lung cancer subtypes in the earlier stages. 833 samples of non-small cell lung cancer from 799 patients who received resection of their lung cancer, were selected for molecular analysis of six known mutations, including EGFR, KRAS, BRAF, PIK3CA, HER2 and ALK. A SNaPshot assay was used for point mutations and fragment analysis searched for insertions and deletions. ALK was evaluated by IHC +/- FISH. Statistical analysis was performed to determine correlations between molecular and clinical/pathological patient data. None of the tested variants were identified in most (66.15%) of cases. The observed frequencies among the total samples vs. only the adenocarcinoma cases were notable different, with the highest frequency being the KRAS mutation (24.49% vs. 35.55%), followed by EGFR (6.96% vs. 10.23%), PIK3CA (1.20% vs. 0.9%), BRAF (1.08% vs. 1.62%), ALK (0.12% vs. 0.18%), while the lowest was the HER2 mutation (0% for both). The statistical analysis yielded correlations between presence of a mutation with gender, cancer type, vascular invasion and smoking history. The outcome of this study will provide data that helps stratify patient prognosis and supports development of more precise treatments, resulting in improved outcomes for future lung cancer patients.


Assuntos
Adenocarcinoma/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Predisposição Genética para Doença , Prognóstico , Adenocarcinoma/classificação , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/classificação , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor ErbB-2/genética
10.
BMC Bioinformatics ; 21(1): 339, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32736513

RESUMO

BACKGROUND: It has been widely accepted that long non-coding RNAs (lncRNAs) play important roles in the development and progression of human diseases. Many association prediction models have been proposed for predicting lncRNA functions and identifying potential lncRNA-disease associations. Nevertheless, among them, little effort has been attempted to measure lncRNA functional similarity, which is an essential part of association prediction models. RESULTS: In this study, we presented an lncRNA functional similarity calculation model, IDSSIM for short, based on an improved disease semantic similarity method, highlight of which is the introduction of information content contribution factor into the semantic value calculation to take into account both the hierarchical structures of disease directed acyclic graphs and the disease specificities. IDSSIM and three state-of-the-art models, i.e., LNCSIM1, LNCSIM2, and ILNCSIM, were evaluated by applying their disease semantic similarity matrices and the lncRNA functional similarity matrices, as well as corresponding matrices of human lncRNA-disease associations coming from either lncRNADisease database or MNDR database, into an association prediction method WKNKN for lncRNA-disease association prediction. In addition, case studies of breast cancer and adenocarcinoma were also performed to validate the effectiveness of IDSSIM. CONCLUSIONS: Results demonstrated that in terms of ROC curves and AUC values, IDSSIM is superior to compared models, and can improve accuracy of disease semantic similarity effectively, leading to increase the association prediction ability of the IDSSIM-WKNKN model; in terms of case studies, most of potential disease-associated lncRNAs predicted by IDSSIM can be confirmed by databases and literatures, implying that IDSSIM can serve as a promising tool for predicting lncRNA functions, identifying potential lncRNA-disease associations, and pre-screening candidate lncRNAs to perform biological experiments. The IDSSIM code, all experimental data and prediction results are available online at https://github.com/CDMB-lab/IDSSIM .


Assuntos
Algoritmos , Biologia Computacional/métodos , Doença/genética , Modelos Genéticos , RNA Longo não Codificante/genética , Semântica , Adenocarcinoma/genética , Área Sob a Curva , Neoplasias da Mama/genética , Bases de Dados Genéticas , Feminino , Humanos , Curva ROC
11.
Am J Surg Pathol ; 44(9): 1224-1234, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32804454

RESUMO

This study determined the frequency and the clinicopathologic and genetic features of colorectal carcinomas driven by oncogenic fusions of the anaplastic lymphoma kinase gene (ALK). Of the 8150 screened tumors, 12 (0.15%) were immunohistochemically ALK-positive with D5F3 antibody. These cancers harbored CAD-ALK (n=1), DIAPH2-ALK (n=2), EML4-ALK (n=2), LOC101929227-ALK (n=1), SLMAP-ALK (n=1), SPTBN1-ALK (n=4), and STRN-ALK (n=1) fusions, as detected by an RNA-based next-generation sequencing assay. ALK fusion carcinomas were diagnosed mostly in older patients with a 9:3 female predominance (median age: 72 y). All tumors, except a rectal one, occurred in the right colon. Most tumors were stage T3 (n=7) or T4 (n=3). Local lymph node and distant metastases were seen at presentation in 9 and 2 patients. These tumors showed moderate (n=6) or poor (n=3) glandular differentiation, solid medullary growth pattern (n=2), and pure mucinous morphology (n=1). DNA mismatch repair-deficient phenotype was identified in 10 cases. Tumor-infiltrating lymphocytes were prominent in 9 carcinomas. In 4 carcinomas, tumor cells showed strong, focal (n=3), or diffuse programmed death-ligand 1 immunoreactivity. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 tumors. Four patients died of disease within 3 years, and 7 were alive with follow-up ranging from 1 to 8 years. No mutations in BRAF, RAS, and in genes encoding components of PI3K-AKT/MTOR pathway were identified. However, 1 tumor had a loss-of-function PTEN mutation. Aberration of p53 signaling, TP53 mutations, and/or nuclear accumulation of p53 protein was seen in 9 cases. ALK fusion colorectal carcinomas are a distinct and rare subtype of colorectal cancers displaying some features of mismatch repair-deficient tumors.


Assuntos
Adenocarcinoma/genética , Quinase do Linfoma Anaplásico/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Fusão Gênica , Rearranjo Gênico , Adenocarcinoma/química , Adenocarcinoma/secundário , Adenocarcinoma/terapia , Idoso , Biomarcadores Tumorais/análise , Neoplasias Colorretais/química , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Análise Mutacional de DNA , Europa (Continente) , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Japão , Metástase Linfática , Masculino , Mutação , Estadiamento de Neoplasias , Fenótipo , Resultado do Tratamento , Estados Unidos
12.
DNA Cell Biol ; 39(9): 1532-1544, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32644844

RESUMO

Increasing evidence suggests that aberrant long noncoding (lnc) RNA expression plays a vital role in gastric cancer (GC) initiation and progression. Thus, we aimed to develop a lncRNA-based risk signature and nomogram to predict overall survival (OS) for patients with GC. Our primary cohort was composed of 341 patients with clinical and lncRNA expression data in The Cancer Genome Atlas stomach adenocarcinoma (TCGA STAD), the internal validation cohort was composed of 172 randomly assigned patients, and the external validation cohort was composed of 300 patients from GSE62254 dataset. A risk signature and nomogram were developed for the primary cohort and validated on the validation cohorts. Furthermore, gene set enrichment analysis (GSEA) was used to investigate the pathway enrichment for the risk signature. The expression patterns of several lncRNAs were also investigated in clinical samples from 10 GC patients. We identified and validated a 14-lncRNA signature highly associated with the OS of patients with GC, which performed well on evaluation with C-index, area under the curve, and calibration curves. In addition, univariate and multivariate Cox regression analyses indicated that the lncRNA signature was an independent predictive factor for GC patients. Therefore, a nomogram incorporating lncRNA signature and clinical factors was constructed to predict OS for patients with GC in primary cohort that suggested powerful predictive values for survival in the TCGA cohort and the other two validation cohorts. In addition, GSEA indicated that the identified lncRNAs may regulate the autophagy pathway, affecting tumorigenesis and prognosis of patients with GC. Experimental validation demonstrated that the expression of lncRNAs showed the same trend both in our clinical samples and STAD dataset. These results suggest that both risk signature and nomogram were effective prognostic indicators for patients with GC.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Adenocarcinoma/patologia , Idoso , Autofagia/genética , Biomarcadores Tumorais/metabolismo , Carcinogênese/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/metabolismo , Neoplasias Gástricas/patologia , Análise de Sobrevida , Transcriptoma
13.
Prostate ; 80(12): 1012-1023, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32649013

RESUMO

BACKGROUND: Small cell neuroendocrine (NE) carcinomas of the prostate classically lose androgen receptor (AR) expression, may harbor loss of the RB1, TP53, and PTEN tumor suppressor genes, and are associated with a poor prognosis. However usual-type adenocarcinomas may also contain areas of NE differentiation, and in this context the molecular features and biological significance are less certain. METHODS: We examined the molecular phenotype and oncologic outcomes of primary prostate adenocarcinomas with ≥5% NE differentiation (≥5% chromogranin A-positive NE cells in any given tumor spot on tissue microarray) using three independent study sets: a set of tumors with paneth cell-like NE differentiation (n = 26), a retrospective case-cohort of intermediate- and high-risk patients enriched for adverse outcomes (n = 267), and primary tumors from a retrospective series of men with eventual castration-resistant metastatic prostate cancer (CRPC) treated with abiraterone or enzalutamide (n = 55). RESULTS: Benign NE cells expressed significantly lower quantified AR levels compared with paired benign luminal cells (P < .001). Similarly, paneth-like NE carcinoma cells or carcinoma cells expressing chromogranin A expressed significantly lower quantified AR levels than paired non-NE carcinoma cells (P < .001). Quantified ERG protein expression, was also lower in chromogranin A-labeled adenocarcinoma cells compared with unlabeled cells (P < .001) and tumors with NE differentiation showed lower gene expression scores for AR activity compared with those without. Despite evidence of lower AR signaling, adenocarcinomas with NE differentiation did not differ by prevalence of TP53 missense mutations, or PTEN or RB1 loss, compared with those without NE differentiation. Finally, NE differentiation was not associated with time to metastasis in intermediate- and high-risk patients (P = .6 on multivariate analysis), nor with progression-free survival in patients with CRPC treated with abiraterone or enzalutamide (P = .9). CONCLUSION: NE differentiation in usual-type primary prostate adenocarcinoma is a molecularly and clinically distinct form of lineage plasticity from that occurring in small cell NE carcinoma.


Assuntos
Células Neuroendócrinas/patologia , Tumores Neuroendócrinos/patologia , Neoplasias da Próstata/patologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/metabolismo , Carcinoma de Células Pequenas/patologia , Diferenciação Celular/fisiologia , Estudos de Coortes , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Células Neuroendócrinas/metabolismo , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/biossíntese , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Proteínas de Ligação a Retinoblastoma/genética , Proteínas de Ligação a Retinoblastoma/metabolismo , Estudos Retrospectivos , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
14.
Anticancer Res ; 40(7): 3765-3779, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620616

RESUMO

BACKGROUND/AIM: Apoptotic peptidase activating factor 1 (APAF-1) is essential regulator of apoptosis and inactivation by DNA methylation is common event in numerous cancer types. We investigated the regulation of APAF-1 through DNA methylation in pancreatic cancer. MATERIALS AND METHODS: Datasets from 44 patients after pancreatoduodenectomy and the pancreatic adenocarcinoma (PDAC) cell lines Capan-2 and MIA PaCa-2 treated with decitabine were analyzed by RT-PCR, immunoblotting, methylation-specific PCR analysis, apoptosis and viability assays to identify effects of APAF-1 regulation. RESULTS: APAF-1 mRNA and protein levels were significantly down-regulated, and APAF-1 methylation status was associated with perineural invasion in PDAC. Decitabine inhibited cell viability and increased apoptosis rates, however failed to restore APAF-1 mRNA and protein levels in cells. CONCLUSION: APAF-1 gene hypermethylation may contribute to the progression of PDAC through perineural invasion. Decitabine could sensitize pancreatic cancer cells to apoptosis and growth retardation, however, not directly through the APAF-1 demethylation process.


Assuntos
Fator Apoptótico 1 Ativador de Proteases/genética , Metilação de DNA/genética , Epigênese Genética/genética , Neoplasias Pancreáticas/genética , Adenocarcinoma/genética , Idoso , Apoptose/genética , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Progressão da Doença , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , RNA Mensageiro/genética
15.
Medicine (Baltimore) ; 99(28): e21160, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664151

RESUMO

BACKGROUND: Previous studies have investigated the correlation between xeroderma pigmentosumcomplementation group C (XPC) variants and prostate adenocarcinoma (PA) risk. Nevertheless, research findings remain inconclusive. METHODS: We conducted a pooled analysis to obtain a more accurate estimation of the relationship on XPC exon15 Lys939Gln polymorphism with susceptibility to PA. Moreover, in silico tools were employed to investigate the effect of XPC expression on PA patients' survival time. RESULTS: A total of 4306 patients and 4779 control subjects were assessed. The overall results indicated that XPC Lys939Gln variant was associated with PA risk (recessive genetic model: odds ratio = 1.15, 95% confidence interval = 1.02-1.30, Pheterogeneity= .044, P = .021, I= 45.2), especially in Asian descendants. Population-based studies revealed similar results (odds ratio = 1.15, 95% confidence interval = 1.01-1.32, Pheterogeneity= .146, P = .040, I = 39.0). In silico tools showed that XPC expression in Caucasian patients was lower than in the normal group. No positive association was observed in African patients. PA subjects with high XPC expression had a longer overall survival time than low expression group. CONCLUSION: Our findings indicated that XPC Lys939Gln variant might contribute to increased PA susceptibility, especially for Asian patients.


Assuntos
Adenocarcinoma/genética , Proteínas de Ligação a DNA/genética , Éxons/genética , Predisposição Genética para Doença/genética , Neoplasias da Próstata/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores de Risco
16.
DNA Cell Biol ; 39(9): 1657-1663, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32552051

RESUMO

Cell adhesion molecules (CAMs) play crucial roles in the genesis and progress of tumor. We investigated the effects of single nucleotide polymorphisms (SNPs) of CAMs, neuronal growth regulator 1 (NEGR1), and Otoancorin (OTOA) on lung cancer susceptibility in Chinese nonsmoking females. Logistic regression and Cox regression analyses were conducted to investigate the effects of SNPs and environmental factors. For rs3102911, genotype TT carriers decreased the risk of lung cancer with an odds ratio (OR) of 0.635. AA genotypes of rs741718 increased the risk of lung cancer with an OR of 3.527. In stratified analysis, genotype AA carriers of rs741718 had a high susceptibility to lung adenocarcinoma compared with GG and AG genotypes. Analyses of association between SNPs and clinical characteristics revealed that rs3102911 as a protective factor and rs741718 as a risk factor influenced the lung cancer occurrence and progression in nonsmoking females.


Assuntos
Adenocarcinoma/genética , Moléculas de Adesão Celular Neuronais/genética , Proteínas Ligadas por GPI/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , China , Feminino , Humanos , Pessoa de Meia-Idade , não Fumantes/estatística & dados numéricos
17.
Am J Gastroenterol ; 115(8): 1201-1209, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32558685

RESUMO

INTRODUCTION: Nonendoscopic Barrett's esophagus (BE) screening may help improve esophageal adenocarcinoma outcomes. We previously demonstrated promising accuracy of methylated DNA markers (MDMs) for the nonendoscopic diagnosis of BE using samples obtained from a capsule sponge-on-string (SOS) device. We aimed to assess the accuracy of these MDMs in an independent cohort using a commercial grade assay. METHODS: BE cases had ≥ 1 cm of circumferential BE with intestinal metaplasia; controls had no endoscopic evidence of BE. The SOS device was withdrawn 8 minutes after swallowing, followed by endoscopy (the criterion standard). Highest performing MDMs from a previous study were blindly assessed on extracted bisulfite-converted DNA by target enrichment long-probe quantitative amplified signal (TELQAS) assays. Optimal MDM combinations were selected and analyzed using random forest modeling with in silico cross-validation. RESULTS: Of 295 patients consented, 268 (91%) swallowed the SOS device; 112 cases and 89 controls met the pre-established inclusion criteria. The median BE length was 6 cm (interquartile range 4-9), and 50% had no dysplasia. The cross-validated sensitivity and specificity of a 5 MDM random forest model were 92% (95% confidence interval 85%-96%) and 94% (95% confidence interval 87%-98%), respectively. Model performance was not affected by age, gender, or smoking history but was influenced by the BE segment length. SOS administration was well tolerated (median [interquartile range] tolerability 2 [0, 4] on 10 scale grading), and 95% preferred SOS over endoscopy. DISCUSSION: Using a minimally invasive molecular approach, MDMs assayed from SOS samples show promise as a safe and accurate nonendoscopic test for BE prediction.


Assuntos
Adenocarcinoma/diagnóstico , Esôfago de Barrett/diagnóstico , Neoplasias Esofágicas/diagnóstico , Marcadores Genéticos , Adenocarcinoma/genética , Adenocarcinoma/patologia , Idoso , Área Sob a Curva , Esôfago de Barrett/genética , Esôfago de Barrett/patologia , Biópsia , Endoscopia por Cápsula , Estudos de Casos e Controles , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Esofagoscopia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Estados Unidos
18.
PLoS One ; 15(6): e0233782, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32520974

RESUMO

Despite recent advances in clinical treatment, pancreatic cancer remains a highly lethal malignancy. In order to improve the survival rate of patients with pancreatic cancer, the development of non-invasive diagnostic methods using effective biomarkers is urgently needed. Here, we developed a highly sensitive method to detect DNA methylation in cell-free (cf)DNA samples based on the enrichment of methyl-CpG binding (MBD) protein coupled with a digital PCR method (MBD-ddPCR). Five DNA methylation markers for the diagnosis of pancreatic cancer were identified through DNA methylation microarray analysis in 37 pancreatic cancers. The sensitivity and specificity of the five markers were validated in another independent cohort of pancreatic cancers (100% and 100%, respectively; n = 46) as well as in The Cancer Genome Atlas data set (96% and 90%, respectively; n = 137). MBD-ddPCR analysis revealed that DNA methylation in at least one of the five markers was detected in 23 (49%) samples of cfDNA from 47 patients with pancreatic cancer. Further, a combination of DNA methylation markers and the KRAS mutation status improved the diagnostic capability of this method (sensitivity and specificity, 68% and 86%, respectively). Genome-wide MBD-sequencing analysis in cancer tissues and corresponding cfDNA revealed that more than 80% of methylated regions were overlapping; DNA methylation profiles of cancerous tissues and cfDNA significantly correlated with each other (R = 0.97). Our data indicate that newly developed MBD-ddPCR is a sensitive method to detect cfDNA methylation and that using five marker genes plus KRAS mutations may be useful for the detection of pancreatic cancers.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Ácidos Nucleicos Livres/genética , Metilação de DNA , Neoplasias Pancreáticas/genética , Adenocarcinoma/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/normas , Ilhas de CpG , Detecção Precoce de Câncer/métodos , Detecção Precoce de Câncer/normas , Feminino , Humanos , Masculino , Proteína 2 de Ligação a Metil-CpG/metabolismo , Pessoa de Meia-Idade , Mutação , Neoplasias Pancreáticas/diagnóstico , Reação em Cadeia da Polimerase/métodos , Reação em Cadeia da Polimerase/normas , Proteínas Proto-Oncogênicas p21(ras)/genética , Sensibilidade e Especificidade
19.
Am J Surg Pathol ; 44(8): 1017-1030, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32568823

RESUMO

A robust morphomolecular classification system for gastric carcinoma is required. A 4-tier morphologic classification is proposed, including diffuse, intestinal, tubular, and lymphoid types. A tissue microarray for mismatch repair immunohistochemistry and Epstein-Barr virus (EBV) in situ hybridization were performed in 329 gastric carcinomas. DNA flow cytometry was used to detect aneuploidy in formalin-fixed paraffin-embedded samples. Lymphoid histology was the third most common histologic pattern at our institute and strongly associated with EBV infection and PMS2/MLH1-deficiency (both P<0.001). HER2 overexpression and SATB2 expression more frequently occurred in intestinal histology (both P<0.001). Loss of ARID1A expression was strikingly associated with lymphoid histology (P<0.001) and negative E-cadherin expression was correlated with diffuse histology (P=0.001). Programmed death-ligand 1 expression was most frequently present in lymphoid-type gastric carcinoma than other histologic subtypes and correlated with the molecular features of PMS2/MLH1-deficiency and EBV infection (all P<0.001). Aneuploidy was detected in 53% of gastric carcinomas and was highly correlated with intestinal type and the least with the lymphoid type (P<0.001). Notably, lymphoid-type gastric carcinoma showed the best outcome, whereas tubular type showed the worst survival rate (P<0.001). We integrated aneuploidy with morphologic patterns to propose a morphomolecular classification scheme, which served as a successful and independent prognostic factor in multivariate 5-year disease-free survival analysis (P<0.001). Overall, we describe an integrated morphomolecular classification system for gastric carcinomas to effectively predict patient outcomes. This system is cost-effective and reliable and can help select target therapeutics and facilitate clinical management.


Assuntos
Adenocarcinoma/química , Adenocarcinoma/genética , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Neoplasias Gástricas/química , Neoplasias Gástricas/genética , Adenocarcinoma/patologia , Adenocarcinoma/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneuploidia , Reparo de Erro de Pareamento de DNA , Intervalo Livre de Doença , Feminino , Herpesvirus Humano 4/genética , Humanos , Masculino , Proteínas de Ligação à Região de Interação com a Matriz/análise , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/análise , Proteína 1 Homóloga a MutL/análise , Estadiamento de Neoplasias , Receptor ErbB-2/análise , Fatores de Risco , Neoplasias Gástricas/patologia , Neoplasias Gástricas/virologia , Taiwan , Fatores de Tempo , Fatores de Transcrição/análise , Adulto Jovem
20.
Medicine (Baltimore) ; 99(24): e20554, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32541478

RESUMO

Colorectal cancer (CRC) represents a major malignancy globally, with microsatellite instability as its second top molecular mechanism of carcinogenesis. Immunohistochemical (IHC), whose sensitivity and specificity exceed 90%, is used routinely to detect 4 MMR proteins (MLH1, PMS2, MSH2, and MSH6) for screening mismatch repair system defects. We aimed to assess associations of clinicopathologic characteristics with MMR status in resectable CRC patients.Stage I-III CRC cases administered surgical resection in Zhejiang Cancer Hospital in 2013 to 2015 were retrospectively analyzed. MLH1, MSH2, MSH6, and PMS2 protein amounts were evaluated immunohistochemically. Clinicopathological information, including age, sex, tumor location, histological subclass, disease stage, regional lymph node (LN) metastasis, American Joint Committee on Cancer (AJCC) 8th edition stage, and survival data were retrospectively reviewed.A total of 133 CRC cases were assessed, including 74 (55.6%), 45 (33.8%), 55 (41.4%), and 77 (57.9%) not expressing MLH1, MSH2, MSH6, and PMS2, respectively. There were significant associations of MLH1, MSH2, MSH6, and PMS2 proteins with age and sex (P < .05). MLH1, MSH2, and MSH6 (but not PMS2) showed positive associations with primary tumor location (P < .05). Of the 133 patients, 70 and 63 cases were affected on the right and left sides, respectively; significant associations of primary site with age and sex were observed (P < .05). Regarding the MMR status, MLH1, MSH2, and MSH6 protein expression levels were positively associated with primary site (P < .05). Five-year overall survival (OS) rates were 84.2% and 79.2% in left-side and right-side cases, respectively; 5-year disease-free survival (DFS) rates were 74.0% and 69.8%, respectively. Survival had no differences between left- and right-side patients in terms of OS (P = .318) and DFS (P = .481).These data demonstrate that 4 major dMMR proteins are expressed differently in left- and right-side CRCs, and survival is comparable in right- and left-side resectable CRC cases with dMMR.


Assuntos
Adenocarcinoma/genética , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Enzimas Reparadoras do DNA/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Estudos Retrospectivos , Adulto Jovem
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