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1.
Medicine (Baltimore) ; 99(9): e19230, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32118724

RESUMO

Spermatogenesis associated serine rich 2 (SPATS2) has been reported to be dysregulated in few types of cancer; however, no reports have investigated SPATS2 in liver cancer. The aim of the present study was to investigate SPATS2 expression in liver cancer and to analyze its association with the prognosis of liver cancer patients.We examined the differential expression of SPATS2 in liver cancer by exploring The Cancer Genome Atlas (TCGA) database. The diagnostic efficiency of SPATS2 was obtained by Receiver Operating Characteristic (ROC) curve. The Chi-Squared test was used to assess clinical relevance. Survival analysis and Cox regression model were used to detect the effect of SPATS2 on the survival of liver cancer patients. Gene Set Enrichment Analysis (GSEA) was used to identify signaling pathways related to SPATS2 expression.SPATS2 is highly expressed in liver cancer (P < 2.2e-16) and has the high diagnostic ability (AUC = 0.964). Survival analysis showed that patients with high SPATS2 expression have an apparently shorter overall survival (OS, P < .0001) and relapse-free survival (RFS, P < .0001). Cox regression analysis showed that high SPATS2 expression might be an independent risk factor for liver cancer (OS, HR = 2.41, P = .000; RFS, HR = 1.90, P < .001). GSEA analysis identified 3 signaling pathways (Mitotic spindle, G2 M checkpoint, E2F targets) that were enriched in the presence of high SPATS2 expression.SPATS2 expression could be a novel diagnostic and prognostic biomarker in liver cancer.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Recidiva Local de Neoplasia/genética , Proteínas/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/mortalidade , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Prognóstico , Proteínas/metabolismo , Curva ROC , Análise de Sobrevida
2.
Medicine (Baltimore) ; 99(11): e19491, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176088

RESUMO

PROM1 has played a pivotal role in the identification and isolation of tumor stem cells. This study aimed to assess the association between PROM1 promoter methylation and head and neck squamous cell carcinoma (HNSCC), and its diagnostic and prognostic value.Bioinformatic analysis was performed using data from the Cancer Genome Atlas-HNSC and Gene Expression Omnibus datasets.The results showed that PROM1 promoter was hypermethylated in HNSCCs compared with normal head and neck tissues (P = 4.58E-37). The area under the receiver-operating characteristic curve based on methylated PROM1 data was 0.799. In addition, PROM1 hypermethylation independently predicted poor overall survival (hazard ratio [HR]: 1.459, 95% confidence interval [CI]: 1.071-1.987, P = .016) and recurrence-free survival (HR: 1.729, 95% CI: 1.088-2.749, P = .021) in HNSCC patients. Moreover, PROM1 methylation was weakly negatively correlated with its mRNA expression (Pearson r = -0.148, P < .001).In summary, our study reveals that methylated PROM1 might serve as a valuable diagnostic biomarker and predictor of poor survival for HNSCC patients. PROM1 hypermethylation might partially contribute to its downregulation in HNSCC.


Assuntos
Antígeno AC133/genética , Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço/genética , Recidiva Local de Neoplasia/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Grupo com Ancestrais do Continente Asiático , Biomarcadores Tumorais/genética , China/epidemiologia , Mineração de Dados , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Análise de Sobrevida
3.
Crit Rev Oncol Hematol ; 146: 102879, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32005411

RESUMO

Cell-free circulating tumor DNA (ct-DNA) reflecting the whole tumor spatial and temporal heterogeneity currently represents the most promising candidate for liquid biopsy strategy in glioma. Unlike other solid tumors, it is now widely accepted that the best source of ct-DNA for glioma patients is the cerebrospinal fluid, since blood levels are usually low and detectable only in few cases. A cerebrospinal fluid ct-DNA liquid biopsy approach may virtually support all the stages of glioma management, from facilitating molecular diagnosis when surgery is not feasible, to monitoring tumor response, identifying early recurrence, tracking longitudinal genomic evolution, providing a new molecular characterization at recurrence and allowing patient selection for targeted therapies. This review traces the history of ct-DNA liquid biopsy in the field of diffuse malignant gliomas, describes its current status and analyzes what are the future perspectives and pitfalls of this potentially revolutionary molecular tool.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/líquido cefalorraquidiano , DNA Tumoral Circulante/líquido cefalorraquidiano , DNA de Neoplasias/metabolismo , Glioma/líquido cefalorraquidiano , Biópsia Líquida/métodos , Células Neoplásicas Circulantes/metabolismo , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , DNA de Neoplasias/genética , Genes Neoplásicos/genética , Glioblastoma/líquido cefalorraquidiano , Glioblastoma/genética , Glioblastoma/patologia , Glioma/genética , Glioma/patologia , Humanos , Mutação , Gradação de Tumores , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Células Neoplásicas Circulantes/patologia
4.
Anticancer Res ; 40(2): 645-652, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014905

RESUMO

BACKGROUND/AIM: In estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, standard chemotherapies as well as adjuvant endocrine therapy might not be enough for prevention of early relapse. MATERIALS AND METHODS: We focused on ER-positive, HER2 immunohistochemistry (IHC) 0 or 1+ breast cancer, and retrospectively examined HER2 gene amplification and TP53 mutation in breast cancer tissues in patients with or without early recurrence. Post-relapse survival in patients with early recurrence was also analyzed by mutation status of HER2 and TP53. RESULTS: Surprisingly, amplification of the HER2 gene was found in 15% of patients with early recurrence. None of the patients without relapse had HER2-amplified tumors. Post-relapse survival in patients with HER2 gene amplification and/or TP53 mutation in primary tumors was shorter than that in patients without these mutations, especially among postmenopausal women. CONCLUSION: HER2 gene amplification exists in ER-positive, HER2 IHC 0 or 1+ breast cancer in patients who developed early distant metastasis.


Assuntos
Neoplasias da Mama/genética , Recidiva Local de Neoplasia/genética , Receptor ErbB-2/genética , Receptores Estrogênicos/metabolismo , Adulto , Idoso , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Feminino , Amplificação de Genes , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/enzimologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/biossíntese , Estudos Retrospectivos , Proteína Supressora de Tumor p53/genética
5.
Nat Commun ; 11(1): 74, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900393

RESUMO

Despite the promising clinical efficacy of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in patients with ALK-rearranged lung cancer, some tumor cells survive and eventually relapse, which may be an obstacle to achieving a cure. Limited information is currently available on the mechanisms underlying the initial survival of tumor cells against alectinib. Using patient-derived cell line models, we herein demonstrate that cancer cells survive a treatment with alectinib by activating Yes-associated protein 1 (YAP1), which mediates the expression of the anti-apoptosis factors Mcl-1 and Bcl-xL, and combinatorial inhibition against both YAP1 and ALK provides a longer tumor remission in ALK-rearranged xenografts when compared with alectinib monotherapy. These results suggest that the inhibition of YAP1 is a candidate for combinatorial therapy with ALK inhibitors to achieve complete remission in patients with ALK-rearranged lung cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Quinase do Linfoma Anaplásico/genética , Apoptose/efeitos dos fármacos , Carbazóis/administração & dosagem , Rearranjo Gênico/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Piperidinas/administração & dosagem , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Quinase do Linfoma Anaplásico/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/fisiopatologia , Inibidores de Proteínas Quinases/administração & dosagem , Fatores de Transcrição/genética
6.
Gynecol Oncol ; 156(1): 38-44, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31699415

RESUMO

OBJECTIVES: Olaparib is approved as maintenance therapy in patients with BRCA mutated platinum sensitive (PS) recurrent ovarian cancer (OC) after response to last platinum based therapy. Few data are available regarding the use out of the registration trials and on response to further treatments after progression. MATERIALS AD METHODS: In this non interventional, retrospective study, patients treated with olaparib in 13 centers, according to the label, have been collected and analyzed. Primary objectives of the study are to describe effectiveness and safety of olaparib in a real world setting with a focus on post progression treatments and response. RESULTS: 234 patients were analyzed. All patients were BRCA mutated and most of them had germline mutations. Around 50% of the patients received olaparib after 3 or more lines of platinum based chemotherapy achieving a radiologic complete (CR) or partial response. 12.4% patients with stable disease were also included. Median PFS was 14.7 months (95% CI:12.6-18), with statistically longer PFS in patients with normal serum Ca125 at baseline, a CR after last platinum based therapy and that received olaparib after second platinum based therapy. Median OS was not reached. Most frequent G3-G4 toxicity was anaemia (6%) with dose discontinuation and dose reduction in 11 (4.7%) and 49 (20.9%) of cases, respectively. Among 66 patients receiving further treatment after olaparib progression and evaluable for response, ORR was 22.2, 11.1% and 9.5% in patients with Platinum Free interval (PFI) of more than 12 months, between 6 and 12 months and less than 6 months, respectively. CONCLUSIONS: Olaparib is effective and safe in real world setting. Data on post-progression treatments seem to suggest cross resistance with chemotherapy and need to be confirmed in larger studies because of the potential importance in clinical practice decisions.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Antineoplásicos/administração & dosagem , Feminino , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Humanos , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Intervalo Livre de Progressão , Estudos Retrospectivos
7.
DNA Cell Biol ; 39(1): 78-91, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31765229

RESUMO

microRNA plays an important role in the development of tumors, including osteosarcoma. However, the role of miR-1225-5p in osteosarcoma is currently unclear. First, we found that miR-1225-5p was downregulated in osteosarcoma cells relative to its levels in normal bone tissue by analyzing GSE28423 data in the GEO database. Using GSE39040, we found that low miR-1225-5p expression is associated with poor prognosis in patients with osteosarcoma, and we also found low miR-1225-5p expression in patients with recurrent osteosarcoma. We later demonstrated that osteosarcoma cell lines transfected with miR-1225-5p mimic had decreased ability to proliferate, migrate, and invade relative to control cells. To elucidate the mechanism by which miR-1225-5p inhibits the development of osteosarcoma, we identified Sox9 as a target gene of miR-1225-5p using the TargetScan website. We confirmed that Sox9 is the target gene of miR-1225-5p using the luciferase reporter assay. We then found that Sox9 is highly expressed in osteosarcoma by analyzing the GSE16088 and GSE42352 datasets and that high expression of Sox9 is associated with poor prognosis in patients with osteosarcoma using the R2 database. Further analysis using the TARGET database uncovered that high Sox9 expression is associated with a high recurrence rate in patients with osteosarcoma. Transfection of Sox9 siRNA inhibited the proliferation, migration, and invasiveness of osteosarcoma cells. We transfected miR-1225-5p together with Sox9 siRNA into osteosarcoma cells, observing strong inhibition of proliferation, migration, and invasiveness. Finally, exogenous expression of Sox9 partially reversed the anticancer effects of miR-1225-5p in osteosarcoma cells. Taken together, our findings suggest that miR-1225-5p functions as a tumor suppressor in osteosarcoma by targeting Sox9, thereby revealing new therapeutic targets for osteosarcoma.


Assuntos
Neoplasias Ósseas/genética , Genes Supressores de Tumor , MicroRNAs/genética , Osteossarcoma/genética , Fatores de Transcrição SOX9/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Criança , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Recidiva Local de Neoplasia/genética , Osteossarcoma/patologia , Prognóstico , Interferência de RNA
8.
Int J Radiat Oncol Biol Phys ; 106(3): 496-502, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31759077

RESUMO

PURPOSE: Variability exists in the adjuvant treatment for endometrial cancer (EC) based on surgical pathology and institutional preference. The radiosensitivity index (RSI) is a previously validated multigene expression index that estimates tumor radiosensitivity. We evaluate RSI as a genomic predictor for pelvic failure (PF) in EC patients treated with adjuvant radiation therapy (RT). METHODS AND MATERIALS: Using our institutional tissue biorepository, we identified EC patients treated between January 1999 and April 2011 with primarily endometrioid histology (n = 176; 86%) who received various adjuvant therapies. The RSI 10-gene signature was calculated for each sample using the previously published algorithm. Radiophenotype was determined using the previously identified cutpoint where RSI ≥ 0.375 denotes radioresistance (RR) and RSI < 0.375 describes radiosensitivity. RESULTS: A total of 204 patients were identified, of which 83 (41%) were treated with adjuvant RT. Median follow-up was 38.5 months. All patients underwent hysterectomy with bilateral salpingo-oophorectomy with the majority undergoing lymph node dissection (n = 181; 88%). In patients treated with radiation, RR tumors were more likely to experience PF (3-year pelvic control 84% vs 100%; P = .02) with worse PF-free survival (PFFS) (3-year PFFS 65% vs 89%; P = .04). Furthermore, in the patients who did not receive RT, there was no difference in PF (P = .87) or PFFS (P = .57) between the RR/radiosensitive tumors. On multivariable analysis, factors that continued to predict for PF included the RR phenotype (hazard ratio [HR], 12.2; P = .003), lymph node involvement (HR, 4.4; P = .02), and serosal or adnexal involvement (HR, 5.3; P = .01). CONCLUSIONS: On multivariable analysis, RSI was found to be a significant predictor of PF in patients treated with adjuvant RT. We propose using RSI to predict which patients are at higher risk for failing in the pelvis and may be candidates for treatment escalation in the adjuvant setting.


Assuntos
Neoplasias do Endométrio/genética , Neoplasias do Endométrio/radioterapia , Perfilação da Expressão Gênica , Recidiva Local de Neoplasia/genética , Neoplasias Pélvicas/genética , Tolerância a Radiação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Histerectomia/métodos , Histerectomia/estatística & dados numéricos , Excisão de Linfonodo/estatística & dados numéricos , Pessoa de Meia-Idade , Análise Multivariada , Fenótipo , Intervalo Livre de Progressão , Radioterapia Adjuvante/efeitos adversos
9.
Virchows Arch ; 476(2): 317-322, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31385070

RESUMO

We here document a sarcoma with a recently reported MGA-NUTM1 fusion. A 49-year-old man presented with a nodule in the right lung, which grew to a giant mass in 5 years. The tumor showed uniform oval to spindle cell proliferation in a hypervascular stroma, associated with focal myxoid change and peculiar collagen deposition resembling an osteoid. The tumor showed an undifferentiated phenotype, including negativity for cytokeratin, although it was immunoreactive to BCOR and MUC4, and was initially suspected as BCOR-associated sarcoma. After complete resection, the tumor recurred in the mediastinal lymph node, and the patient died of the disease. RNA sequencing detected MGA (exon 22)-NUTM1 (exon 3), which was confirmed by reverse transcriptase-polymerase chain reaction, Sanger sequencing, fluorescence in situ hybridization, and NUT immunohistochemistry. Clinicopathological features of the present case were similar to some of the reported cases of MGA-NUTM1 sarcomas, suggesting the emergence of a distinct tumor subtype.


Assuntos
Proteínas de Neoplasias/genética , Recidiva Local de Neoplasia/patologia , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Sarcoma/patologia , Biomarcadores Tumorais/análise , Humanos , Hibridização in Situ Fluorescente/métodos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Recidiva Local de Neoplasia/genética , Proteínas Nucleares/metabolismo , Proteínas Repressoras/genética , Sarcoma/genética , Neoplasias de Tecidos Moles/patologia , Fatores de Transcrição/genética
10.
J Cancer Res Clin Oncol ; 146(3): 659-670, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31754832

RESUMO

BACKGROUND: The use of alkylating chemotherapy versus bevacizumab for recurrent glioblastoma remains controversial. Here, we tested the hypothesis that the activity of alkylators, but not that of bevacizumab, would be associated with the O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status. METHODS: We analyzed a cohort of patients treated at centers of the German Glioma Network or the University Hospital Zurich with alkylating agent-based chemotherapy (n = 260) or bevacizumab without or with irinotecan (n = 84) for first recurrence of glioblastoma. Outcome was stratified for O6-methylguanine DNA methyltransferase (MGMT) status and crossover to bevacizumab or alkylators at further progression. RESULTS: Median post-recurrence survival-1 (PRS-1) for patients receiving alkylating agents at first recurrence was longer than with bevacizumab (11.1 versus 7.4 months, p < 0.001). The use of alkylators was associated with longer PRS-1 for patients with a methylated versus unmethylated MGMT promoter (p = 0.017). For patients receiving bevacizumab, PRS-1 was not different with or without MGMT promoter methylation. PRS-1 was longer in patients receiving alkylating chemotherapy compared to bevacizumab for patients with methylated (p < 0.001) or unmethylated MGMT promoter (p = 0.034). For patients with alkylators at first recurrence receiving bevacizumab at any further recurrence, PRS-1 was longer than in patients receiving bevacizumab first and alkylators thereafter (p = 0.002). CONCLUSIONS: This study confirms limited value of bevacizumab in recurrent glioblastoma independent of MGMT status. Alkylating agents have activity in recurrent glioblastoma, especially in the context of MGMT promoter methylation.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/genética , Metilação de DNA/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Glioblastoma/genética , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Intervalo Livre de Progressão , Regiões Promotoras Genéticas/genética , Estudos Retrospectivos , Proteínas Supressoras de Tumor/genética , Adulto Jovem
11.
Gynecol Oncol ; 156(1): 194-202, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31757464

RESUMO

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


Assuntos
Carcinoma Endometrioide/genética , DNA Polimerase II/genética , Neoplasias do Endométrio/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Adulto , Idoso , Carcinoma Endometrioide/enzimologia , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/terapia , Estudos de Coortes , Reparo de Erro de Pareamento de DNA , DNA Polimerase II/metabolismo , Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/terapia , Feminino , Humanos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Prognóstico , Estudos Prospectivos
12.
Anticancer Res ; 39(12): 6939-6943, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810965

RESUMO

BACKGROUND/AIM: In spite of early detection, appoximately 15% of the small renal cell carcinomas (RCC) will develop metastasis within 5 years follow-up. The aim of this study was to identify new biomarkers to estimate the postoperative relapse of the most common conventional RCC. PATIENTS AND METHODS: Tissue multi arrays of conventional RCC without metastasis at the time of operation from a cohort of 634 patients were analysed by immunohistochemistry for expression of the chitinase 3-like protein 2 (CHI3L2). Cancer specific survival of patients was estimated with Kaplan-Meier analysis, univariate and multivariate Cox regression models. RESULTS: Kaplan-Meier analysis estimated a shorter cancer-free survival for patients with CHI3L2 positive tumors. In multivariate analysis, the CHI3L2 positivity associated with a 3.5 times higher risk for tumor relapse (p<0.001). CONCLUSION: Expression of CHI3L2 in tumor cells of conventional RCC define a group of patients at high risk for postoperative progression.


Assuntos
Carcinoma de Células Renais/metabolismo , Quitinases/metabolismo , Neoplasias Renais/metabolismo , Macrófagos/metabolismo , Recidiva Local de Neoplasia/metabolismo , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/cirurgia , Quitinases/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/cirurgia , Nefrectomia , Prognóstico , Análise de Sobrevida , Análise Serial de Tecidos , Regulação para Cima
13.
PLoS One ; 14(12): e0223341, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31860637

RESUMO

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Although most cSCCs have good prognosis, a subgroup of high-risk cSCC has a higher frequency of recurrence and mortality. Therefore, the identification of molecular risk factors associated with this aggressive subtype is of major interest. In this work we carried out a global-scale approach to investigate the DNA-methylation profile in patients at different stages, from premalignant actinic keratosis to low-risk invasive and high-risk non-metastatic and metastatic cSCC. The results showed massive non-sequential changes in DNA-methylome and identified a minimal methylation signature that discriminates between stages. Importantly, a direct comparison of low-risk and high-risk stages revealed epigenetic traits characteristic of high-risk tumours. Finally, a prognostic prediction model in cSCC patients identified a methylation signature able to predict the overall survival of patients. Thus, the analysis of DNA-methylation in cSCC revealed changes during the evolution of the disease through the different stages that can be of great value not only in the diagnosis but also in the prognosis of the disease.


Assuntos
Carcinoma de Células Escamosas/genética , Epigênese Genética/genética , Neoplasias Cutâneas/genética , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Impressões Digitais de DNA/métodos , Metilação de DNA/genética , Progressão da Doença , Epigenômica/métodos , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Ceratose Actínica/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias/métodos , Prognóstico , Fatores de Risco , Neoplasias Cutâneas/patologia
14.
PLoS Comput Biol ; 15(11): e1007460, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31682594

RESUMO

Radiation therapy is an important and effective treatment option for prostate cancer, but high-risk patients are prone to relapse due to radioresistance of cancer cells. Molecular mechanisms that contribute to radioresistance are not fully understood. Novel computational strategies are needed to identify radioresistance driver genes from hundreds of gene copy number alterations. We developed a network-based approach based on lasso regression in combination with network propagation for the analysis of prostate cancer cell lines with acquired radioresistance to identify clinically relevant marker genes associated with radioresistance in prostate cancer patients. We analyzed established radioresistant cell lines of the prostate cancer cell lines DU145 and LNCaP and compared their gene copy number and expression profiles to their radiosensitive parental cells. We found that radioresistant DU145 showed much more gene copy number alterations than LNCaP and their gene expression profiles were highly cell line specific. We learned a genome-wide prostate cancer-specific gene regulatory network and quantified impacts of differentially expressed genes with directly underlying copy number alterations on known radioresistance marker genes. This revealed several potential driver candidates involved in the regulation of cancer-relevant processes. Importantly, we found that ten driver candidates from DU145 (ADAMTS9, AKR1B10, CXXC5, FST, FOXL1, GRPR, ITGA2, SOX17, STARD4, VGF) and four from LNCaP (FHL5, LYPLAL1, PAK7, TDRD6) were able to distinguish irradiated prostate cancer patients into early and late relapse groups. Moreover, in-depth in vitro validations for VGF (Neurosecretory protein VGF) showed that siRNA-mediated gene silencing increased the radiosensitivity of DU145 and LNCaP cells. Our computational approach enabled to predict novel radioresistance driver gene candidates. Additional preclinical and clinical studies are required to further validate the role of VGF and other candidate genes as potential biomarkers for the prediction of radiotherapy responses and as potential targets for radiosensitization of prostate cancer.


Assuntos
Perfilação da Expressão Gênica/métodos , Recidiva Local de Neoplasia/genética , Tolerância a Radiação/genética , Apoptose , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Biologia Computacional/métodos , Dosagem de Genes/genética , Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Inativação Gênica , Humanos , Masculino , Fatores de Crescimento Neural/genética , Neoplasias da Próstata/genética , RNA Mensageiro/genética , RNA Interferente Pequeno , Recidiva , Transdução de Sinais/genética , Transcriptoma/genética
15.
Anticancer Res ; 39(11): 5943-5951, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704819

RESUMO

BACKGROUND/AIM: To investigate the function of preferentially expressed antigen of melanoma (PRAME) in esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: mRNA expression levels of PRAME were analyzed in resected esophageal tissues of 150 ESCC patients and correlated with clinicopathological parameters. We also investigated the potential function of PRAME by analyzing coordinately expressed genes in 13 ESCC cell lines. RESULTS: RT-qPCR analysis of clinical samples revealed aberrantly high PRAME expression in tumors compared with normal esophageal tissues. High PRAME expression was significantly associated with shorter disease-specific survival and hematogenous recurrence, but not with overall recurrence. The cumulative incidence of hematogenous recurrence was significantly greater for patients with high compared to those with low PRAME expression. In vitro, PCR array analysis revealed that PRAME was coordinately expressed with EGFR, ITGB, and TCF3. CONCLUSION: PRAME is overexpressed in ESCC tissues and may serve as a novel biomarker for predicting hematogenous recurrence.


Assuntos
Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/secundário , Recidiva Local de Neoplasia/patologia , RNA Mensageiro/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Estudos de Coortes , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Prognóstico , RNA Mensageiro/genética , Taxa de Sobrevida
16.
Medicine (Baltimore) ; 98(48): e17815, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770197

RESUMO

To study the clinical significance of HINT2 expression in patients with HCC.We investigated HINT2 mRNA expression in tumors and adjacent non-tumor hepatic tissues from 106 HCC patients using quantitative real-time PCR. Appropriate statistical methods were then applied to assess the relationships between the HINT2 mRNA level and clinical parameters.HINT2 was significantly down-regulated in HCC (P < .0001). No significant correlation was found between HINT2 expression and clinicopathological factors in HCC patients. A Kaplan-Meier survival curve showed that HINT2 expression is related to recurrence-free survival (P < .05). Multivariate analyses revealed that tumor size and HINT2 expression are risk factors for HCC recurrence.HINT2 is down-regulated in HCC, and low HINT2 expression predicts earlier tumor recurrence. HINT2 expression may serve as a prognostic indicator of recurrence in HCC.


Assuntos
Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hepáticas/genética , Proteínas Mitocondriais/metabolismo , Recidiva Local de Neoplasia/genética , Idoso , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Regulação para Baixo/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Prognóstico , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco
17.
Biomed Res Int ; 2019: 7391237, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583246

RESUMO

Background: Obtaining tumor specimens and re-evaluating targeted markers is recommended, if possible, in breast cancer patients who relapsed after curative treatment. The biomarker status changes in rebiopsied tumors have been demonstrated to have considerable clinical implications. Objectives: To identify the changes of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status between the primary and recurrent lesions. Materials and Methods: We conducted a study among 67 patients with recurrent breast cancer, recruited from January 2014 to September 2018 in the Vietnam National Cancer Hospital to compare ER, PR, and HER2 status between the primary and recurrent lesions. For each patient, a specimen of their primary tumor and another specimen of recurrent lesions underwent pathological assessment. Immunohistochemistry (IHC) was performed to determine ER, PR, and HER2 status in both specimens. Results: Biomarker status conversion rates (in both directions) between primary and recurrent tumors were 26.9% for ER, 38.8% for PR, and 22.4% for HER2. Overall, IHC subtypes (hormone receptor positive, HER2 amplified, and triple-negative) changed in 25 out of 67 (37.3%) cases. Conversion rates were not statistically significantly different between patients with different recurrent sites and times of recurrence. Eight out of 13 initially triple-negative patients (61.5%) had a change to positive status of either ER, PR, or HER2. Conclusion: A substantial discordance in ER, PR, and HER2 status were observed between primary breast cancer tissues and recurrent lesions. Rebiopsy could bring new therapeutic opportunities in the management of patients with recurrent breast cancer.


Assuntos
Neoplasias da Mama/genética , Receptor alfa de Estrogênio/genética , Receptor ErbB-2/genética , Receptores de Progesterona/genética , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Biópsia , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Neoplasias de Mama Triplo Negativas/patologia
18.
Cancer Invest ; 37(10): 535-545, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31584296

RESUMO

Background: Non-small cell lung cancer (NSCLC) is the first cause of cancer-related mortality for men and women in the United States. In spite of curative resection in early-stage, patient survival is not optimal and recurrence rate is high. Consequently, early detection and staging is essential to increase the patient's survival.Methods: Copy number (CN) changes in cancer populations have been broadly investigated to identify CN gains and deletions associated with cancer. In contrast, in this research, we quantify the similarities and disparities between cancer and paired peripheral blood samples using maximal information coefficient (MIC). We then detect the spatial locations with substantially high and the spatial locations with very low MICs in each chromosome. These locations can potentially help with early diagnosis, treatment, and prevention of cancer by identifying the similarities and disparities between cancer and healthy tissues.Results: Lung cancer data used in this project contains CN pairs for cancer and blood (non-involved) samples for 63 subjects. MIC was obtained to quantify the relation (linear or nonlinear) between cancer-blood pair samples for 63 subjects at each location for each chromosome. MIC values above a high threshold and MIC values below a low threshold were located. Among them top five (with lowest MIC's and with highest MIC's) were identified for each chromosome. For these identified locations, a high MIC score indicates high similarity between blood (non-involved) and cancer samples, while a low MIC score shows lack of similarity between the two samples.Conclusions: The results showed that a few chromosomes have a large number of MICs exceeding a high threshold. These locations can potentially be used to identify early indicators of NSCLC. In contrast, second group of chromosomes have several locations with small MICs which are potential candidates to develop biomarkers for discriminating cancer from the matched blood sample. Moreover, there is a third group of chromosomes with a large number of MICs exceeding a high threshold and a large set of MICs below a low threshold. These locations can help with both finding early indicators of cancer and developing biomarkers for discriminating cancer from non-involved tissue.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Variações do Número de Cópias de DNA/genética , Neoplasias Pulmonares/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias/métodos
19.
Nat Med ; 25(10): 1615-1626, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31591588

RESUMO

Oncogenesis is driven by germline, environmental and stochastic factors. It is unknown how these interact to produce the molecular phenotypes of tumors. We therefore quantified the influence of germline polymorphisms on the somatic epigenome of 589 localized prostate tumors. Predisposition risk loci influence a tumor's epigenome, uncovering a mechanism for cancer susceptibility. We identified and validated 1,178 loci associated with altered methylation in tumoral but not nonmalignant tissue. These tumor methylation quantitative trait loci influence chromatin structure, as well as RNA and protein abundance. One prominent tumor methylation quantitative trait locus is associated with AKT1 expression and is predictive of relapse after definitive local therapy in both discovery and validation cohorts. These data reveal intricate crosstalk between the germ line and the epigenome of primary tumors, which may help identify germline biomarkers of aggressive disease to aid patient triage and optimize the use of more invasive or expensive diagnostic assays.


Assuntos
Metilação de DNA/genética , Mutação em Linhagem Germinativa/genética , Neoplasias da Próstata/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano/genética , Humanos , Masculino , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Locos de Características Quantitativas/genética
20.
Nat Med ; 25(10): 1534-1539, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31591595

RESUMO

Approximately 50% of patients with early-stage non-small-cell lung cancer (NSCLC) who undergo surgery with curative intent will relapse within 5 years1,2. Detection of circulating tumor cells (CTCs) at the time of surgery may represent a tool to identify patients at higher risk of recurrence for whom more frequent monitoring is advised. Here we asked whether CellSearch-detected pulmonary venous CTCs (PV-CTCs) at surgical resection of early-stage NSCLC represent subclones responsible for subsequent disease relapse. PV-CTCs were detected in 48% of 100 patients enrolled into the TRACERx study3, were associated with lung-cancer-specific relapse and remained an independent predictor of relapse in multivariate analysis adjusted for tumor stage. In a case study, genomic profiling of single PV-CTCs collected at surgery revealed higher mutation overlap with metastasis detected 10 months later (91%) than with the primary tumor (79%), suggesting that early-disseminating PV-CTCs were responsible for disease relapse. Together, PV-CTC enumeration and genomic profiling highlight the potential of PV-CTCs as early predictors of NSCLC recurrence after surgery. However, the limited sensitivity of PV-CTCs in predicting relapse suggests that further studies using a larger, independent cohort are warranted to confirm and better define the potential clinical utility of PV-CTCs in early-stage NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Células Neoplásicas Circulantes/patologia , Veias Pulmonares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genoma Humano/genética , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias
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