RESUMO
Genetic and nongenetic factors are involved in the pathogenesis of immune-mediated inflammatory diseases (IMIDs). The best-known genetic factor for susceptibility to IMIDs is the human leukocyte antigen (HLA). The aim of the present study was to evaluate the association of HLA class II genes with the risk of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis (SSc) in the Paraguayan population. We included 254 patients with IMIDs (101 SLE, 103 RA, and 50 SSc) and 50 healthy controls. The haplotypes of five genes corresponding to HLA class II genes and their relationship to the IMIDs studied were determined. Note that 84.6% were women, with a mean age of 43.4 ± 14 years. Among the associated HLA alleles, we found the previously identified risk factors in other populations like HLA-DRB1*03:01 and HLA-DRB1*14:02 for RA, as well as new ones not previously identified, such as DPA1*02:01 for SLE and, DB1*02:01 for RA and SSc. In the genetic association analysis, already known associations have been replicated, and unpublished associations have been identified in Paraguayan patients with IMIDs. This is the first genetic association study in Paraguayan patients with IMIDs.
Assuntos
Artrite Reumatoide , Lúpus Eritematoso Sistêmico , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Masculino , Predisposição Genética para Doença , Alelos , Agentes de Imunomodulação , Lúpus Eritematoso Sistêmico/genética , Cadeias HLA-DRB1/genética , Artrite Reumatoide/genética , HaplótiposRESUMO
El estado mutacional del KRAS ha sido considerado como biomarcador para tratamientos biológicos tras varios ensayos clínicos realizados en pacientes con cáncer colorrectal metastásico. Reportes recientes indican que las frecuencias de mutación del gen KRAS en pacientes con CCR de Asia, Europa y Latinoamérica están entre el 24%, 36% y 40%, respectivamente. Paraguay no cuenta con este tipo de informes, a pesar de registrar anualmente en promedio 75 nuevos casos de pacientes diagnosticados con CCR sólo en el Servicio de Cirugía General del Hospital Central del Instituto de Previsión Social (IPS). El presente trabajo ha implementado este análisis de rutina, prerrequisito obligatorio para la administración de fármacos basados en anticuerpos terapéuticos, y revelado una frecuencia de mutación del gen KRAS del 34% en pacientes paraguayos con CCR que acuden a los Servicios del Hospital Central del IPS
The mutational status of the KRAS has been consider as a biomarker for biological treatments after several clinical trials carried out in patient with metastatic colorectal cancer. Recent reports indicate that the KRAS gene mutation frequencies in CRC patients from Asia, Europe, and Latin America are between 24%, 36%, and 40%, respectively. Paraguay does not have this kind of reports, despite registering an average of 75 new cases of patients diagnosed with CRC per year only in the General Surgery Service of the "Central Hospital - Instituto de Prevision Social (IPS)". The present work has implemented this routine analysis, a mandatory prerequisite for the administration of drugs based on therapeutic antibodies and revealed a KRAS gene mutation frequency of 34% in Paraguayan patients with CRC who attend the IPS Central Hospital Services
Assuntos
Neoplasias Colorretais , Mutação , Estudos Transversais , GenesRESUMO
Pancreatic ductal adenocarcinoma, which represents 80% of pancreatic cancers, is mainly diagnosed when treatment with curative intent is not possible. Consequently, the overall five-year survival rate is extremely dismal-around 5% to 7%. In addition, pancreatic cancer is expected to become the second leading cause of cancer-related death by 2030. Therefore, advances in screening, prevention and treatment are urgently needed. Fortunately, a wide range of approaches could help shed light in this area. Beyond the use of cytological or histological samples focusing in diagnosis, a plethora of new approaches are currently being used for a deeper characterization of pancreatic ductal adenocarcinoma, including genetic, epigenetic, and/or proteo-transcriptomic techniques. Accordingly, the development of new analytical technologies using body fluids (blood, bile, urine, etc.) to analyze tumor derived molecules has become a priority in pancreatic ductal adenocarcinoma due to the hard accessibility to tumor samples. These types of technologies will lead us to improve the outcome of pancreatic ductal adenocarcinoma patients.
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BACKGROUND: Around 50% of cutaneous melanomas harbor the BRAF(V600E) mutation and can be treated with BRAF inhibitors. DNA carrying this mutation can be released into circulation as cell-free BRAF(V600E) (cfBRAF(V600E)). Droplet digital PCR (ddPCR) is an analytically sensitive technique for quantifying small concentrations of DNA. We studied the plasma concentrations of cfBRAF(V600E) by ddPCR in patients with melanoma during therapy with BRAF inhibitors. METHODS: Plasma concentrations of cfBRAF(V600E) were measured in 8 controls and 20 patients with advanced melanoma having the BRAF(V600E) mutation during treatment with BRAF inhibitors at baseline, first month, best response, and progression. RESULTS: The BRAF(V600E) mutation was detected by ddPCR even at a fractional abundance of 0.005% in the wild-type gene. Agreement between tumor tissue BRAF(V600E) and plasma cfBRAF(V600E) was 84.3%. Baseline cfBRAF(V600E) correlated with tumor burden (r = 0.742, P < 0.001). cfBRAF(V600E) concentrations decreased significantly at the first month of therapy (basal median, 216 copies/mL; Q1-Q3, 27-647 copies/mL; first response median, 0 copies/mL; Q1-Q3, 0-49 copies/mL; P < 0.01) and at the moment of best response (median, 0 copies/mL; Q1-Q3, 0-33 copies/mL; P < 0.01). At progression, there was a significant increase in the concentration of cfBRAF(V600E) compared with best response (median, 115 copies/mL; Q1-Q3, 3-707 copies/mL; P = 0.013). Lower concentrations of basal cfBRAF(V600E) were significantly associated with longer overall survival and progression-free survival (27.7 months and 9 months, respectively) than higher basal concentrations (8.6 months and 3 months, P < 0.001 and P = 0.024, respectively). CONCLUSIONS: cfBRAF(V600E) quantification in plasma by ddPCR is useful as a follow-up to treatment response in patients with advanced melanoma.
Assuntos
Análise Mutacional de DNA/métodos , DNA/sangue , Melanoma/tratamento farmacológico , Mutação , Reação em Cadeia da Polimerase/métodos , Proteínas Proto-Oncogênicas B-raf , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , DNA/genética , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Indóis/administração & dosagem , Indóis/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Melanoma/sangue , Melanoma/genética , Melanoma/mortalidade , Pessoa de Meia-Idade , Oximas/administração & dosagem , Oximas/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Resultado do Tratamento , VemurafenibAssuntos
Meningioma/diagnóstico por imagem , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Adenocarcinoma/complicações , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/cirurgia , Idoso de 80 Anos ou mais , Biópsia por Agulha Fina , Neoplasias do Ceco/complicações , Neoplasias do Ceco/diagnóstico por imagem , Neoplasias do Ceco/cirurgia , Feminino , Humanos , Meningioma/complicações , Meningioma/cirurgia , Neoplasias da Coluna Vertebral/complicações , Neoplasias da Coluna Vertebral/cirurgia , Ultrassonografia de IntervençãoAssuntos
Feminino , Gravidez , Recém-Nascido , Lactente , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Humanos , Meningioma/fisiopatologia , Meningioma/cirurgia , Meningioma , Endoscopia , Colo/patologia , Colo , Neoplasias do Colo/complicações , Neoplasias do Colo , Colectomia/métodos , Punção Espinal/métodos , Biópsia por Agulha Fina/instrumentação , Biópsia por Agulha Fina/métodos , Biópsia por Agulha Fina , Endoscopia/métodos , Endoscopia , Neoplasias do Ceco/patologia , Neoplasias do Ceco , Colectomia/instrumentação , ColectomiaRESUMO
Recent advances in the field of RNA research have provided compelling evidence implicating microRNA (miRNA) and long non-coding RNA molecules in many diverse and substantial biological processes, including transcriptional and post-transcriptional regulation of gene expression, genomic imprinting, and modulation of protein activity. Thus, studies of non-coding RNA (ncRNA) may contribute to the discovery of possible biomarkers in human cancers. Considering that the response to chemotherapy can differ amongst individuals, researchers have begun to isolate and identify the genes responsible. Identification of targets of this ncRNA associated with cancer can suggest that networks of these linked to oncogenes or tumor suppressors play pivotal roles in cancer development. Moreover, these ncRNA are attractive drug targets since they may be differentially expressed in malignant versus normal cells and regulate expression of critical proteins in the cell. This review focuses on ncRNAs that are differently expressed in malignant tissue, and discusses some of challenges derived from their use as potential biomarkers of tumor properties.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/genética , MicroRNAs/metabolismo , RNA não Traduzido/metabolismo , Biomarcadores Tumorais/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Polimorfismo de Nucleotídeo Único , PrognósticoRESUMO
BACKGROUND: The immunoglobulin G1 (IgG(1)) monoclonal antibody (MoAb) Cetuximab is active in metastatic colorectal cancer (mCRC) as first or subsequent lines of therapy. Efficacy seems restricted to KRAS wild-type tumours. IgG(1) may also induce antibody dependent cell mediated citotoxicity (ADCC) by recruitment of immune effector cells. ADCC is influenced by Fc gamma receptor (FcγR) polymorphisms. We investigated the association of FcγR polymorphisms and disease control rate (DCR) in mCRC patients treated with chemotherapy plus Cetuximab. PATIENTS AND METHODS: Tumour tissues from 106 patients were screened for KRAS codon 12 and 13 mutations using a sensitive multiplex assay (DxS, Manchester, United Kingdom). NRAS (codons: 12, 13 and 61), PI3K (exon 20) and BRAF (exon 15) were analysed by direct sequencing. Fcγ RIIa and Fcγ RIIIa polymorphisms were genotyped by TaqMan assays. RESULTS: DCR was significantly higher in KRAS wild-type tumours (61% versus 39%, p = 0.049). In epidermal growth factor receptor (EGFR) downstream-mutated mCRC patients, those harbouring an FcγRIIa H/H genotype had a higher DCR than alternative genotypes (67% versus 33%, p = 0.017). By multivariate analysis, FcγRIIa-131H/H remained significantly correlated with DCR (p = 0.008). CONCLUSION: FcγR polymorphisms may play a role in the clinical efficacy of Cetuximab in EGFR downstream mutated mCRC patients. Further research into Cetuximab immune-based mechanisms in KRAS-mutated patients seems warranted.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Colorretais/genética , Receptores ErbB/genética , Polimorfismo Genético , Receptores de IgG/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Proteínas ras/genéticaRESUMO
AIM: To investigate the angiogenesis-related protein expression profile characterizing metastatic colorectal cancer (mCRC) with the aim of identifying prognostic markers. METHODS: The expression of 44 angiogenesis-secreted factors was measured by a novel cytokine antibody array methodology. The study evaluated vascular endothelial growth factor (VEGF) and its soluble vascular endothelial growth factor receptor (sVEGFR)-1 protein levels by enzyme immunoassay (EIA) in a panel of 16 CRC cell lines. mRNA VEGF and VEGF-A isoforms were quantified by quantitative reverse-transcription polymerase chain reaction (Q-RT-PCR) and vascular endothelial growth factor receptor (VEGFR)-2 expression was analyzed by flow cytometry. RESULTS: Metastasis-derived CRC cell lines expressed a distinctive molecular profile as compared with those isolated from a primary tumor site. Metastatic CRC cell lines were characterized by higher expression of angiogenin-2 (Ang-2), macrophage chemoattractant proteins-3/4 (MCP-3/4), matrix metalloproteinase-1 (MMP-1), and the chemokines interferon γ inducible T cell α chemoattractant protein (I-TAC), monocyte chemoattractant protein I-309, and interleukins interleukin (IL)-2 and IL-1α, as compared to primary tumor cell lines. In contrast, primary CRC cell lines expressed higher levels of interferon γ (IFN-γ), insulin-like growth factor-1 (IGF-1), IL-6, leptin, epidermal growth factor (EGF), placental growth factor (PlGF), thrombopoietin, transforming growth factor ß1 (TGF-ß1) and VEGF-D, as compared with the metastatic cell lines. VEGF expression does not significantly differ according to the CRC cellular origin in normoxia. Severe hypoxia induced VEGF expression up-regulation but contrary to expectations, metastatic CRC cell lines did not respond as much as primary cell lines to the hypoxic stimulus. In CRC primary-derived cell lines, we observed a two-fold increase in VEGF expression between normoxia and hypoxia as compared to metastatic cell lines. CRC cell lines express a similar pattern of VEGF isoforms (VEGF121, VEGF165 and VEGF189) despite variability in VEGF expression, where the major transcript was VEGF121. No relevant expression of VEGFR-2 was found in CRC cell lines, as compared to that of human umbilical vein endothelial cells and sVEGFR-1 expression did not depend on the CRC cellular origin. CONCLUSION: A distinct angiogenesis-related expression pattern characterizes metastatic CRC cell lines. Factors other than VEGF appear as prognostic markers and intervention targets in the metastatic CRC setting.
Assuntos
Anticorpos/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Citocinas/metabolismo , Metástase Neoplásica/fisiopatologia , Neovascularização Patológica/metabolismo , Linhagem Celular Tumoral , Citocinas/genética , Perfilação da Expressão Gênica , Humanos , Hipóxia/metabolismo , Análise em Microsséries/métodos , Metástase Neoplásica/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Many antitumor therapies affect rapidly dividing cells. However, tumor proliferation may be driven by cancer stem cells (CSCs), which divide slowly and are relatively resistant to cytotoxic drugs. Thus, many tumors may progress because CSCs are not sensitive to the treatment. In this work, we searched for target genes whose expression is involved in proliferation and chemoresistance of CSCs. Both of these processes could be controlled simultaneously by cell regulators such as microRNAs (miRNAs). Therefore, colonospheres with properties of CSCs were obtained from different colon carcinoma cells, and miRNA profiling was performed. The results showed that miR-451 was downregulated in colonspheres versus parental cells. Surprisingly, expression of miR-451 caused a decrease in self-renewal, tumorigenicity, and chemoresistance to irinotecan of colonspheres. We identified cyclooxygenase-2 (COX-2) as an indirect miR-451 target gene involved in sphere growth. Our results indicate that miR-451 downregulation allows the expression of the direct target gene macrophage migration inhibitory factor, involved in the expression of COX-2. In turn, COX-2 allows Wnt activation, which is essential for CSC growth. Furthermore, miR-451 restoration decreases expression of the ATP-binding cassette drug transporter ABCB1 and results in irinotecan sensitization. These findings correlate well with the lower expression of miR-451 observed in patients who did not respond to irinotecan-based first-line therapy compared with patients who did. Our data suggest that miR-451 is a novel candidate to circumvent recurrence and drug resistance in colorectal cancer and could be used as a marker to predict response to irinotecan in patients with colon carcinoma.
Assuntos
MicroRNAs/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Antineoplásicos/farmacologia , Western Blotting , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Linhagem Celular , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Irinotecano , MicroRNAs/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
We report a new germline mutation in exon 13 of the hMSH2 gene (c.2081T>C; F694S) in a patient diagnosed with colorectal carcinoma. The patient's family fulfilled the clinical criteria of the Bethesda guidelines for Lynch syndrome. The segregation analysis determined the presence of the mutation in the proband's mother (breast cancer younger than 40 years old) and in two healthy daughters. The mutation was not present in 116 normal controls screened. The medical implications for the carrier relatives are discussed.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Mutação em Linhagem Germinativa , Proteína 2 Homóloga a MutS/genética , Estudos de Casos e Controles , Análise Mutacional de DNA , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Espanha , População BrancaRESUMO
Thymidylate synthase (TYMS) is a target of the most widely used chemotherapeutic agents against gastrointestinal malignancies, the fluoropyrimidine-based therapy. TYMS expression levels have been identified as predictive biomarkers for 5-fluoruracil (FU) response in colorectal cancer, but their clinical utility remains controversial. The complexity of fluoropyrimidine response must require more mechanisms that currently have not been completely elucidated. In this context, microRNAs (miRNA) may play a role in modulating chemosensitivity. By carrying out an in silico analysis coupled to experimental validation, we detected that miR-192 and miR-215 target TYMS expression in colorectal cancer cell lines. However, downregulation of TYMS by these miRNAs does not sensitize colorectal cancer cell lines to FU treatment. The overexpression of miR-192/215 significantly reduces cell proliferation by targeting cell cycle progression. This effect was partially associated with p53 status, because reduction of cell proliferation and cell cycle arrest was associated with p21 and p27 induction. The decrease of S-phase cells by these miRNAs mitigates the effects of S phase-specific drugs and suggests that other mechanisms different from TYMS overexpression are essential to direct FU resistance. Finally, ectopic expression of miR-192/215 might have stronger impact to predict FU response than TYMS inhibition. Prospective studies to elucidate the role of these miRNAs as predictive biomarkers to FU are necessary.
Assuntos
Ciclo Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/metabolismo , Timidilato Sintase/genética , Sítios de Ligação , Western Blotting , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Biologia Computacional , Humanos , MicroRNAs/genética , Biossíntese de Proteínas/genética , Transcrição Gênica/efeitos dos fármacos , TransfecçãoRESUMO
In the last years, microRNAs (miRNA) have emerged as new molecular players involved in carcinogenesis. Deregulation of miRNAs expression has been shown in different human cancer but the molecular mechanism underlying the alteration of miRNA expression is unknown. To identify tumor-supressor miRNAs silenced through aberrant epigenetic events in colorectal cancer (CRC), we used a sequential approach. We first identified 5 miRNAs down-regulated in patient with colorectal cancer samples and located around/on a CpG island. Treatment with a DNA methyltransferase inhibitor and a HDAC inhibitor restored expression of 3 of the 5 microRNAs (hsa-miR-9, hsa-miR-129 and hsa-miR-137) in 3 CRC cell lines. Expression of hsa-miR-9 was inversely correlated with methylation of their promoter regions as measure by MSP and bisulphate sequencing. Further, methylation of the hsa-miR-9-1, hsa-miR-129-2 and hsa-miR-137 CpG islands were frequently observed in CRC cell lines and in primary CRC tumors, but not in normal colonic mucosa. Finally, methylation of hsa-miR-9-1 was associated with the presence of lymph node metastasis. In summary, our results aid in the understanding of miRNA gene regulation showing that aberrant DNA methylation and histone modifications work together to induce silencing of miRNAs in CRC.
Assuntos
Neoplasias Colorretais/genética , Metilação de DNA , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Acetilação , Antimetabólitos Antineoplásicos/farmacologia , Azacitidina/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Ilhas de CpG , Inativação Gênica , Inibidores de Histona Desacetilases , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Metástase Linfática , MicroRNAs/metabolismo , Fenilbutiratos/farmacologia , Regiões Promotoras Genéticas , Células Tumorais CultivadasRESUMO
PURPOSE: microRNAs (miRNA) are small RNAs that function as post-transcriptional regulators of gene expression. Recent evidence has shown that some miRNAs can act as oncogenes or tumor suppressors. This study was conducted to evaluate the potential association of miRNA expression with clinical outcome in patients with gastric cancer. EXPERIMENTAL DESIGN: Expression of 250 human mature miRNAs was measured by real-time PCR on paraffin-embedded tumor samples of 21 patients with gastric cancer stage III uniformly treated with surgical resection followed by chemoradiation. We identified the miRNAs correlated with disease-free and overall survival times, and the results were evaluated including 24 other patients. In vitro cell proliferation and radiosensitivity studies were done to support clinical data. RESULTS: The results revealed that down-regulation of miR-451 was associated with worse prognosis. miR-451 was detected by in situ hybridization in epithelial cells and showed decreased expression in gastric and colorectal cancer versus nontumoral tissues. Overexpression of miR-451 in gastric and colorectal cancer cells reduced cell proliferation and increased sensitivity to radiotherapy. Microarray and bioinformatic analysis identified the novel oncogene macrophage migration inhibitory factor (MIF) as a potential target of miR-451. In fact, overexpression of miR-451 down-regulated mRNA and protein levels of MIF and decreased expression of reporter genes with MIF target sequences. Moreover, we found a significant inverse correlation between miR-451 and MIF expression in tumoral gastric biopsies. CONCLUSIONS: These findings support the role of miR-451 as a regulator of cancer proliferation and open new perspectives for the development of effective therapies for chemoradioresistant cancers.
Assuntos
Carcinoma/genética , Neoplasias do Colo/genética , Fatores Inibidores da Migração de Macrófagos/genética , MicroRNAs/metabolismo , Neoplasias Gástricas/genética , Adulto , Idoso , Carcinoma/mortalidade , Carcinoma/patologia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Células Epiteliais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Fatores Inibidores da Migração de Macrófagos/biossíntese , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de SobrevidaRESUMO
Colorectal cancer is the third most common cancer and is highly fatal. During the last several years, research has been primarily based on the study of expression profiles using microarray technology. But now, investigators are putting into practice proteomic analyses of cancer tissues and cells to identify new diagnostic or therapeutic biomarkers for this cancer. Because the proteome reflects the state of a cell, tissue or organism more accurately, much is expected from proteomics to yield better tumor markers for disease diagnosis and therapy monitoring. This review summarizes the most relevant applications of proteomics the biomarker discovery for colorectal cancer.
Assuntos
Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/terapia , Proteômica/métodos , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/metabolismo , Eletroforese em Gel Bidimensional , Humanos , Espectrometria de Massas , Pesquisa/tendênciasRESUMO
Interindividual differences in the toxicity and response to anticancer therapies are currently observed in practically all available treatment regimens. A goal of cancer therapy is to predict patient response and toxicity to drugs in order to facilitate the individualization of patient treatment. Identification of subgroups of patients that differ in their prognosis and response to treatment could help to identify the best available drug therapy according the genetic profile. Several mechanisms have been suggested to contribute to chemo-therapeutic drug resistance: amplification or overexpression of membrane transporters, changes in cellular proteins involved in detoxification or in DNA repair, apoptosis and activation of oncogenes or tumor suppressor genes. Colorectal cancer (CRC) is regarded as intrinsically resistant to chemotherapy. Several molecular markers predictive of CRC therapy have been included during the last decade but their results in different studies complicate their application in practical clinical. The simultaneous testing of multiple markers predictive of response could help to identify more accurately the true role of these polymorphisms in CRC therapy. This review analyzes the role of genetic variants in genes involved in the action mechanisms of the drugs used at present in colorectal cancer.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Farmacogenética/métodos , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Polimorfismo Genético/genética , PrognósticoRESUMO
MicroRNAs (miRNAs) are nonprotein-coding RNAs that function as posttranscriptional gene regulators. They can regulate their targets directly by mRNA cleavage or by repressing their translation, depending on the degree of complementariety between the miRNA and the target. Recent evidences have shown that miRNA control cell growth, apoptosis, and differentiation. Moreover, miRNA expression correlates with cancers and could have a crucial function in tumor progression. Bioinformatic data indicates that each miRNA can control hundreds of target genes, but identification of the accurate miRNA targets will be crucial to exploit the emerging knowledge of miRNA contribution to cancer process. While the miRNA field is still emerging, the benefit of our understanding of miRNA in cancer is potentially enormous, especially if we are able to apply this knowledge to provide new therapies for patients.
Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias/genética , Animais , Apoptose/genética , Processos de Crescimento Celular/genética , Terapia Genética , Humanos , Neoplasias/terapiaRESUMO
The benefit of postoperative adjuvant chemotherapy in patients with Dukes' B colorectal cancer is still uncertain and its routine use is not recommended. The five-year relapse rate is approximately 25-40% and the identification of patients at high risk of recurrence would represent an important strategy for the use of adjuvant chemotherapy. We retrospectively analyzed gene expression profiles in frozen tumor specimens from patients with Dukes' B colorectal cancer by using high density oligonucleotide microarrays. Our results show a subset of 48 genes differentially expressed with an associated probability <0.001 in the t-test. Another statistical procedure based on the Fisher criterion resulted in 11 genes able to separate both groups. We selected the 8 genes present in both subsets. The differential expression of five genes (CHD2, RPS5, ZNF148, BRI3 and MGC23401) in colon cancer progression was confirmed by real-time PCR in an independent set of patients of Dukes' B and C stages.
Assuntos
Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Recidiva Local de Neoplasia/genética , Idoso , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Família Multigênica , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase/métodos , Estudos RetrospectivosRESUMO
EGFR overexpression has been implicated in the development of head and neck squamous cell carcinoma (HNSCC). This study evaluates the prognostic ability of four polymorphisms in EGFR gene for patients diagnosed with HNSCC and treated with chemoradiation. EGFR polymorphisms in the promoter region were not associated with clinical or pathological characteristics. In relation to R497K polymorphism, patients with the Arg/Arg genotype showed the highest risk of disease-specificity mortality and none of the patients with the Lys/Lys genotype died throughout the follow-up period of the study. Patients with (CA)(n) repeats <17 in both alleles tended toward inferior overall survival compared with those with (CA)(n) repeats > or = 17 in both alleles (p=0.07). Moreover, the distribution of patients with any (CA)(n) repeats > or = 17 and both alleles <17 was statistically different across patients who were recorded as having partial response or no response to therapy (p=0.034). Combination analysis of both polymorphisms, (CA)(n) repeats and R497K, suggests that these polymorphisms may be associated with clinical outcome in patients treated with chemoradiation.
Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Receptores ErbB/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/mortalidade , Polimorfismo Genético , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da PolimeraseRESUMO
The ultimate goal of cancer proteomics is to adapt proteomic technologies for routine use in clinical laboratories for the purpose of diagnostic and prognostic classification of disease states, as well as in evaluating drug toxicity and efficacy. The novel technologies allows researchers to facilitate the comprehensive analyses of genomes, transcriptomes, and proteomes in health and disease. The information that is expected from such technologies may soon exert a dramatic change in cancer research and impact dramatically on the care of cancer patients. Analysis of tumor-specific proteomic profiles may also allow better understanding of tumor development and the identification of novel targets for cancer therapy. The localization of gene products, which is often difficult to deduce from the sequence, can be determined experimentally. Mechanisms, such as regulation of protein function by proteolysis, recycling, and isolation in cell compartments, affect gene products, not genes. Finally, protein-protein interactions and the molecular composition of cellular structures can be determined only at the protein level. The biological variability among patient samples as well as the great dynamic range of biomarker concentrations are currently the main challenges facing efforts to deduce diagnostic patterns that are unique to specific disease states. While several strategies exist to address this problem, we have tried to offer a wide perspective about the current possibilities.