RESUMO
Background Quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) may yield preoperative tumor biomarkers relevant for prognosis and therapy in cancer. Purpose To explore the value of preoperative DCE-MRI and DWI for the prediction of aggressive disease in endometrial cancer patients. Material and Methods Preoperative MRI (1.5-T) from 177 patients were analyzed and imaging parameters reflecting tumor microvasculature (from DCE-MRI) and tumor microstructure (from DWI) were estimated. The derived imaging parameters were explored in relation to clinico-pathological stage, histological subtype and grade, molecular markers, and patient outcome. Results Low tumor blood flow (Fb) and low rate constant for contrast agent intravasation (kep) were associated with high-risk histological subtype ( P ≤ 0.04 for both) and tended to be associated with poor prognosis ( P ≤ 0.09). Low tumor apparent diffusion coefficient (ADC) value and large tumor volume were both significantly associated with deep myometrial invasion ( P < 0.001 for both) and were also unfavorable prognostic factors ( P = 0.05 and P < 0.001, respectively). Conclusion DCE-MRI and DWI represent valuable supplements to conventional MRI by providing preoperative imaging biomarkers that predict aggressive disease in endometrial cancer patients.
Assuntos
Meios de Contraste , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/patologia , Aumento da Imagem/métodos , Imageamento por Ressonância Magnética/métodos , Cuidados Pré-Operatórios/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Imagem de Difusão por Ressonância Magnética/métodos , Endométrio/diagnóstico por imagem , Endométrio/patologia , Estudos de Avaliação como Assunto , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Carga TumoralRESUMO
BACKGROUND: Several studies have identified L1 cell adhesion molecule (L1CAM) as a strong prognostic marker in endometrial cancer. To further underline the clinical usefulness of this biomarker, we investigated L1CAM as a predictive marker for lymph node metastases and its prognostic impact in curettage specimens and preoperative plasma samples. In addition, we aimed to validate the prognostic value of L1CAM in hysterectomy specimen. METHODS: Immunohistochemical staining of L1CAM was performed for 795 hysterectomy and 1134 curettage specimen from endometrial cancer patients. The L1CAM level in preoperative blood samples from 372 patients was determined using ELISA. RESULTS: Expression of L1CAM in curettage specimen was significantly correlated to L1CAM level in corresponding hysterectomy specimen (P<0.001). Both in curettage and preoperative plasma samples L1CAM upregulation was significantly associated with features of aggressive disease and poor outcome (P<0.001). The L1CAM was an independent predictor of lymph node metastases, after correction for curettage histology, both in curettage specimen (P=0.002) and plasma samples (P=0.048). In the hysterectomy samples L1CAM was significantly associated with poor outcome (P<0.001). CONCLUSIONS: We demonstrate that preoperative evaluation of L1CAM levels, both in curettage or plasma samples, predicts lymph node metastases and adds valuable information on patient prognosis.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias do Endométrio/sangue , Neoplasias do Endométrio/química , Metástase Linfática , Molécula L1 de Adesão de Célula Nervosa/análise , Idoso , Biomarcadores Tumorais/sangue , Distribuição de Qui-Quadrado , Curetagem , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Histerectomia , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Molécula L1 de Adesão de Célula Nervosa/sangue , Período Pré-Operatório , Prognóstico , Estatísticas não Paramétricas , Regulação para CimaRESUMO
Chromosome 8q24 is the most commonly amplified region across multiple cancer types, and the typical length of the amplification suggests that it may target additional genes to MYC. To explore the roles of the genes most frequently included in 8q24 amplifications, we analyzed the relation between copy number alterations and gene expression in three sets of endometrial cancers (Nâ=â252); and in glioblastoma, ovarian, and breast cancers profiled by TCGA. Among the genes neighbouring MYC, expression of the bromodomain-containing gene ATAD2 was the most associated with amplification. Bromodomain-containing genes have been implicated as mediators of MYC transcriptional function, and indeed ATAD2 expression was more closely associated with expression of genes known to be upregulated by MYC than was MYC itself. Amplifications of 8q24, expression of genes downstream from MYC, and overexpression of ATAD2 predicted poor outcome and increased from primary to metastatic lesions. Knockdown of ATAD2 and MYC in seven endometrial and 21 breast cancer cell lines demonstrated that cell lines that were dependent on MYC also depended upon ATAD2. These same cell lines were also the most sensitive to the histone deacetylase (HDAC) inhibitor Trichostatin-A, consistent with prior studies identifying bromodomain-containing proteins as targets of inhibition by HDAC inhibitors. Our data indicate high ATAD2 expression is a marker of aggressive endometrial cancers, and suggest specific inhibitors of ATAD2 may have therapeutic utility in these and other MYC-dependent cancers.
Assuntos
Adenosina Trifosfatases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Genes myc/fisiologia , Genômica/métodos , ATPases Associadas a Diversas Atividades Celulares , Adenosina Trifosfatases/genética , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Feminino , Genes myc/genética , Humanos , Immunoblotting , Hibridização in Situ FluorescenteRESUMO
Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 Î 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression(AU)
Assuntos
Humanos , Neoplasias do Endométrio/genética , Expressão Gênica/genética , Bibliografia Nacional , UruguaiRESUMO
Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 Î 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression(AU)