ABSTRACT
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.
Subject(s)
Contrast Media , Endometrial Neoplasms/diagnosis , Endometrial Neoplasms/pathology , Image Enhancement/methods , Magnetic Resonance Imaging/methods , Preoperative Care/methods , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor , Diffusion Magnetic Resonance Imaging/methods , Endometrium/diagnostic imaging , Endometrium/pathology , Evaluation Studies as Topic , Female , Follow-Up Studies , Humans , Middle Aged , Neoplasm Invasiveness , Predictive Value of Tests , Prospective Studies , Reproducibility of Results , Sensitivity and Specificity , Tumor BurdenABSTRACT
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.
Subject(s)
Biomarkers, Tumor/analysis , Endometrial Neoplasms/blood , Endometrial Neoplasms/chemistry , Lymphatic Metastasis , Neural Cell Adhesion Molecule L1/analysis , Aged , Biomarkers, Tumor/blood , Chi-Square Distribution , Curettage , Endometrial Neoplasms/mortality , Endometrial Neoplasms/pathology , Enzyme-Linked Immunosorbent Assay , Female , Humans , Hysterectomy , Kaplan-Meier Estimate , Middle Aged , Neural Cell Adhesion Molecule L1/blood , Preoperative Period , Prognosis , Statistics, Nonparametric , Up-RegulationABSTRACT
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.
