Adenosine-to-inosine (A-to-I) RNA editing is a widespread post-transcriptional mechanism, but its genomic landscape and clinical relevance in cancer have not been investigated systematically. We ...characterized the global A-to-I RNA editing profiles of 6,236 patient samples of 17 cancer types from The Cancer Genome Atlas and revealed a striking diversity of altered RNA-editing patterns in tumors relative to normal tissues. We identified an appreciable number of clinically relevant editing events, many of which are in noncoding regions. We experimentally demonstrated the effects of several cross-tumor nonsynonymous RNA editing events on cell viability and provide the evidence that RNA editing could selectively affect drug sensitivity. These results highlight RNA editing as an exciting theme for investigating cancer mechanisms, biomarkers, and treatments.
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•A systematic analysis of genome-wide RNA editing events across tumor types was done•A considerable number of clinically relevant RNA editing events are revealed•The functional effects of cross-tumor nonsynonymous RNA editing events are shown•Evidence that nonsynonymous RNA editing may affect drug sensitivity is provided
Han et al. characterize global A-to-I RNA editing profiles across 17 cancer types and experimentally demonstrate the effects of several cross-tumor nonsynonymous RNA editing events on cell viability and drug sensitivity.
Abstract Background Preoperative histologic examination of tumour tissue is essential when deciding if endometrial cancer surgery should include lymph node sampling. We wanted to investigate if ...biomarkers could improve prediction of lymph node metastasis and outcome. Patients and methods Curettage specimens from 832 endometrial carcinoma patients prospectively recruited from 10 centres in the MoMaTEC trial (Molecular Markers in Treatment of Endometrial Cancer) were investigated for hormone receptor and p53 status. Results Eighteen per cent of tumours were double negative for oestrogen- and progesterone receptors (ER/PR loss), 24% overexpressed p53. Pathologic expression of all markers correlated with nodal metastases, high FIGO (Federation International of Gynecology and Obstetrics) stage, non-endometrioid histology, high grade and poor prognosis (all P < 0.001). ER/PR loss independently predicted lymph node metastasis (odds ratios (OR) 2.0, 95% confidence interval (CI) 1.1–3.7) adjusted for preoperative curettage histology and predicted poor disease-specific survival adjusted for age, FIGO stage, histologic type, grade and myometrial infiltration (hazard ratio (HR) 2.3, 95% CI 1.4–3.9). For lymph node negative endometrioid tumours, ER/PR loss influenced survival independent of grade. Conclusion Double negative hormone receptor status in endometrial cancer curettage independently predicts lymph node metastasis and poor prognosis in a prospective multicentre setting. Implementing hormone receptor status to improve risk-stratification for selecting patients unlikely to benefit from lymphadenectomy seems justified.
Endometrial cancer (EC) is the most common gynaecologic malignancy in developed countries. The main challenge in EC management is to correctly estimate the risk of metastases at diagnosis and the ...risk to develop recurrences in the future. Risk stratification determines the need for surgical staging and adjuvant treatment. Detection of occult, microscopic metastases upstages patients, provides important prognostic information and guides adjuvant treatment. The molecular classification subdivides EC into four prognostic subgroups: POLE ultramutated; mismatch repair deficient (MMRd); nonspecific molecular profile (NSMP); and TP53 mutated (p53abn). How surgical staging should be adjusted based on preoperative molecular profiling is currently unknown. Moreover, little is known whether and how other known prognostic biomarkers affect prognosis prediction independent of or in addition to these molecular subgroups. This review summarizes the factors incorporated in surgical staging (i.e., peritoneal washing, lymph node dissection, omentectomy and peritoneal biopsies), and its impact on prognosis and adjuvant treatment decisions in an era of molecular classification of EC. Moreover, the relation between FIGO stage and molecular classification is evaluated including the current gaps in knowledge and future perspectives.
Recent studies have detailed the genomic landscape of primary endometrial cancers, but the evolution of these cancers into metastases has not been characterized. We performed whole-exome sequencing ...of 98 tumor biopsies including complex atypical hyperplasias, primary tumors and paired abdominopelvic metastases to survey the evolutionary landscape of endometrial cancer. We expanded and reanalyzed The Cancer Genome Atlas (TCGA) data, identifying new recurrent alterations in primary tumors, including mutations in the estrogen receptor cofactor gene NRIP1 in 12% of patients. We found that likely driver events were present in both primary and metastatic tissue samples, with notable exceptions such as ARID1A mutations. Phylogenetic analyses indicated that the sampled metastases typically arose from a common ancestral subclone that was not detected in the primary tumor biopsy. These data demonstrate extensive genetic heterogeneity in endometrial cancers and relative homogeneity across metastatic sites.
Stathmin is a prognostic marker in many cancers, including endometrial cancer. Preclinical studies, predominantly in breast cancer, have suggested that stathmin may additionally be a predictive ...marker for response to paclitaxel. We first evaluated the response to paclitaxel in endometrial cancer cell lines before and after stathmin knock-down. Subsequently we investigated the clinical response to paclitaxel containing chemotherapy in metastatic endometrial cancer in relation to stathmin protein level in tumors. Stathmin level was also determined in metastatic lesions, analyzing changes in biomarker status on disease progression. Knock-down of stathmin improved sensitivity to paclitaxel in endometrial carcinoma cell lines with both naturally higher and lower sensitivity to paclitaxel. In clinical samples, high stathmin level was demonstrated to be associated with poor response to paclitaxel containing chemotherapy and to reduced disease specific survival only in patients treated with such combination. Stathmin level increased significantly from primary to metastatic lesions. This study suggests, supported by both preclinical and clinical data, that stathmin could be a predictive biomarker for response to paclitaxel treatment in endometrial cancer. Re-assessment of stathmin level in metastatic lesions prior to treatment start may be relevant. Also, validation in a randomized clinical trial will be important.
Abstract Objective In endometrial cancer loss of progesterone receptor (PR, gene name PGR ) is associated with aggressive disease and altered response to hormonal treatment. The aim of this study was ...to investigate changes in PR expression level with disease progression, and explore whether differences in gene expression according to PR status can be linked to processes involved in cancer development elucidating new therapeutic opportunities. Methods 686 primary endometrial cancers and 171 metastatic lesions were investigated for PR expression in relation to clinical and histopathological data. Protein levels were investigated by immunohistochemistry and reverse phase protein array, and mRNA levels by DNA oligonucleotide microarray. Results PR protein level was significantly associated with PGR mRNA expression ( P < 0.001) and patient survival ( P < 0.001). Loss of PR increased with disease progression, with 23% of the primary tumours and 76% of metastases demonstrating PR loss. Using a cell cycle progression signature score, PR loss was associated with increased proliferation for both oestrogen receptor (ER) positive and negative tumours. Through a Connectivity Map search, CDK inhibitors and other drugs with anti-proliferative effects were suggested in particular for treatment of patients with loss of PR. Conclusion Loss of PR in endometrial cancer is associated with increased proliferation, poor survival, and increases from primary to metastatic lesions. Based on expression profiles, CDK inhibitors may have activity in PR negative tumours, supporting further testing in clinical trials for patients with systemic endometrial cancer dependent on PR status.
Traditionally, scientific research has focused on studying individual events, such as single mutations, gene function, or the effect that mutating one protein has on a biological phenotype. A range ...of technologies is beginning to provide information that will enable a holistic view of how genomic and epigenetic aberrations in cancer cells can alter the homeostasis of signalling networks within these cells, between cancer cells and the local microenvironment, and at the organ and organism level. This process, termed Systems Biology, needs to be integrated with an iterative approach wherein hypotheses and predictions that arise from modelling are refined and constrained by experimental evaluation. Systems biology approaches will be vital for developing and implementing effective strategies to deliver personalized cancer therapy. Specifically, these approaches will be important to select those patients who are most likely to benefit from targeted therapies and for the development and implementation of rational combinatorial therapies. Systems biology can help to increase therapy efficacy or bypass the emergence of resistance, thus converting the current-often short term-effects of targeted therapies into durable responses, ultimately to improve patient quality of life and provide a cure.
The aim of this study was to explore the relation between preoperative tumor size based on magnetic resonance imaging (MRI) and the surgical pathologic staging parameters (deep myometrial invasion, ...cervical stroma invasion, and metastatic lymph nodes) and to assess the prognostic impact of tumor size in endometrial carcinomas. Interobserver variability for the different tumor size measurements was also assessed.
Preoperative pelvic MRI of 212 patients with histologically confirmed endometrial carcinomas was read independently by 3 radiologists. Maximum tumor diameters were measured in 3 orthogonal planes (anteroposterior, transverse, and craniocaudal planes CC), and tumor volumes were estimated. Tumor size was analyzed in relation to surgical staging results and patient survival. The multivariate analyses were adjusted for preoperative risk status based on endometrial biopsy. Intraclass correlation coefficients and receiver operating characteristics curves for the different tumor measurements were also calculated.
Anteroposterior tumor diameter independently predicted deep myometrial invasion (P < 0.001), whereas CC tumor diameter tended to independently predict lymph node metastases (P = 0.06). Based on receiver operating characteristic curves, the following tumor size cutoff values were identified: anteroposterior diameter greater than 2 cm predicted deep myometrial invasion (unadjusted odds ratio OR, 12.4; P < 0.001; adjusted OR, 6.7; P < 0.001) and CC diameter greater than 4 cm predicted lymph node metastases (unadjusted OR, 6.2; P < 0.001; adjusted OR, 4.9; P = 0.009). Large tumor size was associated with reduced progression/recurrence-free survival (P ≤ 0.005 for all size parameters), and CC diameter had an independent impact on survival (adjusted hazards ratio, 1.04; P = 0.009). The interobserver variability for the different size measurements was very low (intraclass correlation coefficient, 0.78-0.85).
Anteroposterior tumor diameter greater than 2 cm predicts deep myometrial invasion, and CC tumor diameter greater than 4 cm predicts lymph node metastases. Tumor size is a strong prognostic factor in endometrial carcinomas. Preoperative tumor measurements based on MRI may potentially improve preoperative risk stratification models and thus enable better tailored surgical treatment in endometrial cancer.
We hypothesized that estrogen receptor-α (ER-α) status in endometrial carcinomas, associated with poor prognosis, is reflected in transcriptional signatures suggesting targets for new therapy.
...Endometrial carcinoma samples in a primary investigation cohort (n = 76) and three independent validation cohorts (n = 155/286/111) were analyzed through integrated molecular profiling. Biomarkers were assessed by immunohistochemistry (IHC), DNA oligonucleotide microarray, quantitative PCR (qPCR), single-nucleotide polymorphism (SNP) array, and Sanger sequencing in the cohorts, annotated for comprehensive histopathologic and clinical data, including follow-up.
ER-α immunohistochemical staining was strongly associated with mRNA expression of the receptor gene (ESR1) and patient survival (both P < 0.001). ER-α negativity associated with activation of genes involved in Wnt-, Sonic Hedgehog-, and TGF-β signaling in the investigation cohort, indicating epithelial-mesenchymal transition (EMT). The association between low ER-α and EMT was validated in three independent datasets. Furthermore, phosphoinositide 3-kinase (PI3K) and mTOR inhibitors were among the top-ranked drug signatures negatively correlated with the ER-α-negative tumors. Low ER-α was significantly associated with PIK3CA amplifications but not mutations. Also, low ER-α was correlated to high expression of Stathmin, a marker associated with PTEN loss, and a high PI3K activation signature.
Lack of ER-α in endometrial cancer is associated with EMT and reduced survival. We present a rationale for investigating ER-α's potential to predict response to PI3K/mTOR inhibitors in clinical trials and also suggest EMT inhibitors to ER-α-negative endometrial carcinomas.
Protein levels and function are poorly predicted by genomic and transcriptomic analysis of patient tumours. Therefore, direct study of the functional proteome has the potential to provide a wealth of ...information that complements and extends genomic, epigenomic and transcriptomic analysis in The Cancer Genome Atlas (TCGA) projects. Here we use reverse-phase protein arrays to analyse 3,467 patient samples from 11 TCGA 'Pan-Cancer' diseases, using 181 high-quality antibodies that target 128 total proteins and 53 post-translationally modified proteins. The resultant proteomic data are integrated with genomic and transcriptomic analyses of the same samples to identify commonalities, differences, emergent pathways and network biology within and across tumour lineages. In addition, tissue-specific signals are reduced computationally to enhance biomarker and target discovery spanning multiple tumour lineages. This integrative analysis, with an emphasis on pathways and potentially actionable proteins, provides a framework for determining the prognostic, predictive and therapeutic relevance of the functional proteome.
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