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1.  Design of a multi-signature ensemble classifier predicting neuroblastoma patients' outcome 
BMC Bioinformatics  2012;13(Suppl 4):S13.
Neuroblastoma is the most common pediatric solid tumor of the sympathetic nervous system. Development of improved predictive tools for patients stratification is a crucial requirement for neuroblastoma therapy. Several studies utilized gene expression-based signatures to stratify neuroblastoma patients and demonstrated a clear advantage of adding genomic analysis to risk assessment. There is little overlapping among signatures and merging their prognostic potential would be advantageous. Here, we describe a new strategy to merge published neuroblastoma related gene signatures into a single, highly accurate, Multi-Signature Ensemble (MuSE)-classifier of neuroblastoma (NB) patients outcome.
Gene expression profiles of 182 neuroblastoma tumors, subdivided into three independent datasets, were used in the various phases of development and validation of neuroblastoma NB-MuSE-classifier. Thirty three signatures were evaluated for patients' outcome prediction using 22 classification algorithms each and generating 726 classifiers and prediction results. The best-performing algorithm for each signature was selected, validated on an independent dataset and the 20 signatures performing with an accuracy > = 80% were retained.
We combined the 20 predictions associated to the corresponding signatures through the selection of the best performing algorithm into a single outcome predictor. The best performance was obtained by the Decision Table algorithm that produced the NB-MuSE-classifier characterized by an external validation accuracy of 94%. Kaplan-Meier curves and log-rank test demonstrated that patients with good and poor outcome prediction by the NB-MuSE-classifier have a significantly different survival (p < 0.0001). Survival curves constructed on subgroups of patients divided on the bases of known prognostic marker suggested an excellent stratification of localized and stage 4s tumors but more data are needed to prove this point.
The NB-MuSE-classifier is based on an ensemble approach that merges twenty heterogeneous, neuroblastoma-related gene signatures to blend their discriminating power, rather than numeric values, into a single, highly accurate patients' outcome predictor. The novelty of our approach derives from the way to integrate the gene expression signatures, by optimally associating them with a single paradigm ultimately integrated into a single classifier. This model can be exported to other types of cancer and to diseases for which dedicated databases exist.
PMCID: PMC3314564  PMID: 22536959
2.  Artificial neural network classifier predicts neuroblastoma patients’ outcome 
BMC Bioinformatics  2016;17(Suppl 12):83-93.
More than fifty percent of neuroblastoma (NB) patients with adverse prognosis do not benefit from treatment making the identification of new potential targets mandatory. Hypoxia is a condition of low oxygen tension, occurring in poorly vascularized tissues, which activates specific genes and contributes to the acquisition of the tumor aggressive phenotype. We defined a gene expression signature (NB-hypo), which measures the hypoxic status of the neuroblastoma tumor. We aimed at developing a classifier predicting neuroblastoma patients’ outcome based on the assessment of the adverse effects of tumor hypoxia on the progression of the disease.
Multi-layer perceptron (MLP) was trained on the expression values of the 62 probe sets constituting NB-hypo signature to develop a predictive model for neuroblastoma patients’ outcome. We utilized the expression data of 100 tumors in a leave-one-out analysis to select and construct the classifier and the expression data of the remaining 82 tumors to test the classifier performance in an external dataset. We utilized the Gene set enrichment analysis (GSEA) to evaluate the enrichment of hypoxia related gene sets in patients predicted with “Poor” or “Good” outcome.
We utilized the expression of the 62 probe sets of the NB-Hypo signature in 182 neuroblastoma tumors to develop a MLP classifier predicting patients’ outcome (NB-hypo classifier). We trained and validated the classifier in a leave-one-out cross-validation analysis on 100 tumor gene expression profiles. We externally tested the resulting NB-hypo classifier on an independent 82 tumors’ set. The NB-hypo classifier predicted the patients’ outcome with the remarkable accuracy of 87 %. NB-hypo classifier prediction resulted in 2 % classification error when applied to clinically defined low-intermediate risk neuroblastoma patients. The prediction was 100 % accurate in assessing the death of five low/intermediated risk patients. GSEA of tumor gene expression profile demonstrated the hypoxic status of the tumor in patients with poor prognosis.
We developed a robust classifier predicting neuroblastoma patients’ outcome with a very low error rate and we provided independent evidence that the poor outcome patients had hypoxic tumors, supporting the potential of using hypoxia as target for neuroblastoma treatment.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-016-1194-3) contains supplementary material, which is available to authorized users.
PMCID: PMC5123344
Neuroblastoma; Hypoxia; Outcome prediction; Gene set enrichment analysis; Gene signature
3.  Use of Attribute Driven Incremental Discretization and Logic Learning Machine to build a prognostic classifier for neuroblastoma patients 
BMC Bioinformatics  2014;15(Suppl 5):S4.
Cancer patient's outcome is written, in part, in the gene expression profile of the tumor. We previously identified a 62-probe sets signature (NB-hypo) to identify tissue hypoxia in neuroblastoma tumors and showed that NB-hypo stratified neuroblastoma patients in good and poor outcome [1]. It was important to develop a prognostic classifier to cluster patients into risk groups benefiting of defined therapeutic approaches. Novel classification and data discretization approaches can be instrumental for the generation of accurate predictors and robust tools for clinical decision support. We explored the application to gene expression data of Rulex, a novel software suite including the Attribute Driven Incremental Discretization technique for transforming continuous variables into simplified discrete ones and the Logic Learning Machine model for intelligible rule generation.
We applied Rulex components to the problem of predicting the outcome of neuroblastoma patients on the bases of 62 probe sets NB-hypo gene expression signature. The resulting classifier consisted in 9 rules utilizing mainly two conditions of the relative expression of 11 probe sets. These rules were very effective predictors, as shown in an independent validation set, demonstrating the validity of the LLM algorithm applied to microarray data and patients' classification. The LLM performed as efficiently as Prediction Analysis of Microarray and Support Vector Machine, and outperformed other learning algorithms such as C4.5. Rulex carried out a feature selection by selecting a new signature (NB-hypo-II) of 11 probe sets that turned out to be the most relevant in predicting outcome among the 62 of the NB-hypo signature. Rules are easily interpretable as they involve only few conditions.
Furthermore, we demonstrate that the application of a weighted classification associated with the rules improves the classification of poorly represented classes.
Our findings provided evidence that the application of Rulex to the expression values of NB-hypo signature created a set of accurate, high quality, consistent and interpretable rules for the prediction of neuroblastoma patients' outcome. We identified the Rulex weighted classification as a flexible tool that can support clinical decisions. For these reasons, we consider Rulex to be a useful tool for cancer classification from microarray gene expression data.
PMCID: PMC4095004  PMID: 25078098
Logic Learning Machine; Attribute Driven Incremental Discretization; Explicit rules; NB-hypo-II signature; Neuroblastoma; Hypoxia; Classifier; Weighted Classification
4.  Transcribed-ultra conserved region expression is associated with outcome in high-risk neuroblastoma 
BMC Cancer  2009;9:441.
Neuroblastoma is the most common, pediatric, extra-cranial, malignant solid tumor. Despite multimodal therapeutic protocols, outcome for children with a high-risk clinical phenotype remains poor, with long-term survival still less than 40%. Hereby, we evaluated the potential of non-coding RNA expression to predict outcome in high-risk, stage 4 neuroblastoma.
We analyzed expression of 481 Ultra Conserved Regions (UCRs) by reverse transcription-quantitative real-time PCR and of 723 microRNAs by microarrays in 34 high-risk, stage 4 neuroblastoma patients.
First, the comparison of 8 short- versus 12 long-term survivors showed that 54 UCRs were significantly (P < 0.0491) over-expressed in the former group. For 48 Ultra Conserved Region (UCRs) the expression levels above the cut-off values defined by ROC curves were strongly associated with good-outcome (OS: 0.0001

Our pilot study suggests that a deregulation of the microRNA/T-UCR network may play an important role in the pathogenesis of neuroblastoma. After further validation on a larger independent set of samples, such findings may be applied as the first T-UCR prognostic signature for high-risk neuroblastoma patients.
PMCID: PMC2804711  PMID: 20003513
Molecular Cancer  2010;9:185.
Hypoxia is a condition of low oxygen tension occurring in the tumor microenvironment and it is related to poor prognosis in human cancer. To examine the relationship between hypoxia and neuroblastoma, we generated and tested an in vitro derived hypoxia gene signature for its ability to predict patients' outcome.
We obtained the gene expression profile of 11 hypoxic neuroblastoma cell lines and we derived a robust 62 probesets signature (NB-hypo) taking advantage of the strong discriminating power of the l1-l2 feature selection technique combined with the analysis of differential gene expression. We profiled gene expression of the tumors of 88 neuroblastoma patients and divided them according to the NB-hypo expression values by K-means clustering. The NB-hypo successfully stratifies the neuroblastoma patients into good and poor prognosis groups. Multivariate Cox analysis revealed that the NB-hypo is a significant independent predictor after controlling for commonly used risk factors including the amplification of MYCN oncogene. NB-hypo increases the resolution of the MYCN stratification by dividing patients with MYCN not amplified tumors in good and poor outcome suggesting that hypoxia is associated with the aggressiveness of neuroblastoma tumor independently from MYCN amplification.
Our results demonstrate that the NB-hypo is a novel and independent prognostic factor for neuroblastoma and support the view that hypoxia is negatively correlated with tumors' outcome. We show the power of the biology-driven approach in defining hypoxia as a critical molecular program in neuroblastoma and the potential for improvement in the current criteria for risk stratification.
PMCID: PMC2908582  PMID: 20624283
PLoS ONE  2014;9(10):e108818.
Identifying relevant signatures for clinical patient outcome is a fundamental task in high-throughput studies. Signatures, composed of features such as mRNAs, miRNAs, SNPs or other molecular variables, are often non-overlapping, even though they have been identified from similar experiments considering samples with the same type of disease. The lack of a consensus is mostly due to the fact that sample sizes are far smaller than the numbers of candidate features to be considered, and therefore signature selection suffers from large variation. We propose a robust signature selection method that enhances the selection stability of penalized regression algorithms for predicting survival risk. Our method is based on an aggregation of multiple, possibly unstable, signatures obtained with the preconditioned lasso algorithm applied to random (internal) subsamples of a given cohort data, where the aggregated signature is shrunken by a simple thresholding strategy. The resulting method, RS-PL, is conceptually simple and easy to apply, relying on parameters automatically tuned by cross validation. Robust signature selection using RS-PL operates within an (external) subsampling framework to estimate the selection probabilities of features in multiple trials of RS-PL. These probabilities are used for identifying reliable features to be included in a signature. Our method was evaluated on microarray data sets from neuroblastoma, lung adenocarcinoma, and breast cancer patients, extracting robust and relevant signatures for predicting survival risk. Signatures obtained by our method achieved high prediction performance and robustness, consistently over the three data sets. Genes with high selection probability in our robust signatures have been reported as cancer-relevant. The ordering of predictor coefficients associated with signatures was well-preserved across multiple trials of RS-PL, demonstrating the capability of our method for identifying a transferable consensus signature. The software is available as an R package rsig at CRAN (
PMCID: PMC4190101  PMID: 25295525
PLoS Medicine  2010;7(7):e1000307.
Jen Jen Yeh and colleagues developed and validated a six-gene signature in patients with pancreatic ductal adenocarcinoma that may be used to better stage the disease in these patients and assist in treatment decisions.
Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease. For patients with localized PDAC, surgery is the best option, but with a median survival of less than 2 years and a difficult and prolonged postoperative course for most, there is an urgent need to better identify patients who have the most aggressive disease.
Methods and Findings
We analyzed the gene expression profiles of primary tumors from patients with localized compared to metastatic disease and identified a six-gene signature associated with metastatic disease. We evaluated the prognostic potential of this signature in a training set of 34 patients with localized and resected PDAC and selected a cut-point associated with outcome using X-tile. We then applied this cut-point to an independent test set of 67 patients with localized and resected PDAC and found that our signature was independently predictive of survival and superior to established clinical prognostic factors such as grade, tumor size, and nodal status, with a hazard ratio of 4.1 (95% confidence interval [CI] 1.7–10.0). Patients defined to be high-risk patients by the six-gene signature had a 1-year survival rate of 55% compared to 91% in the low-risk group.
Our six-gene signature may be used to better stage PDAC patients and assist in the difficult treatment decisions of surgery and to select patients whose tumor biology may benefit most from neoadjuvant therapy. The use of this six-gene signature should be investigated in prospective patient cohorts, and if confirmed, in future PDAC clinical trials, its potential as a biomarker should be investigated. Genes in this signature, or the pathways that they fall into, may represent new therapeutic targets.
Please see later in the article for the Editors' Summary
Editors' Summary
Pancreatic cancer kills nearly a quarter of a million people every year. It begins when a cell in the pancreas (an organ lying behind the stomach that produces digestive enzymes and hormones such as insulin, which controls blood sugar levels) acquires genetic changes that allow it to grow uncontrollably and to spread around the body (metastasize). Nearly all pancreatic cancers are “pancreatic ductal adenocarcinomas” (PDACs)—tumors that start in the cells that line the tubes in the pancreas that take digestive juices to the gut. Because PDAC rarely causes any symptoms early in its development, it has already metastasized in about half of patients before it is diagnosed. Consequently, the average survival time after a diagnosis of PDAC is only 5–8 months. At present, the only chance for cure is surgical removal (resection) of the tumor, part of the pancreas, and other nearby digestive organs. The operation that is needed for the majority of patients—the Whipple procedure—is only possible in the fifth of patients whose tumor is found when it is small enough to be resectable but even with postoperative chemotherapy, these patients only live for 23 months after surgery on average, possibly because they have micrometastases at the time of their operation.
Why Was This Study Done?
Despite this poor overall outcome, about a quarter of patients with resectable PDAC survive for more than 5 years after surgery. Might some patients, therefore, have a less aggressive form of PDAC determined by the biology of the primary (original) tumor? If this is the case, it would be useful to be able to stratify patients according to the aggressiveness of their disease so that patients with very aggressive disease could be given chemotherapy before surgery (neoadjuvant therapy) to kill any micrometastases. At present neoadjuvant therapy is given to patients with locally advanced, unresectable tumors. In this study, the researchers compare gene expression patterns in primary tumor samples collected from patients with localized PDAC and from patients with metastatic PDAC between 1999 and 2007 to try to identify molecular markers that distinguish between more and less aggressive PDACs.
What Did the Researchers Do and Find?
The researchers identified a six-gene signature that was associated with metastatic disease using a molecular biology approach called microarray hybridization and a statistical method called significance analysis of microarrays to analyze gene expression patterns in primary tumor samples from 15 patients with localized PDAC and 15 patients with metastatic disease. Next, they used a training set of tumor samples from another 34 patients with localized and resected PDAC, microarray hybridization, and a graphical method called X-tile to select a combination of expression levels of the six genes that discriminated optimally between high-risk (aggressive) and low-risk (less aggressive) tumors on the basis of patient survival (a “cut-point”). When the researchers applied this cut-point to an independent set of 67 tumor samples from patients with localized and resected PDAC, they found that 42 patients had high-risk tumors. These patients had an average survival time of 15 months; 55% of them were alive a year after surgery. The remaining 25 patients, who had low-risk tumors, had an average survival time of 49 months and 91% of them were alive a year after resection.
What Do These Findings Mean?
These and other findings identify a six-gene signature that can predict outcomes in patients with localized, resectable PDAC better than, and independently of, established clinical markers of outcome. If the predictive ability of this signature can be confirmed in additional patients, it could be used to help patients make decisions about their treatment. For example, a patient wondering whether to risk the Whipple procedure (2%–6% of patients die during this operation and more than 50% have serious postoperative complications), the knowledge that their tumor was low risk might help them decide to have the operation. Conversely, a patient in poor health with a high-risk tumor might decide to spare themselves the trauma of major surgery. The six-gene signature might also help clinicians decide which patients would benefit most from neoadjuvant therapy. Finally, the genes in this signature, or the biological pathways in which they participate, might represent new therapeutic targets for the treatment of PDAC.
Additional Information
Please access these Web sites via the online version of this summary at
The US National Cancer Institute provides information for patients and health professionals about all aspects of pancreatic cancer (in English and Spanish), including a booklet for patients
The American Cancer Society also provides detailed information about pancreatic cancer
The UK National Health Service and Cancer Research UK include information for patients on pancreatic cancer on their Web sites
MedlinePlus provides links to further resources on pancreatic cancer (in English and Spanish)
Cure Pancreatic Cancer provides information about scientific and medical research related to the diagnosis, treatment, cure, and prevention of pancreatic cancer
Pancreatic Cancer Action Network is a US organization that supports research, patient support, community outreach, and advocacy for a cure for pancreatic cancer
PMCID: PMC2903589  PMID: 20644708
More accurate assessment of prognosis is important to further improve the choice of risk-related therapy in neuroblastoma (NB) patients. In this study, we aimed to establish and validate a prognostic miRNA signature for children with NB and tested it in both fresh frozen and archived formalin-fixed paraffin-embedded (FFPE) samples.
Experimental Design
Four hundred-thirty human mature miRNAs were profiled in two patient subgroups with maximally divergent clinical courses. Univariate logistic regression analysis was used to select miRNAs correlating with NB patient survival. A 25-miRNA gene signature was built using 51 training samples, tested on 179 test samples, and validated on an independent set of 304 fresh frozen tumor samples and 75 archived FFPE samples.
The 25-miRNA signature significantly discriminates the test patients with respect to progression-free and overall survival (P < 0.0001), both in the overall population and in the cohort of high-risk patients. Multivariate analysis indicates that the miRNA signature is an independent predictor of patient survival after controlling for current risk factors. The results were confirmed in an external validation set. In contrast to a previously published mRNA classifier, the 25-miRNA signature was found to be predictive for patient survival in a set of 75 FFPE neuroblastoma samples.
In this study, we present the largest NB miRNA expression study so far, including more than 500 NB patients. We established and validated a robust miRNA classifier, able to identify a cohort of high-risk NB patients at greater risk for adverse outcome using both fresh frozen and archived material.
PMCID: PMC4008338  PMID: 22031095
PLoS Medicine  2014;11(12):e1001770.
In this study, Lee and colleagues develop a genomic predictor that can identify patients at high risk for late recurrence of hepatocellular carcinoma (HCC) and provided new biomarkers for risk stratification.
Typically observed at 2 y after surgical resection, late recurrence is a major challenge in the management of hepatocellular carcinoma (HCC). We aimed to develop a genomic predictor that can identify patients at high risk for late recurrence and assess its clinical implications.
Methods and Findings
Systematic analysis of gene expression data from human liver undergoing hepatic injury and regeneration revealed a 233-gene signature that was significantly associated with late recurrence of HCC. Using this signature, we developed a prognostic predictor that can identify patients at high risk of late recurrence, and tested and validated the robustness of the predictor in patients (n = 396) who underwent surgery between 1990 and 2011 at four centers (210 recurrences during a median of 3.7 y of follow-up). In multivariate analysis, this signature was the strongest risk factor for late recurrence (hazard ratio, 2.2; 95% confidence interval, 1.3–3.7; p = 0.002). In contrast, our previously developed tumor-derived 65-gene risk score was significantly associated with early recurrence (p = 0.005) but not with late recurrence (p = 0.7). In multivariate analysis, the 65-gene risk score was the strongest risk factor for very early recurrence (<1 y after surgical resection) (hazard ratio, 1.7; 95% confidence interval, 1.1–2.6; p = 0.01). The potential significance of STAT3 activation in late recurrence was predicted by gene network analysis and validated later. We also developed and validated 4- and 20-gene predictors from the full 233-gene predictor. The main limitation of the study is that most of the patients in our study were hepatitis B virus–positive. Further investigations are needed to test our prediction models in patients with different etiologies of HCC, such as hepatitis C virus.
Two independently developed predictors reflected well the differences between early and late recurrence of HCC at the molecular level and provided new biomarkers for risk stratification.
Please see later in the article for the Editors' Summary
Editors' Summary
Primary liver cancer—a tumor that starts when a liver cell acquires genetic changes that allow it to grow uncontrollably—is the second-leading cause of cancer-related deaths worldwide, killing more than 600,000 people annually. If hepatocellular cancer (HCC; the most common type of liver cancer) is diagnosed in its early stages, it can be treated by surgically removing part of the liver (resection), by liver transplantation, or by local ablation, which uses an electric current to destroy the cancer cells. Unfortunately, the symptoms of HCC, which include weight loss, tiredness, and jaundice (yellowing of the skin and eyes), are vague and rarely appear until the cancer has spread throughout the liver. Consequently, HCC is rarely diagnosed before the cancer is advanced and untreatable, and has a poor prognosis (likely outcome)—fewer than 5% of patients survive for five or more years after diagnosis. The exact cause of HCC is unclear, but chronic liver (hepatic) injury and inflammation (caused, for example, by infection with hepatitis B virus [HBV] or by alcohol abuse) promote tumor development.
Why Was This Study Done?
Even when it is diagnosed early, HCC has a poor prognosis because it often recurs. Patients treated for HCC can experience two distinct types of tumor recurrence. Early recurrence, which usually happens within the first two years after surgery, arises from the spread of primary cancer cells into the surrounding liver that left behind during surgery. Late recurrence, which typically happens more than two years after surgery, involves the development of completely new tumors and seems to be the result of chronic liver damage. Because early and late recurrence have different clinical courses, it would be useful to be able to predict which patients are at high risk of which type of recurrence. Given that injury, inflammation, and regeneration seem to prime the liver for HCC development, might the gene expression patterns associated with these conditions serve as predictive markers for the identification of patients at risk of late recurrence of HCC? Here, the researchers develop a genomic predictor for the late recurrence of HCC by examining gene expression patterns in tissue samples from livers that were undergoing injury and regeneration.
What Did the Researchers Do and Find?
By comparing gene expression data obtained from liver biopsies taken before and after liver transplantation or resection and recorded in the US National Center for Biotechnology Information Gene Expression Omnibus database, the researchers identified 233 genes whose expression in liver differed before and after liver injury (the hepatic injury and regeneration, or HIR, signature). Statistical analyses indicate that the expression of the HIR signature in archived tissue samples was significantly associated with late recurrence of HCC in three independent groups of patients, but not with early recurrence (a significant association between two variables is one that is unlikely to have arisen by chance). By contrast, a tumor-derived 65-gene signature previously developed by the researchers was significantly associated with early recurrence but not with late recurrence. Notably, as few as four genes from the HIR signature were sufficient to construct a reliable predictor for late recurrence of HCC. Finally, the researchers report that many of the genes in the HIR signature encode proteins involved in inflammation and cell death, but that others encode proteins involved in cellular growth and proliferation such as STAT3, a protein with a well-known role in liver regeneration.
What Do These Findings Mean?
These findings identify a gene expression signature that was significantly associated with late recurrence of HCC in three independent groups of patients. Because most of these patients were infected with HBV, the ability of the HIR signature to predict late occurrence of HCC may be limited to HBV-related HCC and may not be generalizable to HCC related to other causes. Moreover, the predictive ability of the HIR signature needs to be tested in a prospective study in which samples are taken and analyzed at baseline and patients are followed to see whether their HCC recurs; the current retrospective study analyzed stored tissue samples. Importantly, however, the HIR signature associated with late recurrence and the 65-gene signature associated with early recurrence provide new insights into the biological differences between late and early recurrence of HCC at the molecular level. Knowing about these differences may lead to new treatments for HCC and may help clinicians choose the most appropriate treatments for their patients.
Additional Information
Please access these websites via the online version of this summary at
The US National Cancer Institute provides information about all aspects of cancer, including detailed information for patients and professionals about primary liver cancer (in English and Spanish)
The American Cancer Society also provides information about liver cancer (including information on support programs and services; available in several languages)
The UK National Health Service Choices website provides information about primary liver cancer (including a video about coping with cancer)
Cancer Research UK (a not-for-profit organization) also provides detailed information about primary liver cancer (including information about living with primary liver cancer)
MD Anderson Cancer Center provides information about symptoms, diagnosis, treatment, and prevention of primary liver cancer
MedlinePlus provides links to further resources about liver cancer (in English and Spanish)
PMCID: PMC4275163  PMID: 25536056
Cancer research  2010;70(20):7841-7850.
Neuroblastoma is a common childhood tumor and accounts for 15% of pediatric cancer deaths. To investigate the microRNA (miRNA) profile and role of Dicer and Drosha in neuroblastoma, we assessed the expression of 162 human miRNAs, Dicer and Drosha in 66 neuroblastoma tumors by using real-time PCR methods. We found global downregulation of miRNA expression in advanced neuroblastoma and identified 27 miRNAs that can clearly distinguish low- from high-risk patients. Furthermore, expression levels of Dicer or Drosha were low in high-risk neuroblastoma tumors, which accounted for global downregulation of miRNAs in advanced disease and correlated with poor outcome. Notably, for patients with non–MYCN-amplified tumors, low expression of Dicer can serve as a significant and independent predictor of poor outcome (hazard ratio, 9.6; P = 0.045; n = 52). Using plausible neural networks to select a combination of 15 biomarkers that consist of 12 miRNAs' signature, expression levels of Dicer and Drosha, and age at diagnosis, we were able to segregate all patients into four distinct patterns that were highly predictive of clinical outcome. In vitro studies also showed that knockdown of either Dicer or Drosha promoted the growth of neuroblastoma cell lines. Our results reveal that a combination of 15 biomarkers can delineate risk groups of neuroblastoma and serve as a powerful predictor of clinical outcome. Moreover, our findings of growth promotion by silencing Dicer/Drosha implied their potential use as therapeutic targets for neuroblastoma.
PMCID: PMC4095771  PMID: 20805302
British Journal of Cancer  2012;107(6):967-976.
Neuroblastoma remains a major cause of cancer-linked mortality in children. miR-204 has been used in microRNA expression signatures predictive of neuroblastoma patient survival. The aim of this study was to explore the independent association of miR-204 with survival in a neuroblastoma cohort, and to investigate the phenotypic effects mediated by miR-204 expression in neuroblastoma.
Neuroblastoma cell lines were transiently transfected with miR-204 mimics and assessed for cell viability using MTS assays. Apoptosis levels in cell lines were evaluated by FACS analysis of Annexin V-/propidium iodide-stained cells transfected with miR-204 mimics and treated with chemotherapy drug or vehicle control. Potential targets of miR-204 were validated using luciferase reporter assays.
miR-204 expression in primary neuroblastoma tumours was predictive of patient event-free and overall survival, independent of established known risk factors. Ectopic miR-204 expression significantly increased sensitivity to cisplatin and etoposide in vitro. miR-204 direct targeting of the 3′ UTR of BCL2 and NTRK2 (TrkB) was confirmed.
miR-204 is a novel predictor of outcome in neuroblastoma, functioning, at least in part, through increasing sensitivity to cisplatin by direct targeting and downregulation of anti-apoptotic BCL2. miR-204 also targets full-length NTRK2, a potent oncogene involved with chemotherapy drug resistance in neuroblastoma.
PMCID: PMC3464768  PMID: 22892391
miR-204; neuroblastoma; BCL2; NTRK2; tumour suppressor; cisplatin
Various multigene predictors of breast cancer clinical outcome have been commercialized, but proved to be prognostic only for hormone receptor (HR) subsets overexpressing estrogen or progesterone receptors. Hormone receptor negative (HRneg) breast cancers, particularly those lacking HER2/ErbB2 overexpression and known as triple-negative (Tneg) cases, are heterogeneous and generally aggressive breast cancer subsets in need of prognostic subclassification, since most early stage HRneg and Tneg breast cancer patients are cured with conservative treatment yet invariably receive aggressive adjuvant chemotherapy.
An unbiased search for genes predictive of distant metastatic relapse was undertaken using a training cohort of 199 node-negative, adjuvant treatment naïve HRneg (including 154 Tneg) breast cancer cases curated from three public microarray datasets. Prognostic gene candidates were subsequently validated using a different cohort of 75 node-negative, adjuvant naïve HRneg cases curated from three additional datasets. The HRneg/Tneg gene signature was prognostically compared with eight other previously reported gene signatures, and evaluated for cancer network associations by two commercial pathway analysis programs.
A novel set of 14 prognostic gene candidates was identified as outcome predictors: CXCL13, CLIC5, RGS4, RPS28, RFX7, EXOC7, HAPLN1, ZNF3, SSX3, HRBL, PRRG3, ABO, PRTN3, MATN1. A composite HRneg/Tneg gene signature index proved more accurate than any individual candidate gene or other reported multigene predictors in identifying cases likely to remain free of metastatic relapse. Significant positive correlations between the HRneg/Tneg index and three independent immune-related signatures (STAT1, IFN, and IR) were observed, as were consistent negative associations between the three immune-related signatures and five other proliferation module-containing signatures (MS-14, ONCO-RS, GGI, CSR/wound and NKI-70). Network analysis identified 8 genes within the HRneg/Tneg signature as being functionally linked to immune/inflammatory chemokine regulation.
A multigene HRneg/Tneg signature linked to immune/inflammatory cytokine regulation was identified from pooled expression microarray data and shown to be superior to other reported gene signatures in predicting the metastatic outcome of early stage and conservatively managed HRneg and Tneg breast cancer. Further validation of this prognostic signature may lead to new therapeutic insights and spare many newly diagnosed breast cancer patients the need for aggressive adjuvant chemotherapy.
PMCID: PMC3096978  PMID: 20946665
PLoS Medicine  2006;3(12):e467.
Lung cancer is the leading cause of cancer-related death in the United States. Nearly 50% of patients with stages I and II non-small cell lung cancer (NSCLC) will die from recurrent disease despite surgical resection. No reliable clinical or molecular predictors are currently available for identifying those at high risk for developing recurrent disease. As a consequence, it is not possible to select those high-risk patients for more aggressive therapies and assign less aggressive treatments to patients at low risk for recurrence.
Methods and Findings
In this study, we applied a meta-analysis of datasets from seven different microarray studies on NSCLC for differentially expressed genes related to survival time (under 2 y and over 5 y). A consensus set of 4,905 genes from these studies was selected, and systematic bias adjustment in the datasets was performed by distance-weighted discrimination (DWD). We identified a gene expression signature consisting of 64 genes that is highly predictive of which stage I lung cancer patients may benefit from more aggressive therapy. Kaplan-Meier analysis of the overall survival of stage I NSCLC patients with the 64-gene expression signature demonstrated that the high- and low-risk groups are significantly different in their overall survival. Of the 64 genes, 11 are related to cancer metastasis (APC, CDH8, IL8RB, LY6D, PCDHGA12, DSP, NID, ENPP2, CCR2, CASP8, and CASP10) and eight are involved in apoptosis (CASP8, CASP10, PIK3R1, BCL2, SON, INHA, PSEN1, and BIK).
Our results indicate that gene expression signatures from several datasets can be reconciled. The resulting signature is useful in predicting survival of stage I NSCLC and might be useful in informing treatment decisions.
Meta-analysis of several lung cancer gene expression studies yields a set of 64 genes whose expression profile is useful in predicting survival of patients with early-stage lung cancer and possibly informing treatment decisions.
Editors' Summary
Lung cancer is the commonest cause of cancer-related death worldwide. Most cases are of a type called non-small cell lung cancer (NSCLC) and are mainly caused by smoking. Like other cancers, how NSCLC is treated depends on the “stage” at which it is detected. Stage IA NSCLCs are small and confined to the lung and can be removed surgically; patients with slightly larger stage IB tumors often receive chemotherapy after surgery. In stage II NSCLC, cancer cells may be present in lymph nodes near the tumor. Surgery plus chemotherapy is the usual treatment for this stage and for some stage III NSCLCs. However, in this stage, the tumor can be present throughout the chest and surgery is not always possible. For such cases and in stage IV NSCLC, where the tumor has spread throughout the body, patients are treated with chemotherapy alone. The stage at which NSCLC is detected also determines how well patients respond to treatment. Those who can be treated surgically do much better than those who can't. So, whereas only 2% of patients with stage IV lung cancer survive for 5 years after diagnosis, about 70% of patients with stage I or II lung cancer live at least this long.
Why Was This Study Done?
Even stage I and II lung cancers often recur and there is no accurate way to identify the patients in which this will happen. If there was, these patients could be given aggressive chemotherapy, so the search is on for a “molecular signature” to help identify which NSCLCs are likely to recur. Unlike normal cells, cancer cells divide uncontrollably and can move around the body. These behavioral differences are caused by changes in their genetic material that alter their patterns of RNA transcription and protein expression. In this study, the researchers have investigated whether data from several microarray studies (a technique used to catalog the genes expressed in cells) can be pooled to construct a gene expression signature that predicts the survival of patients with stage I NSCLC.
What Did the Researchers Do and Find?
The researchers took the data from seven independent microarray studies (including a new study of their own) that recorded gene expression profiles related to survival time (less than 2 years and greater than 5 years) for stage I NSCLC. Because these studies had been done in different places with slightly different techniques, the researchers applied a statistical tool called distance-weighted discrimination to smooth out any systematic differences among the studies before identifying 64 genes whose expression was associated with survival. Most of these genes are involved in cell adhesion, cell motility, cell proliferation, and cell death, all processes that are altered in cancer cells. The researchers then developed a statistical model that allowed them to use the gene expression and survival data to calculate risk scores for nearly 200 patients in five of the datasets. When they separated the patients into high and low risk groups on the basis of these scores, the two groups were significantly different in terms of survival time. Indeed, the gene expression signature was better at predicting outcome than routine staging. Finally, the researchers validated the gene expression signature by showing that it predicted survival with more than 85% accuracy in two independent datasets.
What Do These Findings Mean?
The 64 gene expression signature identified here could help clinicians prepare treatment plans for patients with stage I NSCLC. Because it accurately predicts survival in patients with adenocarcinoma or squamous cell cancer (the two major subtypes of NSCLC), it potentially indicates which of these patients should receive aggressive chemotherapy and which can be spared this unpleasant treatment. Previous attempts to establish gene expression signatures to predict outcome have used data from small groups of patients and have failed when tested in additional patients. In contrast, this new signature seems to be generalizable. Nevertheless, its ability to predict outcomes must be confirmed in further studies before it is routinely adopted by oncologists for treatment planning.
Additional Information.
Please access these Web sites via the online version of this summary at
US National Cancer Institute information on lung cancer for patients and health professionals.
MedlinePlus encyclopedia entries on small-cell and non-small-cell lung cancer.
Cancer Research UK, information on patients about all aspects of lung cancer.
Wikipedia pages on DNA microarrays and expression profiling (note that Wikipedia is a free online encyclopedia that anyone can edit).
PMCID: PMC1716187  PMID: 17194181
Oncotarget  2015;7(2):1960-1972.
Accurate assessment of neuroblastoma outcome prediction remains challenging. Therefore, this study aims at establishing novel prognostic tumor DNA methylation biomarkers. In total, 396 low- and high-risk primary tumors were analyzed, of which 87 were profiled using methyl-CpG-binding domain (MBD) sequencing for differential methylation analysis between prognostic patient groups. Subsequently, methylation-specific PCR (MSP) assays were developed for 78 top-ranking differentially methylated regions and tested on two independent cohorts of 132 and 177 samples, respectively. Further, a new statistical framework was used to identify a robust set of MSP assays of which the methylation score (i.e. the percentage of methylated assays) allows accurate outcome prediction. Survival analyses were performed on the individual target level, as well as on the combined multimarker signature. As a result of the differential DNA methylation assessment by MBD sequencing, 58 of the 78 MSP assays were designed in regions previously unexplored in neuroblastoma, and 36 are located in non-promoter or non-coding regions. In total, 5 individual MSP assays (located in CCDC177, NXPH1, lnc-MRPL3-2, lnc-TREX1-1 and one on a region from chromosome 8 with no further annotation) predict event-free survival and 4 additional assays (located in SPRED3, TNFAIP2, NPM2 and CYYR1) also predict overall survival. Furthermore, a robust 58-marker methylation signature predicting overall and event-free survival was established. In conclusion, this study encompasses the largest DNA methylation biomarker study in neuroblastoma so far. We identified and independently validated several novel prognostic biomarkers, as well as a prognostic 58-marker methylation signature.
PMCID: PMC4811509  PMID: 26646589
neuroblastoma; DNA methylation; prognosis; biomarker
Cancer research  2004;64(19):6883-6891.
Currently, patients with neuroblastoma are classified into risk groups (e.g., according to the Children’s Oncology Group risk-stratification) to guide physicians in the choice of the most appropriate therapy. Despite this careful stratification, the survival rate for patients with high-risk neuroblastoma remains <30%, and it is not possible to predict which of these high-risk patients will survive or succumb to the disease. Therefore, we have performed gene expression profiling using cDNA microarrays containing 42,578 clones and used artificial neural networks to develop an accurate predictor of survival for each individual patient with neuroblastoma. Using principal component analysis we found that neuroblastoma tumors exhibited inherent prognostic specific gene expression profiles. Subsequent artificial neural network-based prognosis prediction using expression levels of all 37,920 good-quality clones achieved 88% accuracy. Moreover, using an artificial neural network-based gene minimization strategy in a separate analysis we identified 19 genes, including 2 prognostic markers reported previously, MYCN and CD44, which correctly predicted outcome for 98% of these patients. In addition, these 19 predictor genes were able to additionally partition Children’s Oncology Group-stratified high-risk patients into two subgroups according to their survival status (P = 0.0005). Our findings provide evidence of a gene expression signature that can predict prognosis independent of currently known risk factors and could assist physicians in the individual management of patients with high-risk neuroblastoma.
PMCID: PMC1298184  PMID: 15466177
PLoS Medicine  2013;10(10):e1001538.
Using a microarray-based approach, Michael Levin and colleagues develop a disease risk score to distinguish active from latent tuberculosis, as well as tuberculosis from other diseases, using whole blood samples.
Please see later in the article for the Editors' Summary
A major impediment to tuberculosis control in Africa is the difficulty in diagnosing active tuberculosis (TB), particularly in the context of HIV infection. We hypothesized that a unique host blood RNA transcriptional signature would distinguish TB from other diseases (OD) in HIV-infected and -uninfected patients, and that this could be the basis of a simple diagnostic test.
Methods and Findings
Adult case-control cohorts were established in South Africa and Malawi of HIV-infected or -uninfected individuals consisting of 584 patients with either TB (confirmed by culture of Mycobacterium tuberculosis [M.TB] from sputum or tissue sample in a patient under investigation for TB), OD (i.e., TB was considered in the differential diagnosis but then excluded), or healthy individuals with latent TB infection (LTBI). Individuals were randomized into training (80%) and test (20%) cohorts. Blood transcriptional profiles were assessed and minimal sets of significantly differentially expressed transcripts distinguishing TB from LTBI and OD were identified in the training cohort. A 27 transcript signature distinguished TB from LTBI and a 44 transcript signature distinguished TB from OD. To evaluate our signatures, we used a novel computational method to calculate a disease risk score (DRS) for each patient. The classification based on this score was first evaluated in the test cohort, and then validated in an independent publically available dataset (GSE19491).
In our test cohort, the DRS classified TB from LTBI (sensitivity 95%, 95% CI [87–100]; specificity 90%, 95% CI [80–97]) and TB from OD (sensitivity 93%, 95% CI [83–100]; specificity 88%, 95% CI [74–97]). In the independent validation cohort, TB patients were distinguished both from LTBI individuals (sensitivity 95%, 95% CI [85–100]; specificity 94%, 95% CI [84–100]) and OD patients (sensitivity 100%, 95% CI [100–100]; specificity 96%, 95% CI [93–100]).
Limitations of our study include the use of only culture confirmed TB patients, and the potential that TB may have been misdiagnosed in a small proportion of OD patients despite the extensive clinical investigation used to assign each patient to their diagnostic group.
In our study, blood transcriptional signatures distinguished TB from other conditions prevalent in HIV-infected and -uninfected African adults. Our DRS, based on these signatures, could be developed as a test for TB suitable for use in HIV endemic countries. Further evaluation of the performance of the signatures and DRS in prospective populations of patients with symptoms consistent with TB will be needed to define their clinical value under operational conditions.
Please see later in the article for the Editors' Summary
Editors' Summary
Tuberculosis (TB), caused by Mycobacterium tuberculosis, is curable and preventable, but according to the World Health Organization (WHO), in 2011, 8.7 million people had symptoms of TB (usually a productive cough and fever) and 1.4 million people—95% from low- and middle-income countries—died from this infection. Worldwide, TB is also the leading cause of death in people with HIV. For over a century, diagnosis of TB has relied on clinical and radiological features, sputum microscopy, and tuberculin skin testing but all of these tests have major disadvantages, especially in people who are also infected with HIV (HIV/TB co-infection) in whom results are often atypical or falsely negative. Furthermore, current tests cannot distinguish between inactive (latent) and active TB infection. Therefore, there is a need to identify biomarkers that can differentiate TB from other diseases common to African populations, where the burden of the HIV/TB pandemic is greatest.
Why Was This Study Done?
Previous studies have suggested that TB may be associated with specific transcriptional profiles (identified by microarray analysis) in the blood of the infected patient (host), which might make it possible to differentiate TB from other conditions. However, these studies have not included people co-infected with HIV and have included in the differential diagnosis diseases that are unrepresentative of the range of conditions common to African patients. In this study of patients from Malawi and South Africa, the researchers investigated whether blood RNA expression could distinguish TB from other conditions prevalent in African populations and form the basis of a diagnostic test for TB (through a process using transcription signatures).
What Did the Researchers Do and Find?
The researchers recruited patients with suspected TB attending one clinic in Cape Town, South Africa between 2007 and 2010 and in one hospital in Karonga district, Malawi between 2007 and 2009 (the training and test cohorts). Each patient underwent a series of tests for TB (and had a blood test for HIV) and was diagnosed as having TB if there was microbiological evidence confirming the presence of Mycobacterium tuberculosis. At recruitment, each patient also had blood taken for microarray analysis and following this assessment, the researchers selected minimal transcript sets that distinguished TB from latent TB infection and TB from other diseases, even in HIV-infected individuals. In order to help form the basis of a simple, low cost, diagnostic test, the researchers then developed a statistical method for the translation of multiple transcript RNA signatures into a disease risk score, which the researchers then checked using a separate cohort of South African patients (the independent validation cohort).
Using these methods, after screening 437 patients in Malawi and 314 in South Africa, the researchers recruited 273 patients to the Malawi cohort and 311 adults to the South African cohort (the training and test cohorts). Following technical failures, 536 microarray samples were available for analysis. The researchers identified a set of 27 transcripts that could distinguish between TB and latent TB and a set of 44 transcripts that could distinguish TB from other diseases. These multi-transcript signatures were then used to calculate a single value disease risk score for every patient. In the test cohorts, the disease risk score had a high sensitivity (95%) and specificity (90%) for distinguishing TB from latent TB infection (sensitivity is a measure of true positives, correctly identified as such and specificity is a measure of true negatives, correctly identified as such) and for distinguishing TB from other diseases (sensitivity 93% and specificity 88%). In the independent validation cohort, the researchers found that patients with TB could be distinguished from patients with latent TB infection (sensitivity 95% and specificity 94%) and also from patients with other diseases (sensitivity 100% and specificity 96%).
What Do These Findings Mean?
These findings suggest that a distinctive set of RNA transcriptional signatures forming a disease risk score might provide the basis of a diagnostic test that can distinguish active TB from latent TB infection (27 signatures) and also from other diseases (44 signatures), such as pneumonia, that are prevalent in African populations. There is a concern that using transcriptional signatures as a clinical diagnostic tool in resource poor settings might not be feasible because they are complex and costly. The relatively small number of transcripts in the signatures described here may increase the potential for using this approach (transcriptional profiling) as a clinical diagnostic tool using a single blood test. In order to make most use of these findings, there is an urgent need for the academic research community and for industry to develop innovative methods to translate multi-transcript signatures into simple, cheap tests for TB suitable for use in African health facilities.
Additional Information
Please access these websites via the online version of this summary at 10.1371/journal.pmed.1001538.
Wikipedia has definitions of tests for gene expression (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The National Center for Biotechnology Information has a fact sheet on microarray analysis
MedlinePlus has links to further information about tuberculosis (in English and Spanish)
The World Health Organization has up-to-date information on TB
The Stop TB partnership is working towards tuberculosis elimination; patient stories about tuberculosis/HIV coinfection are available
PMCID: PMC3805485  PMID: 24167453
Clinical guidelines for breast cancer treatment differ in their selection of patients at a high risk of recurrence who are eligible to receive adjuvant systemic treatment (AST). The 70-gene signature is a molecular tool to better guide AST decisions. The aim of this study was to evaluate whether adding the 70-gene signature to clinical risk prediction algorithms can optimize outcome prediction and consequently treatment decisions in early stage, node-negative breast cancer patients. A 70-gene signature was available for 427 patients participating in the RASTER study (cT1-3N0M0). Median follow-up was 61.6 months. Based on 5-year distant-recurrence free interval (DRFI) probabilities survival areas under the curve (AUC) were calculated and compared for risk estimations based on the six clinical risk prediction algorithms: Adjuvant! Online (AOL), Nottingham Prognostic Index (NPI), St. Gallen (2003), the Dutch National guidelines (CBO 2004 and NABON 2012), and PREDICT plus. Also, survival AUC were calculated after adding the 70-gene signature to these clinical risk estimations. Systemically untreated patients with a high clinical risk estimation but a low risk 70-gene signature had an excellent 5-year DRFI varying between 97.1 and 100 %, depending on the clinical risk prediction algorithms used in the comparison. The best risk estimation was obtained in this cohort by adding the 70-gene signature to CBO 2012 (AUC: 0.644) and PREDICT (AUC: 0.662). Clinical risk estimations by all clinical algorithms improved by adding the 70-gene signature. Patients with a low risk 70-gene signature have an excellent survival, independent of their clinical risk estimation. Adding the 70-gene signature to clinical risk prediction algorithms improves risk estimations and therefore might improve the identification of early stage node-negative breast cancer patients for whom AST has limited value. In this cohort, the PREDICT plus tool in combination with the 70-gene signature provided the best risk prediction.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-014-2954-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4031388  PMID: 24760482
Breast cancer; 70-Gene signature; Prognosis prediction; Adjuvant systemic treatment; Clinical guidelines
The purpose of this study was to further define the biology of the 11q− neuroblastoma tumor subgroup by the integration of aCGH with miRNA expression profiling data to determine if improved patient stratification is possible.
Experimental Design
A set of primary neuroblastoma (n=160) which was broadly representative of all genetic subtypes was analyzed by aCGH and for the expression of 430 miRNAs. A 15 miRNA expression signature previously demonstrated to be predictive of clinical outcome was used to analyze an independent cohort of 11q− tumors (n=37).
Loss of 4p and gain of 7q occurred at a significantly higher frequency in the 11q−tumors, further defining the genetic characteristics of this subtype. The 11q− tumors could be split into two subgroups using a miRNA expression survival signature which differed significantly in both clinical outcome and the overall frequency of large scale genomic imbalances, with the poor survival subgroup having significantly more imbalances. MiRNAs from the expression signature which were up-regulated in unfavorable tumors were predicted to target down-regulated genes from a published mRNA expression classifier of clinical outcome at a higher than expected frequency, indicating the miRNAs might contribute to the regulation of genes within the signature.
We demonstrate that two distinct biological subtypes of neuroblastoma with loss of 11q occur which differ in their miRNA expression profiles, frequency of segmental imbalances and clinical outcome. A miRNA expression signature, combined with an analysis of segmental imbalances, provides greater prediction of EFS and OS outcomes than 11q status by itself, improving patient stratification.
PMCID: PMC2880207  PMID: 20406844
aCGH; MYCN; neuroblastoma; miRNA
BMC Bioinformatics  2013;14(Suppl 7):S12.
Neuroblastoma is the most common pediatric solid tumor. About fifty percent of high risk patients die despite treatment making the exploration of new and more effective strategies for improving stratification mandatory. Hypoxia is a condition of low oxygen tension occurring in poorly vascularized areas of the tumor associated with poor prognosis. We had previously defined a robust gene expression signature measuring the hypoxic component of neuroblastoma tumors (NB-hypo) which is a molecular risk factor. We wanted to develop a prognostic classifier of neuroblastoma patients' outcome blending existing knowledge on clinical and molecular risk factors with the prognostic NB-hypo signature. Furthermore, we were interested in classifiers outputting explicit rules that could be easily translated into the clinical setting.
Shadow Clustering (SC) technique, which leads to final models called Logic Learning Machine (LLM), exhibits a good accuracy and promises to fulfill the aims of the work. We utilized this algorithm to classify NB-patients on the bases of the following risk factors: Age at diagnosis, INSS stage, MYCN amplification and NB-hypo. The algorithm generated explicit classification rules in good agreement with existing clinical knowledge. Through an iterative procedure we identified and removed from the dataset those examples which caused instability in the rules. This workflow generated a stable classifier very accurate in predicting good and poor outcome patients. The good performance of the classifier was validated in an independent dataset. NB-hypo was an important component of the rules with a strength similar to that of tumor staging.
The novelty of our work is to identify stability, explicit rules and blending of molecular and clinical risk factors as the key features to generate classification rules for NB patients to be conveyed to the clinic and to be used to design new therapies. We derived, through LLM, a set of four stable rules identifying a new class of poor outcome patients that could benefit from new therapies potentially targeting tumor hypoxia or its consequences.
PMCID: PMC3633028  PMID: 23815266
EBioMedicine  2015;2(11):1814-1820.
Prognosis associated with metastatic renal cell carcinoma (mRCC) can vary widely.
This study used pretreatment nephrectomy specimens from a randomized phase III trial. Expression levels of candidate genes were determined from archival tumors using the OpenArray® platform for TaqMan® RT-qPCR. The dataset was randomly divided at 2:1 ratio into training (n = 221) and testing (n = 103) sets to develop a multigene prognostic signature.
Gene expressions were measured in 324 patients. In the training set, multiple models testing 424 candidate genes identified a prognostic signature containing 8 genes plus MSKCC clinical risk factors. In the testing set, the time dependent (td) AUC for a prognostic model containing the 8 genes with and without MSKCC risk factors were 0.72 and 0.69, respectively. The tdAUC for the clinical risk factors alone was 0.61. Additional primary mRCCs from patients with mRCC (n = 12) were sampled in multiple sites and standard deviations of gene expressions within a tumor were used as a measure of heterogeneity. All 8 genes in the final prognostic model met our criteria for minimal heterogeneity.
A molecular prognostic signature based on 8 genes was developed and is ready for external validation in this patient population and other related settings such as nonmetastatic RCC.
•Metastatic renal cell carcinomas have a wide range of prognoses.•Pretreatment nephrectomy specimens from a randomized phase III trial were analyzed.•A prognostic signature was developed with 8 genes and MSKCC clinical risk factors.•The prognostic signature accurately predicted overall survival for metastatic RCC.
Kidney cancer can have a wide range of survival outcomes. Tumors obtained from patients with metastatic kidney cancer who enrolled in a multicenter clinical trial of bevacizumab and interferon were used to develop a molecular signature for predicting survival. A total of 424 candidate genes were considered. A molecular signature was developed that included 8 gene levels and well-accepted clinical risk factors. The signature accurately predicted survival for metastatic kidney cancer. This signature can be further developed for clinical use, to help counsel patients, assist with treatment planning, and determine eligibility for clinical trials.
PMCID: PMC4740313  PMID: 26870806
Renal cell carcinoma; Prognostic markers; Prognostic signature; Expression profile
PLoS ONE  2013;8(11):e79843.
Chemotherapy induces apoptosis and tumor regression primarily through activation of p53-mediated transcription. Neuroblastoma is a p53 wild type malignancy at diagnosis and repression of p53 signaling plays an important role in its pathogenesis. Recently developed small molecule inhibitors of the MDM2-p53 interaction are able to overcome this repression and potently activate p53 dependent apoptosis in malignancies with intact p53 downstream signaling. We used the small molecule MDM2 inhibitor, Nutlin-3a, to determine the p53 drug response signature in neuroblastoma cells. In addition to p53 mediated apoptotic signatures, GSEA and pathway analysis identified a set of p53-repressed genes that were reciprocally over-expressed in neuroblastoma patients with the worst overall outcome in multiple clinical cohorts. Multifactorial regression analysis identified a subset of four genes (CHAF1A, RRM2, MCM3, and MCM6) whose expression together strongly predicted overall and event-free survival (p<0.0001). The expression of these four genes was then validated by quantitative PCR in a large independent clinical cohort. Our findings further support the concept that oncogene-driven transcriptional networks opposing p53 activation are essential for the aggressive behavior and poor response to therapy of high-risk neuroblastoma.
PMCID: PMC3865347  PMID: 24348903
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Human Genomics  2016;10(Suppl 1):12.
Table of contents
O1 The metabolomics approach to autism: identification of biomarkers for early detection of autism spectrum disorder
A. K. Srivastava, Y. Wang, R. Huang, C. Skinner, T. Thompson, L. Pollard, T. Wood, F. Luo, R. Stevenson
O2 Phenome-wide association study for smoking- and drinking-associated genes in 26,394 American women with African, Asian, European, and Hispanic descents
R. Polimanti, J. Gelernter
O3 Effects of prenatal environment, genotype and DNA methylation on birth weight and subsequent postnatal outcomes: findings from GUSTO, an Asian birth cohort
X. Lin, I. Y. Lim, Y. Wu, A. L. Teh, L. Chen, I. M. Aris, S. E. Soh, M. T. Tint, J. L. MacIsaac, F. Yap, K. Kwek, S. M. Saw, M. S. Kobor, M. J. Meaney, K. M. Godfrey, Y. S. Chong, J. D. Holbrook, Y. S. Lee, P. D. Gluckman, N. Karnani, GUSTO study group
O4 High-throughput identification of specific qt interval modulating enhancers at the SCN5A locus
A. Kapoor, D. Lee, A. Chakravarti
O5 Identification of extracellular matrix components inducing cancer cell migration in the supernatant of cultivated mesenchymal stem cells
C. Maercker, F. Graf, M. Boutros
O6 Single cell allele specific expression (ASE) IN T21 and common trisomies: a novel approach to understand DOWN syndrome and other aneuploidies
G. Stamoulis, F. Santoni, P. Makrythanasis, A. Letourneau, M. Guipponi, N. Panousis, M. Garieri, P. Ribaux, E. Falconnet, C. Borel, S. E. Antonarakis
O7 Role of microRNA in LCL to IPSC reprogramming
S. Kumar, J. Curran, J. Blangero
O8 Multiple enhancer variants disrupt gene regulatory network in Hirschsprung disease
S. Chatterjee, A. Kapoor, J. Akiyama, D. Auer, C. Berrios, L. Pennacchio, A. Chakravarti
O9 Metabolomic profiling for the diagnosis of neurometabolic disorders
T. R. Donti, G. Cappuccio, M. Miller, P. Atwal, A. Kennedy, A. Cardon, C. Bacino, L. Emrick, J. Hertecant, F. Baumer, B. Porter, M. Bainbridge, P. Bonnen, B. Graham, R. Sutton, Q. Sun, S. Elsea
O10 A novel causal methylation network approach to Alzheimer’s disease
Z. Hu, P. Wang, Y. Zhu, J. Zhao, M. Xiong, David A Bennett
O11 A microRNA signature identifies subtypes of triple-negative breast cancer and reveals MIR-342-3P as regulator of a lactate metabolic pathway
A. Hidalgo-Miranda, S. Romero-Cordoba, S. Rodriguez-Cuevas, R. Rebollar-Vega, E. Tagliabue, M. Iorio, E. D’Ippolito, S. Baroni
O12 Transcriptome analysis identifies genes, enhancer RNAs and repetitive elements that are recurrently deregulated across multiple cancer types
B. Kaczkowski, Y. Tanaka, H. Kawaji, A. Sandelin, R. Andersson, M. Itoh, T. Lassmann, the FANTOM5 consortium, Y. Hayashizaki, P. Carninci, A. R. R. Forrest
O13 Elevated mutation and widespread loss of constraint at regulatory and architectural binding sites across 11 tumour types
C. A. Semple
O14 Exome sequencing provides evidence of pathogenicity for genes implicated in colorectal cancer
E. A. Rosenthal, B. Shirts, L. Amendola, C. Gallego, M. Horike-Pyne, A. Burt, P. Robertson, P. Beyers, C. Nefcy, D. Veenstra, F. Hisama, R. Bennett, M. Dorschner, D. Nickerson, J. Smith, K. Patterson, D. Crosslin, R. Nassir, N. Zubair, T. Harrison, U. Peters, G. Jarvik, NHLBI GO Exome Sequencing Project
O15 The tandem duplicator phenotype as a distinct genomic configuration in cancer
F. Menghi, K. Inaki, X. Woo, P. Kumar, K. Grzeda, A. Malhotra, H. Kim, D. Ucar, P. Shreckengast, K. Karuturi, J. Keck, J. Chuang, E. T. Liu
O16 Modeling genetic interactions associated with molecular subtypes of breast cancer
B. Ji, A. Tyler, G. Ananda, G. Carter
O17 Recurrent somatic mutation in the MYC associated factor X in brain tumors
H. Nikbakht, M. Montagne, M. Zeinieh, A. Harutyunyan, M. Mcconechy, N. Jabado, P. Lavigne, J. Majewski
O18 Predictive biomarkers to metastatic pancreatic cancer treatment
J. B. Goldstein, M. Overman, G. Varadhachary, R. Shroff, R. Wolff, M. Javle, A. Futreal, D. Fogelman
O19 DDIT4 gene expression as a prognostic marker in several malignant tumors
L. Bravo, W. Fajardo, H. Gomez, C. Castaneda, C. Rolfo, J. A. Pinto
O20 Spatial organization of the genome and genomic alterations in human cancers
K. C. Akdemir, L. Chin, A. Futreal, ICGC PCAWG Structural Alterations Group
O21 Landscape of targeted therapies in solid tumors
S. Patterson, C. Statz, S. Mockus
O22 Genomic analysis reveals novel drivers and progression pathways in skin basal cell carcinoma
S. N. Nikolaev, X. I. Bonilla, L. Parmentier, B. King, F. Bezrukov, G. Kaya, V. Zoete, V. Seplyarskiy, H. Sharpe, T. McKee, A. Letourneau, P. Ribaux, K. Popadin, N. Basset-Seguin, R. Ben Chaabene, F. Santoni, M. Andrianova, M. Guipponi, M. Garieri, C. Verdan, K. Grosdemange, O. Sumara, M. Eilers, I. Aifantis, O. Michielin, F. de Sauvage, S. Antonarakis
O23 Identification of differential biomarkers of hepatocellular carcinoma and cholangiocarcinoma via transcriptome microarray meta-analysis
S. Likhitrattanapisal
O24 Clinical validity and actionability of multigene tests for hereditary cancers in a large multi-center study
S. Lincoln, A. Kurian, A. Desmond, S. Yang, Y. Kobayashi, J. Ford, L. Ellisen
O25 Correlation with tumor ploidy status is essential for correct determination of genome-wide copy number changes by SNP array
T. L. Peters, K. R. Alvarez, E. F. Hollingsworth, D. H. Lopez-Terrada
O26 Nanochannel based next-generation mapping for interrogation of clinically relevant structural variation
A. Hastie, Z. Dzakula, A. W. Pang, E. T. Lam, T. Anantharaman, M. Saghbini, H. Cao, BioNano Genomics
O27 Mutation spectrum in a pulmonary arterial hypertension (PAH) cohort and identification of associated truncating mutations in TBX4
C. Gonzaga-Jauregui, L. Ma, A. King, E. Berman Rosenzweig, U. Krishnan, J. G. Reid, J. D. Overton, F. Dewey, W. K. Chung
O28 NORTH CAROLINA macular dystrophy (MCDR1): mutations found affecting PRDM13
K. Small, A. DeLuca, F. Cremers, R. A. Lewis, V. Puech, B. Bakall, R. Silva-Garcia, K. Rohrschneider, M. Leys, F. S. Shaya, E. Stone
O29 PhenoDB and genematcher, solving unsolved whole exome sequencing data
N. L. Sobreira, F. Schiettecatte, H. Ling, E. Pugh, D. Witmer, K. Hetrick, P. Zhang, K. Doheny, D. Valle, A. Hamosh
O30 Baylor-Johns Hopkins Center for Mendelian genomics: a four year review
S. N. Jhangiani, Z. Coban Akdemir, M. N. Bainbridge, W. Charng, W. Wiszniewski, T. Gambin, E. Karaca, Y. Bayram, M. K. Eldomery, J. Posey, H. Doddapaneni, J. Hu, V. R. Sutton, D. M. Muzny, E. A. Boerwinkle, D. Valle, J. R. Lupski, R. A. Gibbs
O31 Using read overlap assembly to accurately identify structural genetic differences in an ashkenazi jewish trio
S. Shekar, W. Salerno, A. English, A. Mangubat, J. Bruestle
O32 Legal interoperability: a sine qua non for international data sharing
A. Thorogood, B. M. Knoppers, Global Alliance for Genomics and Health - Regulatory and Ethics Working Group
O33 High throughput screening platform of competent sineups: that can enhance translation activities of therapeutic target
H. Takahashi, K. R. Nitta, A. Kozhuharova, A. M. Suzuki, H. Sharma, D. Cotella, C. Santoro, S. Zucchelli, S. Gustincich, P. Carninci
O34 The undiagnosed diseases network international (UDNI): clinical and laboratory research to meet patient needs
J. J. Mulvihill, G. Baynam, W. Gahl, S. C. Groft, K. Kosaki, P. Lasko, B. Melegh, D. Taruscio
O36 Performance of computational algorithms in pathogenicity predictions for activating variants in oncogenes versus loss of function mutations in tumor suppressor genes
R. Ghosh, S. Plon
O37 Identification and electronic health record incorporation of clinically actionable pharmacogenomic variants using prospective targeted sequencing
S. Scherer, X. Qin, R. Sanghvi, K. Walker, T. Chiang, D. Muzny, L. Wang, J. Black, E. Boerwinkle, R. Weinshilboum, R. Gibbs
O38 Melanoma reprogramming state correlates with response to CTLA-4 blockade in metastatic melanoma
T. Karpinets, T. Calderone, K. Wani, X. Yu, C. Creasy, C. Haymaker, M. Forget, V. Nanda, J. Roszik, J. Wargo, L. Haydu, X. Song, A. Lazar, J. Gershenwald, M. Davies, C. Bernatchez, J. Zhang, A. Futreal, S. Woodman
O39 Data-driven refinement of complex disease classification from integration of heterogeneous functional genomics data in GeneWeaver
E. J. Chesler, T. Reynolds, J. A. Bubier, C. Phillips, M. A. Langston, E. J. Baker
O40 A general statistic framework for genome-based disease risk prediction
M. Xiong, L. Ma, N. Lin, C. Amos
O41 Integrative large-scale causal network analysis of imaging and genomic data and its application in schizophrenia studies
N. Lin, P. Wang, Y. Zhu, J. Zhao, V. Calhoun, M. Xiong
O42 Big data and NGS data analysis: the cloud to the rescue
O. Dobretsberger, M. Egger, F. Leimgruber
O43 Cpipe: a convergent clinical exome pipeline specialised for targeted sequencing
S. Sadedin, A. Oshlack, Melbourne Genomics Health Alliance
O44 A Bayesian classification of biomedical images using feature extraction from deep neural networks implemented on lung cancer data
V. A. A. Antonio, N. Ono, Clark Kendrick C. Go
O45 MAV-SEQ: an interactive platform for the Management, Analysis, and Visualization of sequence data
Z. Ahmed, M. Bolisetty, S. Zeeshan, E. Anguiano, D. Ucar
O47 Allele specific enhancer in EPAS1 intronic regions may contribute to high altitude adaptation of Tibetans
C. Zeng, J. Shao
O48 Nanochannel based next-generation mapping for structural variation detection and comparison in trios and populations
H. Cao, A. Hastie, A. W. Pang, E. T. Lam, T. Liang, K. Pham, M. Saghbini, Z. Dzakula
O49 Archaic introgression in indigenous populations of Malaysia revealed by whole genome sequencing
Y. Chee-Wei, L. Dongsheng, W. Lai-Ping, D. Lian, R. O. Twee Hee, Y. Yunus, F. Aghakhanian, S. S. Mokhtar, C. V. Lok-Yung, J. Bhak, M. Phipps, X. Shuhua, T. Yik-Ying, V. Kumar, H. Boon-Peng
O50 Breast and ovarian cancer prevention: is it time for population-based mutation screening of high risk genes?
I. Campbell, M.-A. Young, P. James, Lifepool
O53 Comprehensive coverage from low DNA input using novel NGS library preparation methods for WGS and WGBS
C. Schumacher, S. Sandhu, T. Harkins, V. Makarov
O54 Methods for large scale construction of robust PCR-free libraries for sequencing on Illumina HiSeqX platform
H. DoddapaneniR. Glenn, Z. Momin, B. Dilrukshi, H. Chao, Q. Meng, B. Gudenkauf, R. Kshitij, J. Jayaseelan, C. Nessner, S. Lee, K. Blankenberg, L. Lewis, J. Hu, Y. Han, H. Dinh, S. Jireh, K. Walker, E. Boerwinkle, D. Muzny, R. Gibbs
O55 Rapid capture methods for clinical sequencing
J. Hu, K. Walker, C. Buhay, X. Liu, Q. Wang, R. Sanghvi, H. Doddapaneni, Y. Ding, N. Veeraraghavan, Y. Yang, E. Boerwinkle, A. L. Beaudet, C. M. Eng, D. M. Muzny, R. A. Gibbs
O56 A diploid personal human genome model for better genomes from diverse sequence data
K. C. C. Worley, Y. Liu, D. S. T. Hughes, S. C. Murali, R. A. Harris, A. C. English, X. Qin, O. A. Hampton, P. Larsen, C. Beck, Y. Han, M. Wang, H. Doddapaneni, C. L. Kovar, W. J. Salerno, A. Yoder, S. Richards, J. Rogers, J. R. Lupski, D. M. Muzny, R. A. Gibbs
O57 Development of PacBio long range capture for detection of pathogenic structural variants
Q. Meng, M. Bainbridge, M. Wang, H. Doddapaneni, Y. Han, D. Muzny, R. Gibbs
O58 Rhesus macaques exhibit more non-synonymous variation but greater impact of purifying selection than humans
R. A. Harris, M. Raveenedran, C. Xue, M. Dahdouli, L. Cox, G. Fan, B. Ferguson, J. Hovarth, Z. Johnson, S. Kanthaswamy, M. Kubisch, M. Platt, D. Smith, E. Vallender, R. Wiseman, X. Liu, J. Below, D. Muzny, R. Gibbs, F. Yu, J. Rogers
O59 Assessing RNA structure disruption induced by single-nucleotide variation
J. Lin, Y. Zhang, Z. Ouyang
P1 A meta-analysis of genome-wide association studies of mitochondrial dna copy number
A. Moore, Z. Wang, J. Hofmann, M. Purdue, R. Stolzenberg-Solomon, S. Weinstein, D. Albanes, C.-S. Liu, W.-L. Cheng, T.-T. Lin, Q. Lan, N. Rothman, S. Berndt
P2 Missense polymorphic genetic combinations underlying down syndrome susceptibility
E. S. Chen
P4 The evaluation of alteration of ELAM-1 expression in the endometriosis patients
H. Bahrami, A. Khoshzaban, S. Heidari Keshal
P5 Obesity and the incidence of apolipoprotein E polymorphisms in an assorted population from Saudi Arabia population
K. K. R. Alharbi
P6 Genome-associated personalized antithrombotical therapy for patients with high risk of thrombosis and bleeding
M. Zhalbinova, A. Akilzhanova, S. Rakhimova, M. Bekbosynova, S. Myrzakhmetova
P7 Frequency of Xmn1 polymorphism among sickle cell carrier cases in UAE population
M. Matar
P8 Differentiating inflammatory bowel diseases by using genomic data: dimension of the problem and network organization
N. Mili, R. Molinari, Y. Ma, S. Guerrier
P9 Vulnerability of genetic variants to the risk of autism among Saudi children
N. Elhawary, M. Tayeb, N. Bogari, N. Qotb
P10 Chromatin profiles from ex vivo purified dopaminergic neurons establish a promising model to support studies of neurological function and dysfunction
S. A. McClymont, P. W. Hook, L. A. Goff, A. McCallion
P11 Utilization of a sensitized chemical mutagenesis screen to identify genetic modifiers of retinal dysplasia in homozygous Nr2e3rd7 mice
Y. Kong, J. R. Charette, W. L. Hicks, J. K. Naggert, L. Zhao, P. M. Nishina
P12 Ion torrent next generation sequencing of recessive polycystic kidney disease in Saudi patients
B. M. Edrees, M. Athar, F. A. Al-Allaf, M. M. Taher, W. Khan, A. Bouazzaoui, N. A. Harbi, R. Safar, H. Al-Edressi, A. Anazi, N. Altayeb, M. A. Ahmed, K. Alansary, Z. Abduljaleel
P13 Digital expression profiling of Purkinje neurons and dendrites in different subcellular compartments
A. Kratz, P. Beguin, S. Poulain, M. Kaneko, C. Takahiko, A. Matsunaga, S. Kato, A. M. Suzuki, N. Bertin, T. Lassmann, R. Vigot, P. Carninci, C. Plessy, T. Launey
P14 The evolution of imperfection and imperfection of evolution: the functional and functionless fractions of the human genome
D. Graur
P16 Species-independent identification of known and novel recurrent genomic entities in multiple cancer patients
J. Friis-Nielsen, J. M. Izarzugaza, S. Brunak
P18 Discovery of active gene modules which are densely conserved across multiple cancer types reveal their prognostic power and mutually exclusive mutation patterns
B. S. Soibam
P19 Whole exome sequencing of dysplastic leukoplakia tissue indicates sequential accumulation of somatic mutations from oral precancer to cancer
D. Das, N. Biswas, S. Das, S. Sarkar, A. Maitra, C. Panda, P. Majumder
P21 Epigenetic mechanisms of carcinogensis by hereditary breast cancer genes
J. J. Gruber, N. Jaeger, M. Snyder
P22 RNA direct: a novel RNA enrichment strategy applied to transcripts associated with solid tumors
K. Patel, S. Bowman, T. Davis, D. Kraushaar, A. Emerman, S. Russello, N. Henig, C. Hendrickson
P23 RNA sequencing identifies gene mutations for neuroblastoma
K. Zhang
P24 Participation of SFRP1 in the modulation of TMPRSS2-ERG fusion gene in prostate cancer cell lines
M. Rodriguez-Dorantes, C. D. Cruz-Hernandez, C. D. P. Garcia-Tobilla, S. Solorzano-Rosales
P25 Targeted Methylation Sequencing of Prostate Cancer
N. Jäger, J. Chen, R. Haile, M. Hitchins, J. D. Brooks, M. Snyder
P26 Mutant TPMT alleles in children with acute lymphoblastic leukemia from México City and Yucatán, Mexico
S. Jiménez-Morales, M. Ramírez, J. Nuñez, V. Bekker, Y. Leal, E. Jiménez, A. Medina, A. Hidalgo, J. Mejía
P28 Genetic modifiers of Alström syndrome
J. Naggert, G. B. Collin, K. DeMauro, R. Hanusek, P. M. Nishina
P31 Association of genomic variants with the occurrence of angiotensin-converting-enzyme inhibitor (ACEI)-induced coughing among Filipinos
E. M. Cutiongco De La Paz, R. Sy, J. Nevado, P. Reganit, L. Santos, J. D. Magno, F. E. Punzalan , D. Ona , E. Llanes, R. L. Santos-Cortes , R. Tiongco, J. Aherrera, L. Abrahan, P. Pagauitan-Alan; Philippine Cardiogenomics Study Group
P32 The use of “humanized” mouse models to validate disease association of a de novo GARS variant and to test a novel gene therapy strategy for Charcot-Marie-Tooth disease type 2D
K. H. Morelli, J. S. Domire, N. Pyne, S. Harper, R. Burgess
P34 Molecular regulation of chondrogenic human induced pluripotent stem cells
M. A. Gari, A. Dallol, H. Alsehli, A. Gari, M. Gari, A. Abuzenadah
P35 Molecular profiling of hematologic malignancies: implementation of a variant assessment algorithm for next generation sequencing data analysis and clinical reporting
M. Thomas, M. Sukhai, S. Garg, M. Misyura, T. Zhang, A. Schuh, T. Stockley, S. Kamel-Reid
P36 Accessing genomic evidence for clinical variants at NCBI
S. Sherry, C. Xiao, D. Slotta, K. Rodarmer, M. Feolo, M. Kimelman, G. Godynskiy, C. O’Sullivan, E. Yaschenko
P37 NGS-SWIFT: a cloud-based variant analysis framework using control-accessed sequencing data from DBGAP/SRA
C. Xiao, E. Yaschenko, S. Sherry
P38 Computational assessment of drug induced hepatotoxicity through gene expression profiling
C. Rangel-Escareño, H. Rueda-Zarate
P40 Flowr: robust and efficient pipelines using a simple language-agnostic approach;ultraseq; fast modular pipeline for somatic variation calling using flowr
S. Seth, S. Amin, X. Song, X. Mao, H. Sun, R. G. Verhaak, A. Futreal, J. Zhang
P41 Applying “Big data” technologies to the rapid analysis of heterogenous large cohort data
S. J. Whiite, T. Chiang, A. English, J. Farek, Z. Kahn, W. Salerno, N. Veeraraghavan, E. Boerwinkle, R. Gibbs
P42 FANTOM5 web resource for the large-scale genome-wide transcription start site activity profiles of wide-range of mammalian cells
T. Kasukawa, M. Lizio, J. Harshbarger, S. Hisashi, J. Severin, A. Imad, S. Sahin, T. C. Freeman, K. Baillie, A. Sandelin, P. Carninci, A. R. R. Forrest, H. Kawaji, The FANTOM Consortium
P43 Rapid and scalable typing of structural variants for disease cohorts
W. Salerno, A. English, S. N. Shekar, A. Mangubat, J. Bruestle, E. Boerwinkle, R. A. Gibbs
P44 Polymorphism of glutathione S-transferases and sulphotransferases genes in an Arab population
A. H. Salem, M. Ali, A. Ibrahim, M. Ibrahim
P46 Genetic divergence of CYP3A5*3 pharmacogenomic marker for native and admixed Mexican populations
J. C. Fernandez-Lopez, V. Bonifaz-Peña, C. Rangel-Escareño, A. Hidalgo-Miranda, A. V. Contreras
P47 Whole exome sequence meta-analysis of 13 white blood cell, red blood cell, and platelet traits
L. Polfus, CHARGE and NHLBI Exome Sequence Project Working Groups
P48 Association of adipoq gene with type 2 diabetes and related phenotypes in african american men and women: The jackson heart study
S. Davis, R. Xu, S. Gebeab, P Riestra, A Gaye, R. Khan, J. Wilson, A. Bidulescu
P49 Common variants in casr gene are associated with serum calcium levels in koreans
S. H. Jung, N. Vinayagamoorthy, S. H. Yim, Y. J. Chung
P50 Inference of multiple-wave population admixture by modeling decay of linkage disequilibrium with multiple exponential functions
Y. Zhou, S. Xu
P51 A Bayesian framework for generalized linear mixed models in genome-wide association studies
X. Wang, V. Philip, G. Carter
P52 Targeted sequencing approach for the identification of the genetic causes of hereditary hearing impairment
A. A. Abuzenadah, M. Gari, R. Turki, A. Dallol
P53 Identification of enhancer sequences by ATAC-seq open chromatin profiling
A. Uyar, A. Kaygun, S. Zaman, E. Marquez, J. George, D. Ucar
P54 Direct enrichment for the rapid preparation of targeted NGS libraries
C. L. Hendrickson, A. Emerman, D. Kraushaar, S. Bowman, N. Henig, T. Davis, S. Russello, K. Patel
P56 Performance of the Agilent D5000 and High Sensitivity D5000 ScreenTape assays for the Agilent 4200 Tapestation System
R. Nitsche, L. Prieto-Lafuente
P57 ClinVar: a multi-source archive for variant interpretation
M. Landrum, J. Lee, W. Rubinstein, D. Maglott
P59 Association of functional variants and protein physical interactions of human MUTY homolog linked with familial adenomatous polyposis and colorectal cancer syndrome
Z. Abduljaleel, W. Khan, F. A. Al-Allaf, M. Athar , M. M. Taher, N. Shahzad
P60 Modification of the microbiom constitution in the gut using chicken IgY antibodies resulted in a reduction of acute graft-versus-host disease after experimental bone marrow transplantation
A. Bouazzaoui, E. Huber, A. Dan, F. A. Al-Allaf, W. Herr, G. Sprotte, J. Köstler, A. Hiergeist, A. Gessner, R. Andreesen, E. Holler
P61 Compound heterozygous mutation in the LDLR gene in Saudi patients suffering severe hypercholesterolemia
F. Al-Allaf, A. Alashwal, Z. Abduljaleel, M. Taher, A. Bouazzaoui, H. Abalkhail, A. Al-Allaf, R. Bamardadh, M. Athar
PMCID: PMC4896275  PMID: 27294413
Clinical Relevance
It remains a critical issue to reliably identify specific patients at high risk for recurrence and metastasis of lung cancer. To date, there has been no clinically applied gene test for predicting lung cancer recurrence. This study validated a 35-gene prognostic signature in various cell types of non-small cell lung cancer. The analysis showed that the 35-gene signature could further stratify patients at stage 1A into distinct prognostic subgroups. This lung cancer prognostic signature is independent of traditional clinicopathological factors, including patient age, clinical stage, tumor differentiation, and tumor grade. This signature had better prognostic performance than other lung cancer signatures, including the 5-gene signature and the 133-gene signature in the studied cohorts. The gene expression and protein expression of the identified biomarkers were validated in real-time RT-PCR and Western blots analysis of clinical specimens. This study indicates that the 35-gene signature could be applied in clinics for patient stratification.
It remains a critical challenge to determine the risk for recurrence in early stage non-small cell lung cancer (NSCLC) patients. Accurate gene expression signatures are needed to classify patients into high- and low-risk groups to improve the selection of patients for adjuvant therapy.
Experimental Design
Multiple published microarray datasets were used to evaluate our previously identified lung cancer prognostic gene signature. Expression of the signature genes was further validated with real-time RT-PCR and Western blot assays of snap frozen lung cancer tumor tissues.
Our previously identified 35-gene signature stratified 264 patients with non-small cell lung cancer into high- and low-risk groups with distinct overall survival rates (P < 0.05, Kaplan-Meier analysis, log-rank tests). The 35-gene signature further stratified patients with clinical stage 1A diseases into poor prognostic and good prognostic subgroups (P = 0.0007, Kaplan-Meier analysis, log-rank tests). This signature is independent of other prognostic factors for non-small cell lung cancer, including age, sex, tumor differentiation, tumor grade, and tumor stage. The expression of the signature genes was validated with real-time RT-PCR analysis of lung cancer tumor specimens. Protein expression of two signature genes, TAL2 and ILF3, was confirmed in lung adenocarcinoma tumors by using Western blot analysis. These two biomarkers showed correlated mRNA and protein over-expression in lung cancer development and progression.
The results indicate that the identified 35-gene signature is an accurate predictor of survival in non-small cell lung cancer. It provides independent prognostic information in addition to traditional clinicopathological criteria.
PMCID: PMC2605664  PMID: 19088038
molecular signature; non-small cell lung cancer; prognosis; microarray analysis; protein expression; Western blots
British Journal of Cancer  2011;105(12):1940-1948.
In neuroblastoma (NB), the presence of segmental chromosome alterations (SCAs) is associated with a higher risk of relapse.
In order to analyse the role of SCAs in infants with localised unresectable/disseminated NB without MYCN amplification, we have performed an array CGH analysis of tumours from infants enroled in the prospective European INES trials.
Tumour samples from 218 out of 300 enroled patients could be analysed. Segmental chromosome alterations were observed in 11%, 20% and 59% of infants enroled in trials INES99.1 (localised unresectable NB), INES99.2 (stage 4s) and INES99.3 (stage 4) (P<0.0001). Progression-free survival was poorer in patients whose tumours harboured SCA, in the whole population and in trials INES99.1 and INES99.2, in the absence of clinical symptoms (log-rank test, P=0.0001, P=0.04 and P=0.0003, respectively). In multivariate analysis, a SCA genomic profile was the strongest predictor of poorer progression-free survival.
In infants with stage 4s MYCN-non-amplified NB, a SCA genomic profile identifies patients who will require upfront treatment even in the absence of other clinical indication for therapy, whereas in infants with localised unresectable NB, a genomic profile characterised by the absence of SCA identifies patients in whom treatment reduction might be possible. These findings will be implemented in a future international trial.
PMCID: PMC3251887  PMID: 22146831
neuroblastoma; infants; genomic profile; segmental chromosome alterations; prognosis
Gene expression profiling has been extensively used to predict outcome in breast cancer patients. We have previously reported on biological hypothesis-driven analysis of gene expression profiling data and we wished to extend this approach through the combinations of various gene signatures to improve the prediction of outcome in breast cancer.
We have used gene expression data (25.000 gene probes) from a previously published study of tumours from 295 early stage breast cancer patients from the Netherlands Cancer Institute using updated follow-up. Tumours were assigned to three prognostic groups using the previously reported Wound-response and hypoxia-response signatures, and the outcome in each of these subgroups was evaluated.
We have assigned invasive breast carcinomas from 295 stages I and II breast cancer patients to three groups based on gene expression profiles subdivided by the wound-response signature (WS) and hypoxia-response signature (HS). These three groups are (1) quiescent WS/non-hypoxic HS; (2) activated WS/non-hypoxic HS or quiescent WS/hypoxic tumours and (3) activated WS/hypoxic HS. The overall survival at 15 years for patients with tumours in groups 1, 2 and 3 are 79%, 59% and 27%, respectively. In multivariate analysis, this signature is not only independent of clinical and pathological risk factors; it is also the strongest predictor of outcome. Compared to a previously identified 70-gene prognosis profile, obtained with supervised classification, the combination of signatures performs roughly equally well and might have additional value in the ER-negative subgroup. In the subgroup of lymph node positive patients, the combination signature outperforms the 70-gene signature in multivariate analysis. In addition, in multivariate analysis, the WS/HS combination is a stronger predictor of outcome compared to the recently reported invasiveness gene signature combined with the WS.
A combination of biological gene expression signatures can be used to identify a powerful and independent predictor for outcome in breast cancer patients.
PMCID: PMC3756930  PMID: 18715778
Microarray analysis; Breast cancer; Prognostic markers; Biological gene expression profiles

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