Molecular Staging of Intracranial Ependymoma in Children and Adults

2010 ◽  
Vol 28 (19) ◽  
pp. 3182-3190 ◽  
Author(s):  
Andrey Korshunov ◽  
Hendrik Witt ◽  
Thomas Hielscher ◽  
Axel Benner ◽  
Marc Remke ◽  
...  
Keyword(s):  
Genetic Markers ◽  
Survival Data ◽  
Copy Number ◽  
Cox Regression ◽  
Prognostic Significance ◽  
Staging System ◽  
Comparative Genomic ◽  
Molecular Staging ◽  
Copy Number Aberrations ◽  
Intracranial Ependymoma

Purpose The biologic behavior of intracranial ependymoma is unpredictable on the basis of current staging approaches. We aimed at the identification of recurrent genetic aberrations in ependymoma and evaluated their prognostic significance to develop a molecular staging system that could complement current classification criteria. Patients and Methods As a screening cohort, we studied a cohort of 122 patients with ependymoma before standardized therapy by using array-based comparative genomic hybridization. DNA copy-number aberrations identified as possible prognostic markers were validated in an independent cohort of 170 patients with ependymoma by fluorescence in situ hybridization analysis. Copy-number aberrations were correlated with clinical, histopathologic, and survival data. Results In the screening cohort, age at diagnosis, gain of 1q, and homozygous deletion of CDKN2A comprised the most powerful independent indicators of unfavorable prognosis. In contrast, gains of chromosomes 9, 15q, and 18 and loss of chromosome 6 were associated with excellent survival. On the basis of these findings, we developed a molecular staging system comprised of three genetic risk groups, which was then confirmed in the validation cohort. Likelihood ratio tests and multivariate Cox regression also demonstrated the clear improvement in predictive accuracy after the addition of these novel genetic markers. Conclusion Genomic aberrations in ependymomas are powerful independent markers of disease progression and survival. By adding genetic markers to established clinical and histopathologic variables, outcome prediction can potentially be improved. Because the analyses can be conducted on routine paraffin-embedded material, it will now be possible to prospectively validate these markers in multicenter clinical trials on population-based cohorts.

Outcome Prediction in Pediatric Medulloblastoma Based on DNA Copy-Number Aberrations of Chromosomes 6q and 17q and the MYC and MYCN Loci

2009 ◽  
Vol 27 (10) ◽  
pp. 1627-1636 ◽  
Author(s):  
Stefan Pfister ◽  
Marc Remke ◽  
Axel Benner ◽  
Frank Mendrzyk ◽  
Grischa Toedt ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Copy Number ◽  
Outcome Prediction ◽  
Array Cgh ◽  
Staging System ◽  
Fish Analysis ◽  
Genomic Amplification ◽  
Molecular Staging ◽  
Clinical Variables ◽  
Copy Number Aberrations

Purpose Medulloblastoma is the most common malignant brain tumor in children. Current treatment decisions are based on clinical variables. Novel tumor-derived biomarkers may improve the risk stratification of medulloblastoma patients. Patients and Methods A model for the molecular risk stratification was proposed from an array-based comparative genomic hybridization (array-CGH) screen (n = 80). Fluorescence in situ hybridization (FISH) analyses for chromosome arms 6q, 17p, and 17q and the MYC and MYCN loci were performed in an independent validation set (n = 260). Copy number aberrations were correlated with clinical, histologic, and survival data. Results Gain of 6q and 17q and genomic amplification of MYC or MYCN were each associated with poor outcome in the array-CGH study (n = 80). In contrast, all patients with 6q-deleted tumors survived. Given these findings, the following hierarchical molecular staging system was defined: (1) MYC/MYCN amplification, (2) 6q gain, (3) 17q gain, (4) 6q and 17q balanced, and (5) 6q deletion. The prognostic value of this staging system was investigated by FISH analysis (n = 260). The addition of molecular markers to clinical risk factors resulted in the identification of a large proportion of patients (72 of 260 patients; 30%) at high risk for relapse and death who would be considered standard risk by application of clinical variables alone. Conclusion Genomic aberrations in medulloblastoma are powerful independent markers of disease progression and survival. By adding genomic markers to established clinical and histologic variables, outcome prediction can be substantially improved. Because the analyses can be conducted on routine paraffin-embedded material, it will be especially feasible to use this novel molecular staging system in large multicenter clinical trials.

Abstract A1-67: Prognostic significance of copy number aberrations in Wilms tumor

2015 ◽  
Author(s):  
Tasnim Chagtai ◽  
Christina Zill ◽  
Linda Dainese ◽  
Jenny Wegert ◽  
Mariana Maschietto ◽  
...  
Keyword(s):  
Copy Number ◽  
Wilms Tumor ◽  
Prognostic Significance ◽  
Copy Number Aberrations

Overall Genomic Pattern Is a Predictor of Outcome in Neuroblastoma

2009 ◽  
Vol 27 (7) ◽  
pp. 1026-1033 ◽  
Author(s):  
Isabelle Janoueix-Lerosey ◽  
Gudrun Schleiermacher ◽  
Evi Michels ◽  
Véronique Mosseri ◽  
Agnès Ribeiro ◽  
...  
Keyword(s):  
Copy Number ◽  
Prognostic Significance ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Comparative Genomic ◽  
Mycn Amplification ◽  
Clinical Markers ◽  
Prognostic Information ◽  
Stage 4 ◽  
Risk Of Relapse

Purpose For a comprehensive overview of the genetic alterations of neuroblastoma, their association and clinical significance, we conducted a whole-genome DNA copy number analysis. Patients and Methods A series of 493 neuroblastoma (NB) samples was investigated by array-based comparative genomic hybridization in two consecutive steps (224, then 269 patients). Results Genomic analysis identified several types of profiles. Tumors presenting exclusively whole-chromosome copy number variations were associated with excellent survival. No disease-related death was observed in this group. In contrast, tumors with any type of segmental chromosome alterations characterized patients with a high risk of relapse. Patients with both numerical and segmental abnormalities clearly shared the higher risk of relapse of segmental-only patients. In a multivariate analysis, taking into account the genomic profile, but also previously described individual genetic and clinical markers with prognostic significance, the presence of segmental alterations with (HR, 7.3; 95% CI, 3.7 to 14.5; P < .001) or without MYCN amplification (HR, 4.5; 95% CI, 2.4 to 8.4; P < .001) was the strongest predictor of relapse; the other significant variables were age older than 18 months (HR, 1.8; 95% CI, 1.2 to 2.8; P = .004) and stage 4 (HR, 1.8; 95% CI, 1.2 to 2.7; P = .005). Finally, within tumors showing segmental alterations, stage 4, age, MYCN amplification, 1p and 11q deletions, and 1q gain were independent predictors of decreased overall survival. Conclusion The analysis of the overall genomic pattern, which probably unravels particular genomic instability mechanisms rather than the analysis of individual markers, is essential to predict relapse in NB patients. It adds critical prognostic information to conventional markers and should be included in future treatment stratification.

scholarly journals Identification of a Glycosyltransferase Signature for Predicting Prognosis and Immune Microenvironment in Neuroblastoma

2022 ◽  
Vol 9 ◽  
Author(s):  
Yongliang Sha ◽  
Lei Han ◽  
Bei Sun ◽  
Qiang Zhao
Keyword(s):  
Immune Cell ◽  
Cox Regression ◽  
Immune Escape ◽  
Cytotoxic T Lymphocyte ◽  
Prognostic Significance ◽  
Tumor Development ◽  
Neuron Specific Enolase ◽  
Staging System ◽  
Support Vector ◽  
Mycn Amplification

Neuroblastoma (NB) is one of the most common solid tumors in children. Glycosyltransferases (GTs) play a crucial role in tumor development and immune escape and have been used as prognostic biomarkers in various tumors. However, the biological functions and prognostic significance of GTs in NB remain poorly understood. The expression data from Gene Expression Omnibus (GEO) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) were collected as training and testing data. Based on a progression status, differentially expressed GTs were identified. We constructed a GTscore through support vector machine, least absolute shrinkage and selection operator, and Cox regression in NB, which included four prognostic GTs and was an independent prognostic risk factor for NB. Patients in the high GTscore group had an older age, MYCN amplification, advanced International Neuroblastoma Staging System stage, and high risk. Samples with high GTscores revealed high disialoganglioside (GD2) and neuron-specific enolase expression levels. In addition, a lack of immune cell infiltration was observed in the high GTscore group. This GTscore was also associated with the expression of chemokines (CCL2, CXCL9, and CXCL10) and immune checkpoint genes (cytotoxic T-lymphocyte–associated protein 4, granzyme H, and granzyme K). A low GTscore was also linked to an enhanced response to anti–PD-1 immunotherapy in melanoma patients, and one type of tumor was also derived from neuroectodermal cells such as NB. In conclusion, the constructed GTscore revealed the relationship between GT expression and the NB outcome, GD2 phenotype, and immune infiltration and provided novel clues for the prediction of prognosis and immunotherapy response in NB.

Adult and Pediatric Medulloblastomas Are Genetically Distinct and Require Different Algorithms for Molecular Risk Stratification

2010 ◽  
Vol 28 (18) ◽  
pp. 3054-3060 ◽  
Author(s):  
Andrey Korshunov ◽  
Marc Remke ◽  
Wiebke Werft ◽  
Axel Benner ◽  
Marina Ryzhova ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Copy Number ◽  
Prognostic Markers ◽  
Tumor Biology ◽  
Staging System ◽  
Risk Groups ◽  
Comparative Genomic ◽  
Dna Copy Number ◽  
Specific Risk ◽  
Dna Copy Number Aberrations

Purpose Medulloblastoma (MB) is the most common malignant brain tumor in children, whereas it rarely presents in adults. We aimed to identify genetic aberrations in 146 adult MBs to evaluate age-dependent differences in tumor biology and adapt age-specific risk stratification models. Methods As a screening set, we studied a cohort of 34 adult MBs by using array-based comparative genomic hybridization comparing molecular results with clinical data. DNA copy number aberrations identified as possible prognostic markers were validated in an independent cohort of 112 adult patients with MB by fluorescent in situ hybridization analysis. Results were compared with the data obtained from 404 pediatric patients with MB. Results CDK6 amplification, 10q loss, and 17q gain are the most powerful prognostic markers in adult MB. Whereas MYC/MYCN oncogene amplifications had a high prognostic value in pediatric MB, these aberrations were rarely observed in adult tumors. Surprisingly, adult MBs with 6q deletion and nuclear β-catenin activation did not share the excellent prognosis with their pediatric counterparts. Conclusion Adult MB is distinct from pediatric MB in terms of genomic aberrations and their impact on clinical outcomes. Therefore, adult MBs require age-specific risk stratification models. We propose a molecular staging system involving three distinct risk groups based on DNA copy number status of 10q and 17q.

scholarly journals Improved Statistical Analysis for Array CGH-Based DNA Copy Number Aberrations

2011 ◽  
Vol 10 ◽  
pp. CIN.S8019
Author(s):  
Hongmei Jiang ◽  
Zhong-Zheng Zhu ◽  
Yue Yu ◽  
Simon Lin ◽  
Lifang Hou
Keyword(s):  
Copy Number ◽  
Cancer Metastasis ◽  
Copy Number Gain ◽  
Statistical Hypothesis ◽  
Comparative Genomic ◽  
Statistical Hypothesis Testing ◽  
Dna Copy Number ◽  
Copy Number Aberrations ◽  
Number Pattern ◽  
Dna Copy Number Aberrations

Array-based comparative genomic hybridization (aCGH) allows measuring DNA copy number at the whole genome scale. In cancer studies, one may be interested in identifying DNA copy number aberrations (CNAs) associated with certain clinicopathological characteristics such as cancer metastasis. We proposed to define test regions based on copy number pattern profiles across multiple samples, using either smoothed log2-ratio or discrete data of copy number gain/loss calls. Association test performed on the refined test regions instead of the probes has improved power due to reduced number of tests. We also compared three types of measurement of copy number levels, normalized log2-ratio, smoothed log2-ratio, and copy number gain or loss calls in statistical hypothesis testing. The relative strengths and weaknesses of the proposed method were demonstrated using both simulation studies and real data analysis of a liver cancer study.

scholarly journals The prognostic significance of different proportion of signet-ring cells of colorectal carcinoma

2021 ◽  
Author(s):  
Wei Chen ◽  
Huajun Cai ◽  
Kui Chen ◽  
Xing Liu ◽  
Weizhong Jiang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
Cox Regression ◽  
Prognostic Significance ◽  
Staging System ◽  
Signet Ring Cell ◽  
Significant Difference ◽  
Signet Ring ◽  
Ajcc Staging System ◽  
Ajcc Staging

While the prognosis of patients with partial SRCC (PSRCC) has been rarely reported, colorectal signet-ring cell carcinoma (SRCC) has been associated with poor prognosis. The aim of this study was to analyze the prognosis of patients with different SRC composition and establish a prediction model. A total of 91 patients with SRC component were included in the study. These patients were divided into two groups: SRCC group (SRC composition > 50%; n=41) and partial SRCC (PSRCC) group (SRC composition ≤ 50%; n=50). COX regression model was used to identify independent prognostic factors for overall survival (OS). A predictive nomogram was established and compared with the 7th AJCC staging system. After a median follow-up of 16 months, no significant difference in OS was observed in either group. Preoperative carcinoembryonic antigen (CEA) level, pN stage, M stage, preoperative ileus, and adjuvant chemotherapy were independent prognostic risk factors for OS (p<0.05). A nomogram for predicting the overall survival of colorectal SRCC was established with a C-index of 0.800, and it showed better performance than that of the 7th AJCC staging system (p<0.001). In summary, the ratio of SRC component was not an independent prognostic factor of the OS. Those patients with less than 50% of SRC component should be given the same clinical attention. A predictive nomogram for survival based on five independent prognostic factors was developed and showed better performance than the 7th AJCC staging system. This resulted to be helpful for individualized prognosis prediction and risk assessment.

scholarly journals Identification and Validation of a Novel RNA-Binding Protein-Related Gene-Based Prognostic Model for Multiple Myeloma

2021 ◽  
Vol 12 ◽  
Author(s):  
Wei Wang ◽  
Shi-wen Xu ◽  
Xia-yin Zhu ◽  
Qun-yi Guo ◽  
Min Zhu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Rna Binding ◽  
Cox Regression ◽  
Rna Binding Proteins ◽  
Prognostic Significance ◽  
Staging System ◽  
The Cancer Genome Atlas ◽  
Prognostic Signature ◽  
Major Pathway ◽  
Risk Status

BackgroundMultiple myeloma (MM) is a malignant hematopoietic disease that is usually incurable. RNA-binding proteins (RBPs) are involved in the development of many tumors, but their prognostic significance has not been systematically described in MM. Here, we developed a prognostic signature based on eight RBP-related genes to distinguish MM cohorts with different prognoses.MethodAfter screening the differentially expressed RBPs, univariate Cox regression was performed to evaluate the prognostic relevance of each gene using The Cancer Genome Atlas (TCGA)-Multiple Myeloma Research Foundation (MMRF) dataset. Lasso and stepwise Cox regressions were used to establish a risk prediction model through the training set, and they were validated in three Gene Expression Omnibus (GEO) datasets. We developed a signature based on eight RBP-related genes, which could classify MM patients into high- and low-score groups. The predictive ability was evaluated using bioinformatics methods. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and gene set enrichment analyses were performed to identify potentially significant biological processes (BPs) in MM.ResultThe prognostic signature performed well in the TCGA-MMRF dataset. The signature includes eight hub genes: HNRNPC, RPLP2, SNRPB, EXOSC8, RARS2, MRPS31, ZC3H6, and DROSHA. Kaplan–Meier survival curves showed that the prognosis of the risk status showed significant differences. A nomogram was constructed with age; B2M, LDH, and ALB levels; and risk status as prognostic parameters. Receiver operating characteristic (ROC) curve, C-index, calibration analysis, and decision curve analysis (DCA) showed that the risk module and nomogram performed well in 1, 3, 5, and 7-year overall survival (OS). Functional analysis suggested that the spliceosome pathway may be a major pathway by which RBPs are involved in myeloma development. Moreover, our signature can improve on the R-International Staging System (ISS)/ISS scoring system (especially for stage II), which may have guiding significance for the future.ConclusionWe constructed and verified the 8-RBP signature, which can effectively predict the prognosis of myeloma patients, and suggested that RBPs are promising biomarkers for MM.

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