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.

Molecular risk stratification in pediatric medulloblastoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9506-9506
Author(s):  
S. M. Pfister ◽  
F. Mendrzyk ◽  
A. Korshunov ◽  
A. Wittmann ◽  
G. Toedt ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Protein Expression ◽  
Wnt Signaling ◽  
Survival Data ◽  
Copy Number ◽  
Prognostic Markers ◽  
Array Cgh ◽  
Beta Catenin ◽  
Dna Copy Number ◽  
Calcium Dependent

9506 Background: Medulloblastoma is the most common malignant brain tumor and a significant cause of cancer mortality in children. Despite considerable therapeutic advances, prognosis remains poor, with a five-year-survival rate of about 60% emphasizing the urgent need for markers to allow for a more accurate tailoring of treatment intensity. Methods: We performed genome-wide analysis of DNA-copy number in 112 medulloblastomas using array-CGH. All patients had received craniospinal irradiation after surgery. Standard adjuvant chemotherapy with lomustine, cisplatin and vincristine or a regimen with equal potency had been administered to 73 patients. To identify novel prognostic markers, DNA copy number information was correlated with survival data using log rank and chi-square tests. For selected candidate genes identified by array-CGH, mRNA and protein expression were analyzed by real-time quantitative PCR, and immunohistochemically on tissue microarrays consisting of medulloblastomas from 189 patients. Results: Copy-number gains of chromosomes 6 and 17q, high-level amplifications of MYC and MYCN, and loss of 9p21.3 (CDKN2A locus) were identified as significant adverse prognostic markers; monosomy 6 was associated with good prognosis. Monosomy 6 and gain of 17q were mutually exclusive, whereas trisomy 6 almost always occurred in conjunction with 17q gain. Tumors with trisomy 6 and 17q gains exhibit strong up-regulation of MAP3K7 (chr. 6) and NLK (17q) mRNA, two key-enzymes of the non-canonical calcium-dependent Wnt-signaling pathway. Furthermore, this subgroup exclusively shows high mRNA-expression of several cancer-retina antigens (e.g. GNGT1, GNGT2, PDE6, RCV1, RDS and NRL). Tumors with monosomy 6, in contrast, display highly activated canonical Wnt signaling as indicated by nuclear protein expression of beta-catenin. Conclusions: We propose a model for the molecular risk stratification of medulloblastoma comprising five risk groups with significantly different survival using copy-number status of MYC, MYCN, and chromosomes 6 and 17q. Furthermore, we give evidence for a role of noncanonical calcium-dependent Wnt-signalling in medulloblastoma metastasis in a subset of tumors. Cancer-retina antigens could be used to facilitate the diagnosis and follow-up of this molecular subgroup. No significant financial relationships to disclose.

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