Malgorzata Pellarin

Isochromosome 17q Is a Negative Prognostic Factor in Poor-Risk Childhood Medulloblastoma Patients

Background: Medulloblastomas are the most common primary malignant childhood intracranial neoplasms. Patients are currently sorted into three risk groups based on clinical criteria: standard, poor, and infant (<18 months old). We hypothesized that genetic copy number aberrations (CNA) predict prognosis and would provide improved criteria for predicting outcome. Methods: DNA from 35 medulloblastoma patients from four Childrens Cancer Group trials was analyzed by comparative genomic hybridization to determine CNAs. The genetic alterations were evaluated using statistical and cluster analyses. Results: The most frequent CNAs were gains on 17q, 7, 1q, and 7q and losses on 17p, 10q, X, 16q, and 11q. Amplification at 5p15.1-p15.3 was also detected. Isochromosome 17q (i(17)(q10)) was associated with poor overall survival (P = 0.03) and event-free survival (P = 0.04) independent of poor risk group classification. Age <3 tended to be associated with <3 CNAs (P = 0.06). Unsupervised cluster analysis sorted the study patients into four subgroups based on CNAs. Supervised analysis using the program Significance Analysis of Microarrays (SAM) quantitatively validated those CNAs identified by unsupervised clustering that significantly distinguished among the four subgroups. Conclusions: Medulloblastomas are genetically heterogeneous and can be categorized into separate genetic subgroups by their CNAs using unsupervised cluster analysis and SAM. i(17)(q10) was a significant independent negative prognostic factor. Infant medulloblastomas may be a distinct genetic subset from those of older patients.

Array Comparative Genomic Hybridization Identifies Genetic Subgroups in Grade 4 Human Astrocytoma

Alterations of DNA copy number are believed to be important indicators of tumor progression in human astrocytoma. We used an array of bacterial artificial chromosomes to map relative DNA copy number in 50 primary glioblastoma multiforme tumors at ∼1.4-Mb resolution. We identified 33 candidate sites for amplification and homozygous deletion in these tumors. We identified three major genetic subgroups within these glioblastoma multiforme tumors: tumors with chromosome 7 gain and chromosome 10 loss, tumors with only chromosome 10 loss in the absence of chromosome 7 gain, and tumors without copy number change in chromosomes 7 or 10. The significance of these genetic groups to therapeutics needs further study.

Two polyamine analogs (BE-4-4-4 and BE-4-4-4-4) directly affect growth, survival, and cell cycle progression in two human brain tumor cell lines

Abstract1,14-Bis-(ethyl)-amino-5,10-diazatetradecaneN1,N11-bis(ethyl)norspermine (BE-4-4-4) and 1,19-bis-(ethylamino)-5,10,15 triazanonadecane (BE-4-4-4-4) are two relatively new polyamine analogs synthesized for use as antineoplastic agents. In human brain tumor cell lines U-251 MG and SF-767, both agents inhibited cell growth, were cytotoxic, induced a variable G1/S block, and depleted intracellular polyamines. Since intracellular polyamine depletion did not always correlate with growth inhibition, cell survival, or cell cycle progression, it cannot completely explain the effects of these agents on growth, survival, and cell cycle progression in U-251 MG and SF-767 cells.

Chromosome transfer experiments link regions on chromosome 7 to radiation resistance in human glioblastoma multiforme

Glioblastoma multiforme (GM) is the most lethal form of brain tumor, with a median survival of approximately 1 year. Treatment options are limited. Radiation therapy is a common form of treatment, but many tumors are resistant. In earlier studies, we found that gain of chromosome 7 is associated with radiation resistance in human primary GM. In this study, we extend that result to a model system in which we transferred chromosome 7 to recipient cells and confirmed radiation resistance as a function of chromosome 7 gain. We identified three candidate regions on chromosome 7 that conferred radiation resistance in our model system.

Comparative Genomic Hybridization

Comparative genomic hybridization (CGH) allows the entire genome of an organism to be scanned for relative changes in DNA copy number (copy number aberrations) (1–3) in a single experiment. Standard CGH can detect aneuploidies, deletions, and unbalanced translocations at a resolution of 5–10 megabases. This is particularly useful in cases where DNA is unstable and where changes in copy number occur. Thus, tumors are often analyzed by CGH, but other applications could include diagnosis of other chromosome based illnesses.