Genetic Alterations in Childhood Medulloblastoma Analyzed by Comparative Genomic Hybridization

Abstract

Despite intensive therapy, the survival of children with medulloblastoma remains disappointing. Moreover, children who survive are affected by serious long-term sequelae of treatment that impair their quality of life. In search of chromosomal aberrations indicative of sites involved in oncogenic transformation and in an attempt to find reliable prognostic markers, the authors analyzed 15 medulloblastomas by comparative genomic hybridization. All neoplasms showed chromosomal abnormalities. The most frequent losses were 17p (7/15 tumors), 8p and 11p (6/15), 10p, 1lq, 16q, and 20q (5/15), and 20p (4/15). Gains were recurrently found at 7q (10/15 tumors), 17q and 18q (9/15 tumors), 7p and 13q (7/15), 18p (6/15), and 1q, 4q, 6q. and 9p (5/15 tumors). Four tumors showed loss of 17p together with gain of 17q, suggesting an isochromosome 17q. High-level amplifications were seen at 1p34, 5p15, 13q34, and 18p11 (one tumor each), and at 2p15 in two tumors, one of which was proven to be N-Myc amplification. The overall pattern of alterations found in this study confirms the findings of other studies and adds two novel regions with chromosomal gains, at 13q and 18q. Previous reports on the relation between 17q gain and survival could not be confirmed, whereas amplification of N-myc or L-myc seems to indicate poor clinical outcome.

Array CGH analysis of pediatric medulloblastomas

“…Losses of genetic material involving 8p have been among the most frequently reported in medulloblastomas (Reardon et al, 1997;Ellison 2002;Michiels et al, 2002;Tong et al, 2004), where the suggestion of a homozygous deletion in the 8p22-23.1 region was described by Yin et al (2002). In our study, 30% of the tumors showed losses involving 8p.…”

“…wiley.com. ] A number of reports of LOH studies and conventional chromosome-based CGH have described wide variation in CNAs in the individual regions of the chromosomes (Schutz et al, 1996;Reardon et al, 1997;Nishizaki et al, 1999;Bayani et al, 2000;Roberts et al, 2001;Eberhart et al, 2002;Michiels et al, 2002;Yin et al, 2002;Cohen et al, 2004;Zakrzewska et al, 2004). Array-based CGH, however, provides a higher-resolution analysis at a genome-wide level of copy number abnormalities within tumors that allow the breakpoints that give rise to CNAs to be determined more precisely.…”

“…Less commonly observed are CNAs involving 16q and 8, and rare changes involving chromosomes 5 and 22 have also been reported (Schutz et al, 1996;Avet-Loiseau et al, 1999;Nicholson et al, 1999;Russo et al, 1999;Gilhuis et al, 2000;Eberhart et al, 2002;Zakrzewska et al, 2004). Amplification of MYC/MYCN oncogenes, sometimes as double minutes, is reportedly rare (3%-5%) but appears to correlate with poor prognosis (Aldosari et al, 2002a;Michiels et al, 2002). Cytogenetic changes identified using comparative genomic hybridization (CGH) have been reported for relatively large numbers of medulloblastoma samples to date, but no pattern has emerged that correlates with survival.…”

Identification of a Novel Homozygous Deletion Region at 6q23.1 in Medulloblastomas Using High-Resolution Array Comparative Genomic Hybridization Analysis

“…This result was further confirmed with FISH using the same BAC clone, RP11-73O6, which is located at 6q23.1. Loss of chromosome 6q had been reported by Michiels et al (35) and Thomas et al (36) in 33.3% and 26.1% of medulloblastomas. Both studies investigated the whole long arm of chromosome 6 and no fine mapping analysis was done.…”

Novel amplifications in pediatric medulloblastoma identified by genome-wide copy number profiling

“…Of those, isochromosome 17q [i(17)(q10)] is the most frequent and is detected in 30-50% of tumors. Moreover, loss of 17p and gain of 17q occurring independently are also common [2,[11][12][13][14]. Other reported chromosomal alterations include trisomy 7 and MYC or MYCN amplification [2,[13][14][15].…”