Hui Angela B Y, Takano Hirokuni, Lo Kwok-Wai, Kuo Wen-Lin, Lam Cleo N Y, Tong Carol Y K, Chang Qing, Gray Joe W, Ng Ho-Keung
Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong SAR, PR China.
Clin Cancer Res. 2005 Jul 1;11(13):4707-16. doi: 10.1158/1078-0432.CCR-05-0128.
The aim of this study is to comprehensively characterize genome copy number aberrations in medulloblastomas using high-resolution array comparative genomic hybridization.
High-density genomic arrays containing 1,803 BAC clones were used to define recurrent chromosomal regions of gains or losses throughout the whole genome of medulloblastoma. A series of 3 medulloblastoma cell lines and 16 primary tumors were investigated.
The detected consistent chromosomal aberrations included gains of 1q21.3-q23.1 (36.8%), 1q32.1 (47.4%), 2p23.1-p25.3 (52.6%), 7 (57.9%), 9q34.13-q34.3 (47.4%), 17p11.2-q25.3 (89.5%), and 20q13.31-q13.33 (42.1%), as well as losses of 3q26.1 (57.9%), 4q31.23-q32.3 (42.1%), 6q23.1-25.3 (57.9%), 8p22-23.3 (79%), 10q24.32-26.2 (57.9%), and 16q23.2-q24.3 (63.2%). One of the most notable aberrations was a homozygous deletion on chromosome 6q23 in the cell line DAOY, and single copy loss on 30.3% primary tumors. Further analyses defined a 0.887 Mbp minimal region of homozygous deletion at 6q23.1 flanked by markers SHGC-14149 (6q22.33) and SHGC-110551 (6q23.1). Quantitative reverse transcription-PCR analysis showed complete loss of expression of two genes located at 6q23.1, AK091351 (hypothetical protein FLJ34032) and KIAA1913, in the cell line DAOY. mRNA levels of these genes was reduced in cell lines D283 and D384, and in 50% and 70% of primary tumors, respectively.
Current array comparative genomic hybridization analysis generates a comprehensive pattern of chromosomal aberrations in medulloblastomas. This information will lead to a better understanding of medulloblastoma tumorigenesis. The delineated regions of gains or losses will indicate locations of medulloblastoma-associated genes. A 0.887 Mbp homozygous deletion region was newly identified at 6q23.1. Frequent detection of reduced expression of AK091351 and KIAA1913 genes implicates them as suppressors of medulloblastoma tumorigenesis.
本研究旨在利用高分辨率阵列比较基因组杂交技术全面表征髓母细胞瘤中的基因组拷贝数畸变。
使用包含1803个BAC克隆的高密度基因组阵列来确定髓母细胞瘤全基因组中反复出现的染色体增加或缺失区域。对一系列3个髓母细胞瘤细胞系和16个原发性肿瘤进行了研究。
检测到的一致染色体畸变包括1q21.3 - q23.1（36.8%）、1q32.1（47.4%）、2p23.1 - p25.3（52.6%）、7（57.9%）、9q34.13 - q34.3（47.4%）、17p11.2 - q25.3（89.5%）和20q13.31 - q13.33（42.1%）的增加，以及3q26.1（57.9%）、4q31.23 - q32.3（42.1%）、6q23.1 - 25.3（57.9%）、8p22 - 23.3（79%）、10q24.32 - 26.2（57.9%）和16q23.2 - q24.3（63.2%）的缺失。最显著的畸变之一是细胞系DAOY中6号染色体q23处的纯合缺失，以及30.3%原发性肿瘤中的单拷贝缺失。进一步分析确定了6q23.1处一个0.887 Mbp的最小纯合缺失区域，其两侧为标记SHGC - 14149（6q22.33）和SHGC - 110551（6q23.1）。定量逆转录 - PCR分析显示，位于6q23.1的两个基因AK091351（假设蛋白FLJ34032）和KIAA1913在细胞系DAOY中完全丧失表达。这些基因的mRNA水平在细胞系D283和D384中降低，在原发性肿瘤中分别有50%和70%降低。
当前的阵列比较基因组杂交分析产生了髓母细胞瘤中染色体畸变的全面模式。这些信息将有助于更好地理解髓母细胞瘤的肿瘤发生机制。划定的增加或缺失区域将指示髓母细胞瘤相关基因的位置。在6q23.1处新鉴定出一个0.887 Mbp的纯合缺失区域。频繁检测到AK091351和KIAA1913基因表达降低表明它们是髓母细胞瘤肿瘤发生的抑制因子。
