基因病灶利用SNP微陣列在整個(gè)基因組范圍內(nèi)對(duì)DNA版本數(shù)異常進(jìn)行高分辨率分析的方法,，被用來(lái)識(shí)別與兒童最常見的癌癥——急性淋巴細(xì)胞性白血病有關(guān)的基因病灶,。對(duì)來(lái)自242位患者的白血病母細(xì)胞所作的分析顯示，在40%的B-先祖細(xì)胞急性淋巴細(xì)胞性白血病病例中,，為B-淋巴細(xì)胞發(fā)育的關(guān)鍵調(diào)控因子編碼的基因發(fā)生刪除,、放大、點(diǎn)突變和結(jié)構(gòu)重排等問題,。PAX5是最常見的目標(biāo),。所獲得的數(shù)據(jù)表明，能夠繞開這些基因病灶所造成障礙的小分子細(xì)胞分化誘導(dǎo)因子可以作為研究新的治療方法的一個(gè)重點(diǎn),，并且更具有普遍意義的是,，它們展示了人們所熟悉的整個(gè)基因組范圍內(nèi)進(jìn)行分析的方法作為識(shí)別癌癥中新的小分子病灶的一種手段所具有的潛力。封面圖片所示為白血病細(xì)胞的熒光原位雜交,，它顯示了9p13染色體上的PAX5向18q11.2位置上的ZNF521的融合,。
部分英文原文：
Article
Nature 446, 758-764 (12 April 2007) | doi:10.1038/nature05690; Received 7 November 2006; Accepted 20 February 2007; Published online 7 March 2007
Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia
Charles G. Mullighan1,6, Salil Goorha1,6, Ina Radtke1, Christopher B. Miller1, Elaine Coustan-Smith2, James D. Dalton1, Kevin Girtman1, Susan Mathew1,7, Jing Ma5, Stanley B. Pounds3, Xiaoping Su5, Ching-Hon Pui2, Mary V. Relling4, William E. Evans4, Sheila A. Shurtleff1 & James R. Downing1
Departments of Pathology,
Oncology,
Biostatistics,
Pharmaceutical Sciences, and the
Hartwell Center for Bioinformatics and Biotechnology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
These authors contributed equally to this work.
Present address: The Department of Pathology & Laboratory Medicine, New York Presbyterian Hospital, Cornell Campus, 525 East 68th Street, F511, New York, New York 10021, USA.
Correspondence to: James R. Downing1 Correspondence and requests for materials should be addressed to J.R.D. (Email: [email protected]).
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Abstract
Chromosomal aberrations are a hallmark of acute lymphoblastic leukaemia (ALL) but alone fail to induce leukaemia. To identify cooperating oncogenic lesions, we performed a genome-wide analysis of leukaemic cells from 242 paediatric ALL patients using high-resolution, single-nucleotide polymorphism arrays and genomic DNA sequencing. Our analyses revealed deletion, amplification, point mutation and structural rearrangement in genes encoding principal regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL cases. The PAX5 gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in reduced levels of PAX5 protein or the generation of hypomorphic alleles. Deletions were also detected in TCF3 (also known as E2A), EBF1, LEF1, IKZF1 (IKAROS) and IKZF3 (AIOLOS). These findings suggest that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis. Moreover, these data demonstrate the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer.
