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Blood, 15 November 2008, Vol. 112, No. 10, pp. 4178-4183. Prepublished online as a Blood First Edition Paper on September 2, 2008; DOI 10.1182/blood-2008-06-165027. This Article Full Text Full Text (PDF) Supplemental Methods, Tables, and Figures All Versions of this Article: blood-2008-06-165027v1 112/10/4178    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Yang, J. J. Articles by Carroll, W. L. Search for Related Content PubMed PubMed Citation Articles by Yang, J. J. Articles by Carroll, W. L. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Genome-wide copy number profiling reveals molecular evolution from diagnosis to relapse in childhood acute lymphoblastic leukemia Jun J. Yang1,*, Deepa Bhojwani1,2,*, Wenjian Yang1, Xiangjun Cai1, Gabriele Stocco1, Kristine Crews1, Jinhua Wang2, Debra Morrison2, Meenakshi Devidas3, Stephen P. Hunger4, Cheryl L. Willman5, Elizabeth A. Raetz2, Ching-hon Pui1, William E. Evans1, Mary V. Relling1, and William L. Carroll2 1 St Jude Children's Research Hospital, Memphis, TN; 2 New York University Cancer Institute, New York, NY; 3 College of Medicine, University of Florida, Gainesville; 4 Children's Hospital and University of Colorado Cancer Center, Aurora; and 5 University of New Mexico Cancer Center, Albuquerque The underlying pathways that lead to relapse in childhood acute lymphoblastic leukemia (ALL) are unknown. To comprehensively characterize the molecular evolution of relapsed childhood B-precursor ALL, we used human 500K single-nucleotide polymorphism arrays to identify somatic copy number alterations (CNAs) in 20 diagnosis/relapse pairs relative to germ line. We identified 758 CNAs, 66.4% of which were less than 1 Mb, and deletions outnumbered amplifications by approximately 2.5:1. Although CNAs persisting from diagnosis to relapse were observed in all 20 cases, 17 patients exhibited differential CNA patterns from diagnosis to relapse. Of the 396 CNAs observed in 20 relapse samples, only 69 (17.4%) were novel (absent in the matched diagnosis samples). EBF1 and IKZF1 deletions were particularly frequent in this relapsed ALL cohort (25.0% and 35.0%, respectively), suggesting their role in disease recurrence. In addition, we noted concordance in global gene expression and DNA copy number changes (P = 2.2 x 10–16). Finally, relapse-specific focal deletion of MSH6 and, consequently, reduced gene expression were found in 2 of 20 cases. In an independent cohort of children with ALL, reduced expression of MSH6 was associated with resistance to mercaptopurine and prednisone, thereby providing a plausible mechanism by which this acquired deletion contributes to drug resistance at relapse. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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