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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.
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Submitted June 24, 2008
Accepted August 10, 2008
Genome-wide copy number profiling reveals molecular evolution from diagnosis to relapse in childhood acute lymphoblastic leukemia
Jun J Yang, Deepa Bhojwani, Wenjian Yang, Xiangjun Cai, Gabriele Stocco, Kristine Crews, Jinhua Wang, Debra Morrison, Meenakshi Devidas, Stephen P Hunger, Cheryl L Willman, Elizabeth A Raetz, Ching-hon Pui, William E Evans, Mary V Relling, and William L Carroll*
St. Jude Children's Research Hospital, Memphis, TN, United States
New York University Cancer Institute, New York, NY, United States
College of Medicine, University of Florida, Gainesville, FL, United States
The Children's Hospital and the University of Colorado Cancer Center, Aurora, CO, United States
University of New Mexico Cancer Center, Albuquerque, NM, United States
* Corresponding author; email: william.carroll{at}nyumc.org.
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 utilized human 500K single-nucleotide polymorphism (SNP) arrays to identify somatic copy number alterations (CNA) in 20 diagnosis/relapse pairs relative to germline. In total, we identified 758 CNAs, 66.4% of which were < 1Mb, and deletions outnumbered amplifications by ~2.5:1. While 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 (i.e. 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. Additionally, 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 was 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.
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