title: Integrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic strategies.
abstract: Despite an increase in survival for children with acute lymphoblastic leukemia (ALL), the outcome after relapse is poor. To understand the genetic events that contribute to relapse and chemoresistance and identify novel targets of therapy, 3 high-throughput assays were used to identify genetic and epigenetic changes at relapse. Using matched diagnosis/relapse bone marrow samples from children with relapsed B-precursor ALL, we evaluated gene expression, copy number abnormalities (CNAs), and DNA methylation. Gene expression analysis revealed a signature of differentially expressed genes from diagnosis to relapse that is different for early (< 36 months) and late (≥ 36 months) relapse. CNA analysis discovered CNAs that were shared at diagnosis and relapse and others that were new lesions acquired at relapse. DNA methylation analysis found increased promoter methylation at relapse. There were many genetic alterations that evolved from diagnosis to relapse, and in some cases these genes had previously been associated with chemoresistance. Integration of the results from all 3 platforms identified genes of potential interest, including CDKN2A, COL6A2, PTPRO, and CSMD1. Although our results indicate that a diversity of genetic changes are seen at relapse, integration of gene expression, CNA, and methylation data suggest a possible convergence on the WNT and mitogen-activated protein kinase pathways.
authors.affiliation: New York University Cancer Institute, New York University Langone Medical Center, NY, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Hogan
authors.forename: Julia A
authors.initials: JA
authors.lastname: Meyer
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.forename: Nicholas
authors.initials: N
authors.lastname: Wong
authors.forename: Wenjian
authors.initials: W
authors.lastname: Yang
authors.forename: Gregory
authors.initials: G
authors.lastname: Condos
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Raetz
authors.forename: Richard
authors.initials: R
authors.lastname: Saffery
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
authors.forename: Deepa
authors.initials: D
authors.lastname: Bhojwani
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Morrison
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
mesh_terms: D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D007223:Infant; D008297:Male; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000628:therapy; D011401:Promoter Regions, Genetic; D012008:Recurrence