Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. JAMA 2009 Jan 28;301(4):393-403
Date
01/30/2009Pubmed ID
19176441Pubmed Central ID
PMC2664534DOI
10.1001/jama.2009.7Scopus ID
2-s2.0-59249100224 (requires institutional sign-in at Scopus site) 188 CitationsAbstract
CONTEXT: Pediatric acute lymphoblastic leukemia (ALL) is the prototype for a drug-responsive malignancy. Although cure rates exceed 80%, considerable unexplained interindividual variability exists in treatment response.
OBJECTIVES: To assess the contribution of inherited genetic variation to therapy response and to identify germline single-nucleotide polymorphisms (SNPs) associated with risk of minimal residual disease (MRD) after remission induction chemotherapy.
DESIGN, SETTING, AND PATIENTS: Genome-wide interrogation of 476,796 germline SNPs to identify genotypes that were associated with MRD in 2 independent cohorts of children with newly diagnosed ALL: 318 patients in St Jude Total Therapy protocols XIIIB and XV and 169 patients in Children's Oncology Group trial P9906. Patients were enrolled between 1994 and 2006 and last follow-up was in 2006.
MAIN OUTCOME MEASURES: Minimal residual disease at the end of induction therapy, measured by flow cytometry.
RESULTS: There were 102 SNPs associated with MRD in both cohorts (median odds ratio, 2.18; P < or = .0125), including 5 SNPs in the interleukin 15 (IL15) gene. Of these 102 SNPs, 21 were also associated with hematologic relapse (P < .05). Of 102 SNPs, 21 were also associated with antileukemic drug disposition, generally linking MRD eradication with greater drug exposure. In total, 63 of 102 SNPs were associated with early response, relapse, or drug disposition.
CONCLUSION: Host genetic variations are associated with treatment response for childhood ALL, with polymorphisms related to leukemia cell biology and host drug disposition associated with lower risk of residual disease.
Author List
Yang JJ, Cheng C, Yang W, Pei D, Cao X, Fan Y, Pounds SB, Neale G, Treviño LR, French D, Campana D, Downing JR, Evans WE, Pui CH, Devidas M, Bowman WP, Camitta BM, Willman CL, Davies SM, Borowitz MJ, Carroll WL, Hunger SP, Relling MVAuthor
Bruce m. Camitta Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdolescentAntineoplastic Combined Chemotherapy Protocols
Child
Child, Preschool
Etoposide
Female
Flow Cytometry
Follow-Up Studies
Genotype
Germ-Line Mutation
Humans
Infant
Linear Models
Linkage Disequilibrium
Male
Methotrexate
Neoplasm, Residual
Odds Ratio
Phenotype
Polymorphism, Single Nucleotide
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Recurrence
Remission Induction
Retrospective Studies
Risk Assessment
Risk Factors
