Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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.


METHODS
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.


CONCLUSIONS
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.
Yang
Jun J
JJ
St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Cheng
Cheng
C
Yang
Wenjian
W
Pei
Deqing
D
Cao
Xueyuan
X
Fan
Yiping
Y
Pounds
Stanley B
SB
Neale
Geoffrey
G
Treviño
Lisa R
LR
French
Deborah
D
Campana
Dario
D
Downing
James R
JR
Evans
William E
WE
Pui
Ching-Hon
CH
Devidas
Meenakshi
M
Bowman
W P
WP
Camitta
Bruce M
BM
Willman
Cheryl L
CL
Davies
Stella M
SM
Borowitz
Michael J
MJ
Carroll
William L
WL
Hunger
Stephen P
SP
Relling
Mary V
MV
D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D016014:Linear Models; D015810:Linkage Disequilibrium; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D018365:Neoplasm, Residual / Q000235:genetics; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D012008:Recurrence; D012074:Remission Induction; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors
D005047:Etoposide; D008727:Methotrexate