title: Genomic ancestry and somatic alterations correlate with age at diagnosis in Hispanic children with B-cell acute lymphoblastic leukemia.
abstract: Hispanic children have a higher incidence of acute lymphoblastic leukemia (ALL) than non-Hispanic whites but tend to be diagnosed at older ages. In genome-wide association studies, Native American ancestry and polymorphisms in six genes have been associated with ALL risk. In multivariable regression models, we investigated whether genomic ancestry, inherited risk SNPs, or acquired somatic alterations were associated with differences in age at diagnosis in Hispanic children with B-cell ALL. Genome-wide array data were used to estimate each participant's percent membership in the three Hispanic ancestral populations: Native American, African, and European. Each 20% increase in European ancestry was associated with a six month younger age at diagnosis (95% CI = 0.36-11.6 months, P = 0.037). Correspondingly, each 20% increase in Native American ancestry was associated with a six-month older age at diagnosis (P = 0.037). Both the TEL-AML1 translocation and high-hyperdiploidy were associated with younger age at diagnosis (24.4 months, P = 2.0 x 10(-4) and 12.4 months, P = 0.011, respectively), while CDKN2A and IKZF1 deletions were associated with older age at diagnosis (19.7 months, P = 7.0 x 10(-4) and 18.1 months, P = 0.012, respectively). No associations with age at diagnosis were observed for RAS mutation, PAX5 deletion or for known heritable risk alleles in IKZF1, CDKN2A, PIP4K2A, GATA3, ARID5B, or CEBPE. Because younger age at diagnosis is associated with improved treatment outcomes for children with ALL, the effect of European ancestry on ALL survival may be mediated by its effect on age at diagnosis, or by proxy, its association with more treatable molecular subtypes of ALL.
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, 94143; Program in Cancer Genetics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, 94143.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Walsh
authors.forename: Adam J
authors.initials: AJ
authors.lastname: de Smith
authors.forename: Tara C
authors.initials: TC
authors.lastname: Welch
authors.forename: Ivan
authors.initials: I
authors.lastname: Smirnov
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Cunningham
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Ma
authors.forename: Anand P
authors.initials: AP
authors.lastname: Chokkalingam
authors.forename: Gary V
authors.initials: GV
authors.lastname: Dahl
authors.forename: William
authors.initials: W
authors.lastname: Roberts
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Barcellos
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Buffler
authors.forename: Catherine
authors.initials: C
authors.lastname: Metayer
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Wiemels
mesh_terms: D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics; D006630:Hispanic or Latino / Q000235:genetics* / Q000706:statistics & numerical data; D006801:Humans; D015994:Incidence; D008297:Male; D020641:Polymorphism, Single Nucleotide; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000453:epidemiology / Q000208:ethnology* / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000453:epidemiology / Q000208:ethnology* / Q000235:genetics*; D014481:United States / Q000453:epidemiology
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