title: Family-based exome-wide assessment of maternal genetic effects on susceptibility to childhood B-cell acute lymphoblastic leukemia in hispanics.
abstract: BACKGROUND
  Children of Hispanic ancestry have a higher incidence of acute lymphoblastic leukemia (ALL) compared with other ethnic groups, but to the authors' knowledge, the genetic basis for these racial disparities remain incompletely understood. Genome-wide association studies of childhood ALL to date have focused on inherited genetic effects; however, maternal genetic effects (the role of the maternal genotype on phenotype development in the offspring) also may play a role in ALL susceptibility.
  
  
  METHODS
  The authors conducted a family-based exome-wide association study of maternal genetic effects among Hispanics with childhood B-cell ALL using the Illumina Infinium HumanExome BeadChip. A discovery cohort of 312 Guatemalan and Hispanic American families and an independent replication cohort of 152 Hispanic American families were used.
  
  
  RESULTS
  Three maternal single-nucleotide polymorphisms (SNPs) approached the study threshold for significance after correction for multiple testing (P<1.0 × 10-6): MTL5 rs12365708 (testis expressed metallothionein-like protein [tesmin]) (relative risk [RR], 2.62; 95% confidence interval [95% CI], 1.61-4.27 [P = 1.8 × 10-5]); ALKBH1 rs6494 (AlkB homolog 1, histone H2A dioxygenase) (RR, 3.77; 95% CI, 1.84-7.74 [P = 3.7 × 10-5]); and NEUROG3 rs4536103 (neurogenin 3) (RR, 1.75; 95% CI, 1.30-2.37 [P = 1.2 × 10-4]). Although effect sizes were similar, these SNPs were not nominally significant in the replication cohort in the current study. In a meta-analysis comprised of the discovery cohort and the replication cohort, these SNPs were still not found to be statistically significant after correction for multiple comparisons (rs12365708: pooled RR, 2.27 [95% CI, 1.48-3.50], P = 1.99 × 10-4; rs6494: pooled RR, 2.31 [95% CI, 1.38-3.85], P = .001; and rs4536103: pooled RR, 1.67 [95% CI, 1.29-2.16] P = 9.23 × 10-5).
  
  
  CONCLUSIONS
  In what to the authors' knowledge is the first family-based based exome-wide association study to investigate maternal genotype effects associated with childhood ALL, the results did not implicate a strong role of maternal genotype on disease risk among Hispanics; however, 3 maternal SNPs were identified that may play a modest role in susceptibility. Cancer 2016;122:3697-704. © 2016 American Cancer Society.
authors.affiliation: Austin Regional Campus, University of Texas School of Public Health, Austin, Texas.
authors.forename: Natalie P
authors.initials: NP
authors.lastname: Archer
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.|Hematologic Malignancies Program, Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Virginia
authors.initials: V
authors.lastname: Perez-Andreu
authors.affiliation: Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Scheurer
authors.affiliation: Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Karen R
authors.initials: KR
authors.lastname: Rabin
authors.affiliation: Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Erin C
authors.initials: EC
authors.lastname: Peckham-Gregory
authors.affiliation: Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Plon
authors.affiliation: Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Zabriskie
authors.affiliation: Department of Pediatrics, University of Illinois College of Medicine at Peoria, Peoria, Illinois.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: De Alarcon
authors.affiliation: Department of Pediatrics, University of Illinois College of Medicine at Peoria, Peoria, Illinois.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Fernandez
authors.affiliation: National Pediatric Oncology Unit, Guatemala City, Guatemala.
authors.forename: Cesar R
authors.initials: CR
authors.lastname: Najera
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.|Hematologic Malignancies Program, Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Jun J
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: National Pediatric Oncology Unit, Guatemala City, Guatemala.|School of Medicine, Francisco Marroquin University, Guatemala City, Guatemala.
authors.forename: Federico
authors.initials: F
authors.lastname: Antillon-Klussmann
authors.affiliation: Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Lupo
mesh_terms: D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D059472:Exome / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006630:Hispanic or Latino / Q000235:genetics*; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D055815:Young Adult
keywords: Hispanics; acute lymphoblastic leukemia (ALL); childhood ALL; exome; genetic epidemiology; maternal genetics