title: Variants in BAK1, SPRY4, and GAB2 are associated with pediatric germ cell tumors: A report from the children's oncology group.
abstract: Germ cell tumors (GCT) are a rare form of childhood cancer that originate from the primordial germ cell. Recent genome-wide association studies (GWAS) have identified susceptibility alleles for adult testicular GCT (TGCT). We test whether these SNPs are associated with GCT in pediatric and adolescent populations. This case-parent triad study includes individuals with GCT diagnosed between ages 0 and 19. We evaluated 26 SNPs from GWAS of adult TGCT and estimated main effects for pediatric GCT within complete trios (N = 366) using the transmission disequilibrium test. We used Estimation of Maternal, Imprinting and interaction effects using Multinomial modelling to evaluate maternal effects in non-Hispanic white trios and dyads (N = 244). We accounted for multiple comparisons using a Bonferroni correction. A variant in SPRY4 (rs4624820) was associated with reduced risk of GCT (OR [95% CI]: 0.70 [0.57, 0.86]). A variant in BAK1 (rs210138) was positively associated with GCT (OR [95% CI]: 1.70 [1.32, 2.18]), with a strong estimated effect for testis tumors (OR [95% CI]: 3.31 [1.89, 5.79]). Finally, a SNP in GAB2 (rs948662) was associated with increased risk for GCT (OR [95% CI]: 1.56 [1.20, 2.03]). Nominal associations (P < 0.05) were noted for eight additional loci. A maternal effect was observed for KITLG SNP rs4474514 (OR [95% CI]: 1.66 [1.21, 2.28]) and a paternal parent-of-origin effect was observed for rs7221274 (P = 0.00007), near TEX14, RAD51C, and PPM1E. We observed associations between SNPs in SPRY4, BAK1, and GAB2 and GCTs. This analysis suggests there may be common genetic risk factors for GCT in all age groups.
authors.affiliation: Division of Epidemiology & Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Erin L
authors.identifier: 0000-0002-9630-9701
authors.initials: EL
authors.lastname: Marcotte
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Nathan
authors.initials: N
authors.lastname: Pankratz
authors.affiliation: Departments of Pediatrics, Molecular Biology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: James F
authors.initials: JF
authors.lastname: Amatruda
authors.affiliation: Dana-Farber/Boston Children's Cancer Center, Boston, Massachusetts.
authors.forename: A Lindsay
authors.initials: AL
authors.lastname: Frazier
authors.affiliation: Department of Preventive Medicine, University of Southern California, Los Angeles, California.
authors.forename: Mark
authors.initials: M
authors.lastname: Krailo
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Stella
authors.initials: S
authors.lastname: Davies
authors.affiliation: The Forsyth Institute, Cambridge, Massachusetts.
authors.forename: Jacqueline R
authors.initials: JR
authors.lastname: Starr
authors.affiliation: Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas.
authors.forename: Ching C
authors.initials: CC
authors.lastname: Lau
authors.affiliation: Division of Epidemiology & Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Michelle
authors.initials: M
authors.lastname: Roesler
authors.affiliation: Division of Epidemiology & Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Erica
authors.initials: E
authors.lastname: Langer
authors.affiliation: Division of Epidemiology & Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hallstrom
authors.affiliation: Division of Epidemiology & Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hooten
authors.affiliation: Division of Epidemiology & Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.|Masonic Cancer Center, Minneapolis, Minnesota.
authors.forename: Jenny N
authors.initials: JN
authors.lastname: Poynter
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002648:Child; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000453:epidemiology* / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055815:Young Adult; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C494772:BAK1 protein, human; C490895:GAB2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C499038:SPRY4 protein, human; D050998:bcl-2 Homologous Antagonist-Killer Protein