Variants in BAK1, SPRY4, and GAB2 are associated with pediatric germ cell tumors: A report from the children's oncology group

Erin L. Marcotte, Nathan Pankratz, James F. Amatruda, A. Lindsay Frazier, Mark Krailo, Stella Davies, Jacqueline R. Starr, Ching C. Lau, Michelle Roesler, Erica Langer, Caroline Hallstrom, Anthony J. Hooten, Jenny N. Poynter

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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.

Original languageEnglish (US)
Pages (from-to)548-558
Number of pages11
JournalGenes Chromosomes and Cancer
Volume56
Issue number7
DOIs
StatePublished - Jul 1 2017

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Germ Cell and Embryonal Neoplasms
Pediatrics
Single Nucleotide Polymorphism
Genome-Wide Association Study
Germ Cells
Testis
Neoplasms
Age Groups
Alleles
Mothers
Population

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Variants in BAK1, SPRY4, and GAB2 are associated with pediatric germ cell tumors : A report from the children's oncology group. / Marcotte, Erin L.; Pankratz, Nathan; Amatruda, James F.; Frazier, A. Lindsay; Krailo, Mark; Davies, Stella; Starr, Jacqueline R.; Lau, Ching C.; Roesler, Michelle; Langer, Erica; Hallstrom, Caroline; Hooten, Anthony J.; Poynter, Jenny N.

In: Genes Chromosomes and Cancer, Vol. 56, No. 7, 01.07.2017, p. 548-558.

Research output: Contribution to journalArticle

Marcotte, Erin L. ; Pankratz, Nathan ; Amatruda, James F. ; Frazier, A. Lindsay ; Krailo, Mark ; Davies, Stella ; Starr, Jacqueline R. ; Lau, Ching C. ; Roesler, Michelle ; Langer, Erica ; Hallstrom, Caroline ; Hooten, Anthony J. ; Poynter, Jenny N. / Variants in BAK1, SPRY4, and GAB2 are associated with pediatric germ cell tumors : A report from the children's oncology group. In: Genes Chromosomes and Cancer. 2017 ; Vol. 56, No. 7. pp. 548-558.
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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.",
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T2 - A report from the children's oncology group

AU - Marcotte, Erin L.

AU - Pankratz, Nathan

AU - Amatruda, James F.

AU - Frazier, A. Lindsay

AU - Krailo, Mark

AU - Davies, Stella

AU - Starr, Jacqueline R.

AU - Lau, Ching C.

AU - Roesler, Michelle

AU - Langer, Erica

AU - Hallstrom, Caroline

AU - Hooten, Anthony J.

AU - Poynter, Jenny N.

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