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

Abstract

Introduction 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). Here we test whether these SNPs are associated with GCT in the pediatric and adolescent population. Methods This case-parent triad study includes individuals with GCT diagnosed between ages 0–19. 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). A Bonferroni correction was used to account for multiple comparisons. Results 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 particularly 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. Maternal effects were observed for KITLG SNP rs4474514 (OR [95% CI]: 1.66 [1.21, 2.28]) and rs7221274 (OR [95% CI]: 2.07 [1.43, 2.99]), near TEX14, RAD51C, and PPM1E. Conclusions 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.

Klinefelter syndrome in males with germ cell tumors: A report from the Children's Oncology Group

“…The study population of children and adolescents with GCTs aged birth to 19 years from the COG CCRN has been described previously . The current analysis included all male cases (433 cases) enrolled in the case‐parent triad study from July 2008 to December 2015.…”

“…The study population of children and adolescents with GCTs aged birth to 19 years from the COG CCRN has been described previously. 10 The current analysis included all male cases (433 cases) enrolled in the case-parent triad study from July 2008 to December 2015. Cases provided saliva samples using at-home collection kits that were returned to the study center, and had one parent willing to participate in the study.…”

“…GCT incidence rates in the United States for males aged birth to 14 years are 3.5 per 1,000,000 persons and increase to 12.0 per 1,000,000 persons among adolescents . Although the majority of male GCTs arise in the testes, extragonadal tumors are common and are hypothesized to arise from abnormal primordial germ cell migration during embryogenesis . Testicular GCTs in adolescents usually are seminomas or mixed seminoma/nonseminoma, whereas testicular tumors in children aged <5 years are primarily yolk sac tumors and teratomas .…”

“…7 Although the majority of male GCTs arise in the testes, extragonadal tumors are common and are hypothesized to arise from abnormal primordial germ cell migration during embryogenesis. 6,10,11 Testicular GCTs in adolescents usually are seminomas or mixed seminoma/nonseminoma, whereas testicular tumors in children aged <5 years are primarily yolk sac tumors and teratomas. 6,12 In contrast, individuals with KS are more likely to develop mediastinal teratomas or GCTs with mixed histology.…”

Association Between BAK1 Gene rs210138 Polymorphisms and Testicular Germ Cell Tumors: A Systematic Review and Meta-Analysis

“…One full-text article was excluded for not about rs210138. Finally, 14 records (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) were included in our systematic review and meta-analysis. Tables 1, 2 displayed characteristics of each study.…”