title: Gene variations in sex hormone pathways and the risk of testicular germ cell tumour: a case-parent triad study in a Norwegian-Swedish population.
abstract: BACKGROUND
  Testicular germ cell tumour (TGCT) is the most common cancer in young men, and an imbalance between the estrogen and androgen levels in utero is hypothesized to influence TGCT risk. Thus, polymorphisms in genes involved in the action of sex hormones may contribute to variability in an individual's susceptibility to TGCT.
  
  
  METHODS
  We conducted a Norwegian-Swedish case-parent study. A total of 105 single-nucleotide polymorphisms (SNPs) in 20 sex hormone pathway genes were genotyped using Sequenom MassArray iPLEX Gold, in 831 complete triads and 474 dyads. To increase the statistical power, the analysis was expanded to include 712 case singletons and 3922 Swedish controls, thus including triads, dyads and the case-control samples in a single test for association. Analysis for allelic associations was performed with the UNPHASED program, using a likelihood-based association test for nuclear families with missing data, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. False discovery rate (FDR) was used to adjust for multiple testing.
  
  
  RESULTS
  Five genetic variants across the ESR2 gene [encoding estrogen receptor beta (ERβ)] were statistically significantly associated with the risk of TGCT. In the case-parent analysis, the markers rs12434245 and rs10137185 were associated with a reduced risk of TGCT (OR = 0.66 and 0.72, respectively; both FDRs <5%), whereas rs2978381 and rs12435857 were associated with an increased risk of TGCT (OR = 1.21 and 1.19, respectively; both FDRs <5%). In the combined case-parent/case-control analysis, rs12435857 and rs10146204 were associated with an increased risk of TGCT (OR = 1.15 and 1.13, respectively; both FDRs <5%), whereas rs10137185 was associated with a reduced risk of TGCT (OR = 0.79, FDR <5%). In addition, we found that three genetic variants in CYP19A1 (encoding aromatase) were statistically significantly associated with the risk of TGCT in the case-parent analysis. The T alleles of the rs2414099, rs8025374 and rs3751592 SNPs were associated with an increased risk of TGCT (OR = 1.30, 1.30 and 1.21, respectively; all FDRs <5%). We found no statistically significant differences in allelic effect estimates between parental inherited genetic variation in the sex hormone pathways and TGCT risk in the offspring, and no evidence of heterogeneity between seminomas and non-seminomas, or between the Norwegian and the Swedish population, in any of the SNPs examined.
  
  
  CONCLUSIONS
  Our findings provide support for ERβ and aromatase being implicated in the aetiology of TGCT. Exploring the functional role of the TGCT risk-associated SNPs will further elucidate the biological mechanisms involved.
authors.affiliation: Oslo and Akershus University College of Applied Sciences, St. Olavs plass, NO-0130 Oslo, Norway. wenche.kristiansen@hioa.no
authors.forename: W
authors.initials: W
authors.lastname: Kristiansen
authors.forename: K E
authors.initials: KE
authors.lastname: Andreassen
authors.forename: R
authors.initials: R
authors.lastname: Karlsson
authors.forename: E L
authors.initials: EL
authors.lastname: Aschim
authors.forename: R M
authors.initials: RM
authors.lastname: Bremnes
authors.forename: O
authors.initials: O
authors.lastname: Dahl
authors.forename: S D
authors.initials: SD
authors.lastname: Fosså
authors.forename: O
authors.initials: O
authors.lastname: Klepp
authors.forename: C W
authors.initials: CW
authors.lastname: Langberg
authors.forename: A
authors.initials: A
authors.lastname: Solberg
authors.forename: S
authors.initials: S
authors.lastname: Tretli
authors.forename: H-O
authors.initials: HO
authors.lastname: Adami
authors.forename: F
authors.initials: F
authors.lastname: Wiklund
authors.forename: T
authors.initials: T
authors.lastname: Grotmol
authors.forename: T B
authors.initials: TB
authors.lastname: Haugen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001141:Aromatase / Q000235:genetics; D016022:Case-Control Studies; D047629:Estrogen Receptor beta / Q000235:genetics; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D012739:Gonadal Steroid Hormones / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics*; D009664:Norway; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D013548:Sweden; D013736:Testicular Neoplasms / Q000235:genetics*
chemical_list: D047629:Estrogen Receptor beta; D005819:Genetic Markers; D012739:Gonadal Steroid Hormones; D001141:Aromatase; C561410:CYP19A1 protein, human