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Genetic variation in the inhibin pathway and risk of testicular germ cell tumors.

ABSTRACT: Gene-knockout studies in mice suggest that INHA, encoding a subunit of gonadotropin-regulating proteins known as inhibins, is a tumor suppressor for testicular stromal cell tumors. It is not known whether genetic variation in the inhibin pathway also influences susceptibility to testicular germ cell tumors (TGCT), the most common testicular cancer in young men. To address this question, we conducted a case-control analysis (577 cases; 707 controls) of single-nucleotide polymorphisms (SNP) in genes in the inhibin pathway among participants in the U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study. Thirty-eight tagging SNPs in six genes (INHA, INHBA, INHBB, INHBC, INHBE, and SMAD4) were genotyped. Odds ratios (OR) and 95% confidence intervals (CI) relating variant genotypes to TGCT risk were calculated using unconditional logistic regression. Among White subjects, an elevated risk of TGCT was observed for carriers of the T allele of the INHA variant rs2059693 (CT genotype: OR, 1.33; 95% CI, 1.04-1.71; TT: OR, 1.60; 95% CI, 1.01-2.52; P(trend) = 0.008). The association with rs2059693 was stronger for nonseminomas, and for teratomas and teratocarcinomas in particular (N = 58; CT: OR, 1.63; 95% CI, 0.89-2.99; TT: OR, 4.54; 95% CI 2.00-10.3; P(trend) = 0.0008). We found no evidence of association with variants in the other investigated genes. These findings suggest that genetic variation in the INHA locus influences TGCT development.

SUBMITTER: Purdue MP

PROVIDER: S-EPMC2997349 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Genetic variation in the inhibin pathway and risk of testicular germ cell tumors.

Purdue Mark P MP Graubard Barry I BI Chanock Stephen J SJ Rubertone Mark V MV Erickson Ralph L RL McGlynn Katherine A KA

Cancer research 20080401 8

Gene-knockout studies in mice suggest that INHA, encoding a subunit of gonadotropin-regulating proteins known as inhibins, is a tumor suppressor for testicular stromal cell tumors. It is not known whether genetic variation in the inhibin pathway also influences susceptibility to testicular germ cell tumors (TGCT), the most common testicular cancer in young men. To address this question, we conducted a case-control analysis (577 cases; 707 controls) of single-nucleotide polymorphisms (SNP) in gen ...[more]

PMID: 18413775

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Project description:Background: Testicular germ cell tumor (TGCT) incidence has increased over the last 40 years in the United States. In contrast to TGCT among infants, it is hypothesized that TGCT in adolescents and young men is the result of sex steroid hormone imbalance during early fetal development. However, little is known about the neonatal period when abrupt hormonal changes occur, and direct supporting evidence is scarce due to the difficulties in obtaining prediagnostic specimens.Methods: We conducted a population-based case-control study examining hormone levels at birth among 91 infants (0-4 years) and 276 adolescents (15-19 years) diagnosed with TGCT, and 344 matched controls. Estrogen and androgen levels were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) from archived newborn dried blood spots. Logistic regression models were used to estimate the association between each hormone level and TGCT risk.Results: Higher levels of androstenedione were associated with increased TGCT risk among adolescents [odds ratio (OR): 2.33, 95% confidence interval (CI): 1.37-3.97 for highest vs. lowest quartile; P trend = 0.003] but not among infants (OR: 0.70, 95% CI: 0.28-1.77). A similar pattern was observed for testosterone (OR: 1.73, 95% CI: 1.00-3.00,) although the trend was not significant (P trend = 0.12). Associations were stronger among non-Hispanic white subjects, relative to Hispanics. There was no difference by tumor histologic subtype. Estriol (the only detectable estrogen) was not associated with TGCT risk in either age group.Conclusions: Higher levels of neonatal androgens were associated with increased risk of TGCT among adolescents, suggesting that early life hormone levels are related to the later development of TGCT.Impact: This is the first study with direct measures of sex steroid hormones to examine the relationship between estrogens and androgens at birth and risk of adolescent TGCT. Cancer Epidemiol Biomarkers Prev; 27(4); 488-95. ©2018 AACR.

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Genetic variation in the inhibin pathway and risk of testicular germ cell tumors.

Publications

Genetic variation in the inhibin pathway and risk of testicular germ cell tumors.

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