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Risk of Testicular Germ Cell Cancer in Relation to Variation in Maternal and Offspring Cytochrome P450 Genes Involved in Catechol Estrogen Metabolism

Departments of ¹ Pediatrics, ² Epidemiology, and ³ Biostatistics, University of Washington; ⁴ Children's Craniofacial Center, Children's Hospital and Regional Medical Center; and ⁵ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington

Requests for reprints: Jacqueline R. Starr, Department of Pediatrics, Children's Craniofacial Center, Children's Hospital and Regional Medical Center, P.O. Box 5371/M2-8, Seattle, WA 98105-0371. Phone: 206-987-3987; Fax: 206-987-3824. E-mail: jrstarr{at}u.washington.edu

The incidence of testicular germ cell carcinoma (TGCC) is highest among men ages 20 to 44 years. Exposure to relatively high circulating maternal estrogen levels during pregnancy has long been suspected as being a risk factor for TGCC. Catechol (hydroxylated) estrogens have carcinogenic potential, thought to arise from reactive catechol intermediates with enhanced capability of forming mutation-inducing DNA adducts. Polymorphisms in maternal or offspring genes encoding estrogen-metabolizing enzymes may influence prenatal catechol estrogen levels and could therefore be biomarkers of TGCC risk. We conducted a population-based, case-parent triad study to evaluate TGCC risk in relation to maternal and/or offspring polymorphisms in CYP1A2, CYP1B1, CYP3A4, and CYP3A5. We identified 18- to 44-year-old men diagnosed with invasive TGCC from 1999 to 2004 through a population-based cancer registry in Washington State and recruited cases and their parents (110 case-parent triads, 50 case-parent dyads). Maternal or offspring carriage of CYP1A2 –163A was associated with reduced risk of TGCC [maternal heterozygote relative risk (RR), 0.6; 95% confidence interval (95% CI), 0.2-1.7; offspring heterozygote RR, 0.7; 95% CI, 0.3-1.5)]. Maternal CYP1B1 ⁴⁸Gly homozygosity was associated with a 2.7-fold increased risk of TGCC (95% CI, 0.9-7.9), with little evidence that Leu⁴³²Val or Asn⁴⁵³Ser genotypes were related to risk. Men were also at increased risk of TGCC if they carried the CYP3A4 –392G (RR, 7.0; 95% CI, 1.6-31) or CYP3A5 6986G (RR, 2.4; 95% CI, 1.1-5.6) alleles. These results support the hypothesis that maternal and/or offspring catechol estrogen activity may influence sons' risk of TGCC.

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