Risk of Testicular Germ Cell Cancer in Relation to Variation in Maternal and Offspring CytochromeP450 Genes Involved in Catechol Estrogen Metabolism

Abstract

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 estrogenmetabolizing 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 À163A 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 Leu 432 Val or Asn 453Ser genotypes were related to risk. Men were also at increased risk of TGCC if they carried the CYP3A4 À392G (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. (Cancer Epidemiol Biomarkers Prev 2005;14(9): 2183-90)

Genetic variation in hormone metabolizing genes and risk of testicular germ cell tumors

“…A study by Starr et al found an inverse association between the CYP1A2 variant rs762551 and TGCT risk [46], consistent with the current study's findings with CYP1A1. Although the current study did not investigate CYP1A2 polymorphisms directly, CYP1A1 and CYP1A2 are in close proximity and in strong LD.…”

Association of testicular germ cell tumor with polymorphisms in estrogen receptor and steroid metabolism genes

“…Recent evidence supports an association of TGCT with polymorphisms in these genes: we and others have reported an association with CAG/GGN repeat length of the androgen receptor gene (Giwercman et al 2004, Garolla et al 2005 and with FSH receptor gene polymorphisms (Ferlin et al 2008a), and an association with some maternal and/or offspring hormonemetabolizing genes of the cytochrome P450 family (CYP1A1, CYP1A2, CYP3A4, and CYP3A5) has been suggested (Starr et al 2005, Figueroa et al 2008.…”

“…Associations with TGCT have been found with mutations in the androgen receptor gene (Garolla et al 2005), different lengths of the CAG and GGC repeats in exon 1 of the androgen receptor gene which modulate the sensitivity of the receptor to androgens (Giwercman et al 2004, Garolla et al 2005, polymorphisms of the FSH receptor gene which modulate FSH sensitivity (Ferlin et al 2008a), and polymorphisms in cytochrome P450 genes involved in estrogen metabolism (Starr et al 2005, Figueroa et al 2008. With regards to Endocrine-Related Cancer (2010) 17 17-25 www.endocrinology-journals.org these latter genes, an association between TGCT and CYP1A2 (rs762551), CYP3A4 (rs2740574), and CYP3A5 (rs776746) gene polymorphisms was found by one study (Starr et al 2005), whereas an association with polymorphisms in CYP1A1 (rs4886605 and rs2606345) gene was found by another one (Figueroa et al 2008). We did not include CYP3A4 and CYP3A5 genes in our screening, nor we included SNPs rs4886605 and rs2606345 in CYP1A1 and rs762551 in CYP1A2; therefore, we were unable to confirm such associations.…”

Low doses x-ray irradiation influence on liver detoxication system in rats with transplanted guerin's carcinoma

“…Поскольку местом взаимодействия субстратов І типа с гемопротеином является гидрофобный участок апофермента [18,19], то весьма вероятно, что в микросомальной мембране в формировании его принимают участие фосфолипиды. Свободнорадикальные состояния последних могут придавать апоферменту цитохрома Р450 определенные конформации и тем самым понижать N-деметилазную активность последнего, что приводит к компенсаторной активации n-гидроксилирования анилина [20,21].…”