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

Abstract

Testicular germ cell tumors (TGCT) that arise in young men are composed of two histologic types, seminomas and nonseminomas. Risk patterns for the two types appear to be similar and may be related to either endogenous or exogenous hormonal exposures in utero. Why similar risk patterns would result in different histologic types is unclear, but could be related to varying genetic susceptibility profiles. Genetic variation in hormone metabolizing genes could potentially modify hormonal exposures, and thereby affect which histologic type a man develops. To examine this hypothesis, 33 single nucleotide polymorphisms (SNPs) in four hormone metabolism candidate genes (CYP1A1, CYP17A1, HSD17B1, HSD17B4) and the androgen receptor gene (AR) were genotyped. Associations with TGCT were evaluated among 577 TGCT cases (254 seminoma, 323 nonseminoma) and 707 controls from the US Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) study. There were no significant associations with TGCT overall based on a test using an additive model. However, compared to homozygotes of the most common allele, two nonredundant SNPs in CYP1A1 were inversely associated with nonseminoma: CYP1A1 promoter SNP rs4886605 OR = 0.75 (95% CI = 0.54-1.04) among the heterozygotes and OR = 0.37, 95% CI = 0.12-1.11 among the homozygotes with a p-value for trend = 0.02; rs2606345 intron 1 SNP, OR = 0.69 (95% CI = 0.51-0.93) among heterozygotes and OR = 0.70 (95% CI = 0.42-1.17) among homozygotes, with a p-value for trend = 0.02. Caution in interpretation is warranted until findings are replicated in other studies; however, the results suggest that genetic variation in CYP1A1 may be associated with nonseminoma.

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.…”

“…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. On the contrary, Figueroa et al (2008) also studied the HSD17B4 gene and they found no association with TGCT; however, SNP rs11205 that we found differently distributed between cases and controls was not included in their study. Taken together these results, although not definitive, strongly suggest that steroid hormone metabolism genes might modulate the susceptibility to TC.…”

“…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.…”

“…Taken together these results, although not definitive, strongly suggest that steroid hormone metabolism genes might modulate the susceptibility to TC. Supporting this idea, it is interesting to note that one polymorphism (rs2830) in the gene encoding for HSD17B1, the enzyme that catalyzes the same reaction of HSD17B4 converting weak estrogen estrone to potent estradiol, has been associated with nonseminoma risk (Figueroa et al 2008). Interestingly, studies on breast cancer showed that other polymorphisms in this gene have been found to be associated with increased estrogen levels (Setiawan et al 2004).…”

Subtype-Specific Risk of Testicular Tumors among Immigrants and Their Descendants in Sweden, 1960 to 2007

“…However, collective evidence from the descriptive literature and marked inconsistencies between analytic studies distinguishing seminomas from nonseminomas indicate that either they are etiological rather than homogeneous, or some heterogeneity exists but the dichotomization is etiologically irrelevant. The findings of gene association studies also suggest that nonseminomas may be worth further investigating for genetic susceptibility (38)(39)(40)(41)(42). As nonseminomas comprised diverse subtypes, analysis of nonseminomas by its subtypes may help us to clarify the gene-environment interaction in the etiology of testicular cancer, but few studies will have sufficient numbers for further differentiation.…”