Is the FSHR 2039A>G variant associated with susceptibility to testicular germ cell cancer?

Testicular germ cell cancer (TGCC) is derived from germ cell neoplasia insitu (GCNIS), which arises due to niche disturbances affecting the Sertoli cells. It is believed that exogenous endocrine factors have a crucial role in governing neoplastic transformation but on a strong hereditary background. Follicle-stimulating hormone (FSH) is the major regulatory hormone of the Sertoli cells. FSH signalling-related single-nucleotide polymorphisms (SNPs) have previously been shown to affect FSH action in men at different levels. We aimed to investigate whether three FSH-related SNPs (FSHR 2039A>G, FSHR -29G>A and FSHB -211G>T) are associated with development of TGCC. A total of 752 Danish and German patients with TGCC from two tertiary andrological referral centres were included. Three control groups comprising 2020 men from the general population, 679 fertile men and 417 infertile men, were also included. Chi-squared test was performed to compare genotype- and allele frequencies. Kruskal-Wallis test was performed to compare age at diagnosis. Patients with TGCC had a higher frequency of the A-allele of FSHR 2039A>G compared to the group of fertile men with an AA-genotype frequency of 30.2% vs. 22.0%, respectively, p=0.002. This variant is associated with higher FSH receptor activity. The distribution of the FSHR 2039A>G did not differ significantly between the patients with TGCC and the infertile or the general population. The frequency of the two other SNPs did not differ between patient with TGCC and any of the control groups. No differences were detected between genotypes and age distribution or histological subtype of the tumours. In conclusion, we observed that a genetic variant associated with FSHR activity may modulate the susceptibility to TGCC.