Variants in KITLG predispose to testicular germ cell cancer independently from spermatogenic function

Abstract

Epidemiological data suggest an association and a common pathogenetic link between male infertility and testicular germ cell tumor (TGCT) development. Genome-wide studies identified that TGCT susceptibility is associated with KITLG (c-KIT ligand), which regulates the formation of primordial germ cells, from which TGCT is believed to arise and spermatogenesis develops. In this study, we analyzed the link between KITLG, TGCT, and spermatogenic disruption by performing an association study between the KITLG markers rs995030 and rs4471514 and 426 TGCT cases and 614 controls with normal and abnormal sperm count. We found that TGCT risk was increased more than twofold per copy of the major G allele and A allele in KITLG rs995030 and rs4471514 (odds ratio (OR)Z2.38, 95% confidence interval (95% CI)Z1.81-3.12; ORZ2.43, 95% CIZ 1.86-3.17 respectively), and homozygotes for the risk allele had a sevenfold increased risk of TGCT. KITLG markers were strongly associated with seminoma subtype (per allele risk increased more than threefold, homozygote risk increased by 13-to 16-fold) and weakly with nonseminoma. KITLG markers were not associated with sperm production, as no difference was observed in men with normozoospermia and azoo-oligozoospermia, both in controls and in TGCT cases. In conclusion, this study provides evidence that KITLG variants are involved in TGCT development and they represent an independent and strong specific risk factor for TGCT independently from spermatogenic function. A shared genetic cause and a common pathogenetic link between TGCT development and impairment of spermatogenesis are not evident from this study.

Male Germ Cell Development in Humans

“…Thus, these cells express many markers which have been described for early germ cells like gonocytes and PGC [24,25]. Recent studies are in line with previous ones, demonstrating the important role of KITLG and DMRT1 gene alterations as main factors involved in TGCT formation [40,41]. As a third important player in TGCT formation, TSPY has to be mentioned.…”

An oncofetal and developmental perspective on testicular germ cell cancer

“…Larger scale GWAS studies consistently identified a number of (other) risk SNPs [148][149][150][151][152][153][154][155] which were validated in additional (targeted) studies: [156][157][158]. The results of genetic studies in subfertile patients [159] and familial TGCC [160,161] populations did not significantly differ from the general population, implying a common genetic base in these risk groups and sporadic GCC cases. Recently all major GWAS studies were combined in a very diligent meta-analysis by Chung and coworkers, verifying 14 previously identified risk SNPs and identifying 5 additional ones [162] (Fig.…”

Prospectively Identified Incident Testicular Cancer Risk in a Familial Testicular Cancer Cohort

“…, family history, undescended testis, infertility) might permit the development of risk stratification models that could identify specific subsets of men with even more dramatic elevations in risk, upon whom more aggressive education and surveillance activities might be appropriately focused (50, 51), especially if it could be demonstrated that the GWAS risk SNPs were not also associated with the clinical risk factors, a question for which limited data are contradictory (52, 53). Thus, for example, men aged 30–34 in our study who were in the top 1% of genetic risk and who also had a personal history of cryptorchidism were estimated to be at a 50-fold increase in TGCT risk relative to average population risk, assuming that the TGCT risk SNPs were not also associated with undescended testicle risk (50).…”