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Department of Histology, Microbiology and Medical Biotechnologies, Centre for Male Gamete Cryopreservation, University of Padova, Via Gabelli 63, 35121 Padova, Italy¹ Department of Management and Engineering, University of Padova, Stradella San Nicola 3, 36100 Vicenza, Italy

(Correspondence should be addressed to C Foresta; Email: carlo.foresta{at}unipd.it)

	Abstract

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The development of testicular germ cell tumour (TGCT) is believed to be under endocrine control but definitive proofs are lacking. Follicle stimulating hormone (FSH) levels are increased in numerous conditions associated with increased risk of TGCT and single nucleotide polymorphisms (SNPs) in the FSH receptor (FSHR) gene influence the sensitivity of the receptor to FSH. However, a possible effect of FSH on testicular carcinogenesis has never been explored. In order to analyse the possible association of FSHR polymorphisms with TGCT, we studied 188 TGTC cases and 152 controls for 12 FSHR SNPs. Only four SNPs were found to be informative, represented by two polymorphisms in exon 10 (Ala307Thr and Ser680Asn), and two polymorphisms in the promoter region (–114 T/C and –29 G/A). Differences in haplotype distribution were seen between TGCT cases and controls. In particular for non-seminoma, the Ala307/Ser680 allele lowers the risk of the disease, alone (P=0.014, relative risk 0.73; 95% confidence interval 0.57–0.92), or in combination with the –29 G allele and/or the –114 T allele. This study suggests for the first time that FSHR gene polymorphisms modulate susceptibility to TGCT. The variants with higher activity of the FSHR are associated with higher risk, suggesting a role for FSH in the carcinogenesis of this tumour.

	Introduction

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Testicular cancer (TC, MIM 273300 [OMIM] ) is the most common cancer in white males aged 20–40 years, with a worldwide incidence of 7.5 per 100 000. About 95% of all TCs are represented by testicular germ cell tumours (TGCTs) and seminoma accounts for 50% of them. TGCTs represent the model of a curable malignancy (Horwich et al. 2006). However, successes in clinical aspects of TGCTs do not correspond to clear identification of molecular biology and carcinogenesis process of this tumour.

Epidemiological hallmarks of TGCT include a peak incidence in a very young adult age, a markedly increasing incidence worldwide (Giwercman et al. 1993, Swerdlow et al. 1998) but with striking geographic and ethnic differences, and association with other reproductive conditions, such as cryptorchidism, testicular atrophy, inguinal hernia and infertility (Horwich et al. 2006, Rajpert-De Meyts 2006).

Epidemiological observations suggest that most probably the majority of cases of TC are not because of a genetic mutation. However, genetic polymorphisms might be responsible for ethnic differences in its prevalence as well as prevalence of other human reproductive disorders. It is plausible that, for example genes that are involved in the hormonal regulation of testicular development and function might contain polymorphic sequences that would slightly alter the sensitivity to hormones, natural or synthetic.

Although definitive proof is still lacking, it is generally assumed that the development of TC is under endocrine control. This hypothesis is supported by clinical observations showing a main peak of TC incidence early after puberty (Oosterhuis & Looijenga 2005). In particular, alterations in the pituitary-testicular hormonal axis and/or alterations in gonadotrophin and sex steroid action are believed to be involved in the development of this tumour and in the progression from the pre-invasive carcinoma in situ (CIS) stage to invasive tumour (Rajpert-De Meyts 2006). Possible hormonal candidates responsible for such tumour development are luteinizing hormone (LH), follicle stimulating hormone (FSH), androgens and oestrogens. Probably, a combination of high LH and FSH levels, high intratesticular androgen levels coupled with lower androgen activity, and high oestradiol levels are necessary for TC development and progression (Garolla et al. 2005, Rajpert-De Meyts 2006). Such a hormonal combination is seen for example in patients with androgen insensitivity syndrome (Muller 1987, Rajpert-De Meyts 2006), which has a high risk of TC. On the contrary, subjects with Kallmann's syndrome having hypogonadotrophic hypogonadism never develop TC.

The association between severe testicular damage and TC development might suggest the hypothesis that FSH could also contribute to testicular carcinogenesis. FSH is essential for testicular development, Sertoli cell function and maintenance of normal spermatogenesis. Importantly, severe testiculopathies, representing a well-established risk factor for TC, exhibit high FSH plasma concentrations (Ferlin et al. 2007). FSH acts through binding to a specific receptor (FSHR) that belongs to the G-protein-coupled receptor family. The FSHR gene (chromosome 2p21) consists of ten exons and nine introns. Exons 1–9 encode the intracellular protein domain, whereas exon 10 encodes for the C-terminal portion of the intracellular, the transmembrane and extracellular domains (Gromoll et al. 1996).

Mutation screening of the FSHR gene revealed various single nucleotide polymorphisms (SNPs) in the core promoter and in the coding region (Gromoll & Simoni 2005, Wunsch et al. 2005). The two most common SNPs in the coding region occur at nucleotides 919 and 2039 in exon 10, in which A/G transitions cause amino acid exchange from threonine to alanine at codon 307 and from asparagine to serine at codon 680 respectively (Simoni et al. 1997, Liu et al. 1998). The most studied SNP in the core promoter occurs at position –29 (Simoni et al. 2002).

FSHR polymorphisms at positions 307 and 680 influence the serum FSH levels in women and the sensitivity of the FSHR to FSH in vivo (Greb et al. 2005). In particular, the Ser680 variant is associated with a less active receptor and the Asn680 variant results in a higher active receptor (Greb et al. 2005). The impact of the FSHR SNPs in men is unclear (Simoni et al. 1999, Song et al. 2001, Ahda et al. 2005, Pengo et al. 2006). Most importantly, FSHR exon 10 SNPs were found to be associated with ovarian cancer of the serous and mucinous types in Chinese women, suggesting that FSHR polymorphisms might affect the susceptibility of women to specific subtypes of ovarian cancer (Yang et al. 2006). However, the possible association of FSHR SNPs with TC has never been studied.

	Materials and methods

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Patients and clinical analyses

Patients and controls were prospectively recruited for this study from January 2005 to December 2006 with the approval of the Hospital Ethical Committee and informed consent was obtained from each subject after full explanation of the purpose and nature of all procedures used. The study was conducted in accordance with the guidelines in The Declaration of Helsinki.

We evaluated 188 consecutive subjects (mean age 29.6±7.1 years) orchiectomised for TGCT, who consulted our Centre for semen cryobanking before initiating chemo- and/or radiotherapy. Totally 104 men were affected by seminoma and 84 by non-seminoma (35 embryonal carcinoma, 30 teratoma, 10 choriocarcinoma and 9 yolk sac tumour). A complete medical history and physical examination was undertaken. Karyotype analysis, Y chromosome microdeletion analysis (Ferlin et al. 2007) and androgen receptor (AR) gene mutation analysis (Ferlin et al. 2006) were performed in all subjects to exclude potential genetic causes of testicular damage. Controls were represented by 152 disease-free age-matched men (mean age 30.1±6.5 years) recruited among blood donors representing the general population. Prior to inclusion, all controls underwent an andrological examination including testicular ultrasound. All cases and controls were from the north-east of Italy.

FSHR gene polymorphisms analysis

In all subjects, after DNA isolation from peripheral leukocytes, the polymorphisms at positions 919 and 2039 (codons 307 and 680 in exon 10, rs6166 and rs6166 in dbSNP respectively) and in promoter –29 position (rs1394205 in dbSNP) were analysed by restriction fragment length polymorphism, as described previously (Pengo et al. 2006). For the SNP Ala307Thr, after digestion with Bsu361 and 2.5% agarose gel electrophoresis, a fragment of 364 bp indicates the Thr/Thr genotype, two fragments of 328 and 36 bp indicate the Ala/Ala genotype and the presence of all the three fragments indicates the heterozygous Ala/Thr. For the SNP Ser680Asn, after digestion with BsrI a fragment of 520 bp indicates the Asn/Asn genotype, two fragments of 413 and 107 bp indicate the Ser/Ser genotype and the presence of all the three fragments indicates the heterozygous Asn/Ser. For the A-29G, after digestion with MboII a fragment of 404 bp indicates homozygosity for A, two fragments of 289 and 115 bp indicate homozygosity for G and the presence of all the three fragments indicates a heterozygous state. The effectiveness of this method was previously verified by direct sequencing analysis of the first 100 DNA samples (Pengo et al. 2006).

The other nine SNPs were selected. Using information registered on the SNP database of the NCBI, we analysed all the coding non-synonymous SNPs reported (one in exon 4 (rs1126714, position 112) and four in exon 10 (rs28928870, position 449; rs6167, position 524; rs287928871, position 567; rs12620825, position 665)) and four SNPs previously identified in the promoter region (–37, –114, –123 and –138; Wunsch et al. 2005). All these SNPs were directly sequenced (ABI PRISM 3730XL DNA Sequencer, Applied Biosystems) using the following primers: 5'-TGGTGAACAGCAAGGAGACTT-3' and 5'-TTGGCAGAGAAAAACCCTGT-3' for the SNPs in the promoter, 5'-CACCTTGGAAAGATGGCATA-3' and 5'-CCCTTCAAAGGCAAGACTGA-3' for SNPs at position 524, 567 and 665, 5'-TCTGAGCTTCATCCAATTTCGA-3' and 5'-GGGAAAGAGCAGCTGCAA-3' for the SNP at position 449, and 5'-CACTGCATGCTCCCTCAATA-3' and 5'-TCCATCACCAAGTATCTCTCCA-3' for the SNP at position 112. The relative position of the 12 SNPs analysed is shown in Fig. 1A.

View larger version (26K): [in this window] [in a new window]   Figure 1 (A) Schematic of the FSHR gene and location of the 12 SNPs studied. The SNPs in the upper part of the figure are those found to represent real polymorphisms, whereas those below were found with the wild-type allele in all cases and controls. (B) LD analysis of the four informative SNPs in cases and controls. The D' and r 2 values are indicated and high LD (D '>0.8 and r 2>0.5) is in grey.

A ²-analysis was used to determine whether the genotype distribution conformed to Hardy–Weinberg equilibrium (HWE). Linkage disequilibrium (LD) analysis among SNPs was performed to determine the disequilibrium coefficient D' and the correlation coefficient r². A pair of SNPs was defined as being in high LD if they had D'>0.8 and r²>0.5. HWE and LD analyses were performed with SNPAlyze version 6.0 (Dynacom Co., Ltd, Kanagawa, Japan). A ²-test was used to evaluate the overall distribution of the FSHR genotypes and haplotypes and their association in the case–control populations. For the same analysis, the Cochran–Armitage test was used when SNPs were not in HWE. The degrees of freedom are calculated from the corresponding contingency tables as the number of cells minus one (the number of rows minus one times the number of columns minus one). Relative risks and the corresponding 95% confidence intervals were used to measure the strength of the association. All statistical tests were two-sided and performed using the statistical software ‘R’ (http://cran.r-project.org). P values less than 0.05 were considered to indicate statistical significance. A Bonferroni–Holm correction was applied to the results of analyses with individual SNPs.

	Results

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Out of the 12 markers selected on SNP databases, only 4 (T-114C, A-29G, A307G and A680G) were actually informative in this set of samples, the remaining 8 being non-polymorphic and showing the wild-type allele in all cases and controls. The observed and expected genotypic frequencies of the four SNPs were in HWE in controls, whereas in TGCT cases SNP 307 and 680 were deviated from HWE (²-test, df=1, P=0.002). Patterns of LD among the four SNPs are illustrated in Fig. 1B by their D' and r² values. SNPs 307 and 680 were in perfect LD in controls and cases, whereas SNPs –114 and –29 were incomplete but not absolute LD in cases, and SNPs –114 and 307/680 were in modest LD in controls.

Table 1 shows the genotype and allele distribution of SNPs –114, –29, 307 and 680 in TGCT cases and controls. The overall distribution of SNPs –114 and –29 did not differ between TGCT cases and controls. The distribution of 307/680 alleles was significantly different between TGCT cases and controls (P=0.043), but this difference was not significant after correcting for multiple testing (P=0.172). However, this data was also significant after Bonferroni–Holm correction when considering non-seminoma cases (P=0.007 before correction and P=0.042 after correction). Although the distribution of SNP 307/680 genotypes in non-seminoma cases with respect to controls (P=0.011) was not significant after correcting for multiple testing (P=0.057), these data indicated a possible trend for a different genotype distribution of these SNPs. These data therefore suggested that the Ala/Ser allele was associated with a lower risk of non-seminoma with a relative risk of 0.73 (95% CI 0.57–0.92, Table 4).

	Discussion

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Exon 10 polymorphisms have been associated with a different sensitivity of the FSHR in previous studies. In particular, different plasma FSH concentrations during the menstrual cycle and different cycle lengths are observed in women depending on the FSHR genotype (Greb et al. 2005). The homozygous Ser680 genotype has been recognised as a predisposition for mild resistance and a low response to FSH action in homozygous women. Significantly higher concentrations of basal FSH have been reported in normal ovulatory subjects (Perez Mayorga et al. 2000, Jun et al. 2006) and anovulatory patients (Sudo et al. 2002, Falconer et al. 2005) carrying this genotype. Furthermore, a different need for FSH is seen in women during controlled ovarian hyperstimulation for in vitro fertilisation techniques. In fact, when compared with the Asn680/Asn680, women with the Ser680/Ser680 genotype need a significantly higher dose of FSH to be administered for ovarian stimulation in order to achieve similar peak oestradiol concentrations (Perez Mayorga et al. 2000, de Castro et al. 2003). Therefore, the Ser680/Ser680 genotype is more ‘resistant’ to FSH action, and thus requires a stronger stimulus for the same biological response. Conversely, the Asn680/Asn680 genotype seems to confer a higher activity to the FSHR.

The impact of –29 SNP, alone or in combination with exon 10 SNPs, is less clear, but does not seem to influence the clinical parameters or plasma FSH concentrations both in women and men (Ahda et al. 2005, Wunsch et al. 2005, Pengo et al. 2006). However, a recent study reported a reduced transcriptional activity of the A allele with respect to the G allele, and lower oestradiol plasma concentrations in women with the A/A genotype (Nakayama et al. 2006). This study, however, did not examine exon 10 SNPs, confirm the transcriptional activity in granulosa cells and determine the FSHR expression. Therefore, the exact functional role of –29 SNP is still debatable. With regard to the –114 polymorphism, in vitro assays showed no differences in transcriptional activity and FSHR expression depending on it (Wunsch et al. 2005) and therefore, this SNP does not seem to have functional roles on the activity of the FSHR.

Altogether, these data indicate that a less active allele (Ser680) of FSHR is associated with a lower risk of TGCT, particularly non-seminoma. Therefore, our data suggest that FSH might be implicated in the development or progression of TGCT. This hypothesis is supported by epidemiological and clinical observations. Although definitive proof is still lacking, it is generally assumed that the development of TGCT is under endocrine control, and a combination of high FSH and LH, coupled with unbalanced androgen/oestrogen levels are key events (Garolla et al. 2005, Rajpert-De Meyts 2006). This condition is exemplified by the androgen insensitivity syndrome caused by mutations in the androgen receptor gene, which represents a well-recognised risk factor for TGCT (Muller 1987, Rajpert-De Meyts 2006). Clinical conditions associated with a higher risk of TGCT (cryptorchidism, testicular atrophy and infertility) are often characterised by increased plasma concentrations of FSH, whereas situations with low gonadotrophin levels (such as hypogonadotrophic hypogonadism) never develop TGCT. Furthermore, the peak incidence of TGCT is in a very young adult age, during or shortly after the pubertal development, which is characterised by increased levels of gonadotrophins.

TGCTs are believed to originate during early testicular development as a consequence of disturbances in the microenvironment of the differentiating foetal germ cells (Rajpert-De Meyts 2006). The proliferating and invasive capacities of precancerous cells are then probably triggered by the drastic hormonal changes associated with puberty (Horwich et al. 2006, Rajpert-De Meyts 2006). The present developmental model for the pathogenesis of TGCT (Giwercman et al. 1993, Almstrup et al. 2006, Horwich et al. 2006) suggests that both seminoma and non-seminoma may then originate from this CIS state. In light of the results of the present study it is tempting to speculate that FSH (probably in conjunction with other genetic and environmental factors) may facilitate the transformation of gonocytes in pre-CIS cells during early gonadal differentiation, or pre-CIS to CIS cells, or CIS cells to seminoma and non-seminoma during puberty.

However, our study showed that the association with FSHR gene polymorphisms is stronger for non-seminoma than for seminoma, and therefore an increased FSH activity seems to predispose to the transformation of CIS above all into non-seminoma. These data therefore suggest that these two classes of TGCTs might have different pathogenesis or that the variants of the FSHR gene might be involved in the progression of the precursor lesion, either to seminoma or to non-seminoma. Importantly, studies dealing with genetic predisposition of TGCT found differences between seminoma and non-seminoma. For example, the gr/gr deletion of the Y chromosome is strongly associated with seminoma than with non-seminoma (Nathanson et al. 2005), whereas the longer CAG repeats on the androgen receptor gene are mainly associated with non-seminoma (Giwercman et al. 2004). The recent study on FSHR gene SNPs in ovarian cancer showed an association with serous and mucinous cancers but not with endometrioid and clear cell types (Yang et al. 2006).

The main limitation of our study is related to the relative low number of TGCT cases (188), and therefore the association between FSHR gene haplotypes and TC should be verified on a larger number of patients possibly of different ethnic origin. Population stratification could also be involved leading to false association. However, although we cannot completely exclude population stratification we limited it by carefully selecting both cases and controls from a microgeographically controlled part of Italy. Therefore, the associations found, although not definitive, are highly suggestive of a role for FSHR polymorphisms in modulating the risk of TGCT.

In conclusion, our data provide evidence that FSHR gene haplotypes are a risk factor for TGCT, particularly non-seminoma. The variants associated with a higher risk of TGCT are those with a higher activity of the FSHR, whereas variants more resistant to FSH protect against the development of TGCT, suggesting a role for FSH in the transformation process of gonocytes into CIS cells and/or from CIS to overt TGCT, principally non-seminoma. The principle actions of FSH are related to steroidogenesis and gametogenesis in the testis and ovary. However, our data and the recent reports on the association of FSHR gene polymorphisms with ovarian cancer (Yang et al. 2006) and hypertension (Nakayama et al. 2006) and on the role of FSH in the pathogenesis of osteoporosis (Sun et al. 2006), highlight important roles of this hormone other than the well-established actions in reproduction.

	Acknowledgements

 
This work was supported in part by grants from the University of Padova (to A F) and the Italian Ministry of University and Research (to C F). The authors declare that there is no conflict of interest that would prejudice the impartiality of this work.

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This Article Abstract Full Text (PDF) All Versions of this Article: ERC-07-0257v1 15/2/429    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ferlin, A. Articles by Foresta, C. Search for Related Content PubMed PubMed Citation Articles by Ferlin, A. Articles by Foresta, C.