Analysis of single nucleotide polymorphisms of FSH receptor gene suggests association with testicular cancer susceptibility

Ferlin, Alberto; Pengo, Manuel; Selice, Riccardo; Salmaso, Luigi; Garolla, Andrea; Foresta, Carlo

doi:10.1677/erc-07-0257

Cited by 38 publications

(38 citation statements)

References 33 publications

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“…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.…”

Section: Introductionsupporting

confidence: 58%

“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Ferlin¹,

Ganz²,

Pengo³

et al. 2010

Endocrine-Related Cancer

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It is generally assumed that the development of testicular germ cell tumor (TGCT) is under endocrine control. In particular, unbalanced androgen/estrogen levels and/or activity are believed to represent the key events for TGCT development and progression. Furthermore, recent evidence has suggested a strong genetic component for TGCT. In this study, we analyzed whether a genetic variation in estrogen receptor (ESR) genes and steroid hormone metabolism genes is associated with TGCT. We genotyped for 17 polymorphic markers in 11 genes in 234 TGCT cases and 218 controls: ESR (ESR1 and ESR2); CYP19A1 (aromatase); 17b-hydroxysteroid dehydrogenase types 1 and 4 (HSD17B1 and HSD17B4) dehydrogenases that convert potent androgens and estrogens to weak hormones; cytochrome P450 hydroxylating enzymes CYP1A1, CYP1A2, and CYP1B1; and the metabolic enzymes COMT, SULT1A1, and SULT1E1. We observed a significant association of rs11205 in HSD17B4 with TGCT. TGCT risk was increased twofold per copy of the minor A allele at this locus (odds ratios (OR)Z2.273, 95% confidence interval (CI)Z1.737-2.973). Homozygous carriage of the minor A allele was associated with an over fourfold increased risk of TGCT (ORZ4.561, 95% CIZ2.615-7.955) compared with homozygous carriage of the major G allele. The risk was increased both for seminoma (ORZ5.327, 95% CIZ2.857-9.931) and for nonseminoma (ORZ3.222, 95% CIZ1.471-7.059). We found for the first time an association of polymorphisms in HSD17B4 gene with TGCT. Our findings expand the current knowledge on the role of genetic contribution in testicular cancer susceptibility, and support the hypothesis that variations in hormone metabolism genes might change the hormonal environment implicated in testicular carcinogenesis.

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Section: Introductionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

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

Ferlin¹,

Ganz²,

Pengo³

et al. 2010

Endocrine-Related Cancer

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“…Studies dealing with genetic predisposition of TGCT frequently found differences between seminoma and nonseminoma. The gr/gr deletion of the Y chromosome is strongly associated with seminoma than with nonseminoma (Nathanson et al 2005), longer CAG repeats on the androgen receptor gene are mainly associated with nonseminoma (Giwercman et al 2004), and we also found higher association of FSH receptor (FSHR) polymorphisms only with nonseminoma (Ferlin et al 2008), and on the contrary stronger association of hydroxysteroid (17-beta) dehydrogenase 4 (HSD17B4) markers with seminoma (Ferlin et al 2010). Therefore, it might also be possible that the two classes of TGCTs might have different pathogenesis.…”

Section: Discussionmentioning

confidence: 48%

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

Ferlin¹,

Pengo²,

Pizzol³

et al. 2011

Endocrine-Related Cancer

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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.

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“…Most of these studies included genes involved in reproduction (Ferlin et al, 2010;Ferlin et al, 2008;Figueroa et al, 2008;Giwercman et al, 2004;Heimdal et al, 1995;Kristiansen et al, 2011;Lundin et al, 2007;Nathanson et al, 2005;Purdue et al, 2008;Rajpert-De Meyts et al, 2002;Vastermark et al, 2011). We have previously shown that the variant allele rs12014709 in the androgen receptor (AR) is significantly associated with a doubled risk for having TGCC in the same population as the current study (Vastermark et al, 2011).…”

Section: Discussionmentioning

confidence: 64%

Association of polymorphisms in genes encoding hormone receptors ESR1, ESR2 and LHCGR with the risk and clinical features of testicular germ cell cancer

Brokken

Lundberg-Giwercman

De-Meyts

et al. 2012

Molecular and Cellular Endocrinology

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Testicular germ cell cancer (TGCC) is the most common malignancy in young men. Genetic variants known to be associated with risk of TGCC only partially account for the observed familial risks. We aimed to identify additional polymorphisms associated with risk as well as histological and clinical features of TGCC in 367 patients and 214 controls. Polymorphisms in ESR2 (rs1256063; OR=0.53, 95% CI: 0.35-0.79) and LHCGR (rs4597581; OR=0.68, 95% CI: 0.51-0.89, and rs4953617; OR=1.88, 95% CI: 1.21-2.94) associated with risk of TGCC. Polymorphisms in ESR1 (rs9397080; OR=1.85, 95% CI: 1.18-2.91) and LHCGR (rs7371084; OR=2.37, 95% CI: 1.26-4.49) associated with risk of seminoma and metastasis, respectively. SNPs in ESR1 (rs9397080) and LHCGR (rs7371084) were predictors of higher LH levels and higher androgen sensitivity index in healthy subjects. The results suggest that polymorphisms in ESR1, ESR2 and LHCGR contribute to the risk of developing TGCC, histological subtype, and risk to metastasis.

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Analysis of single nucleotide polymorphisms of FSH receptor gene suggests association with testicular cancer susceptibility

Cited by 38 publications

References 33 publications

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

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

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

Association of polymorphisms in genes encoding hormone receptors ESR1, ESR2 and LHCGR with the risk and clinical features of testicular germ cell cancer

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