Investigation of six testicular germ cell tumor susceptibility genes suggests a parent-of-origin effect in SPRY4.

Recent genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) associated with testicular germ cell tumor (TGCT) risk in the genes ATF7IP, BAK1, DMRT1, KITLG, SPRY4 and TERT. In the present study, we validate these associations in a Scandinavian population, and explore effect modification by parental sex and differences in associations between the major histological subtypes seminoma and non-seminoma. A total of 118 SNPs in the six genes were genotyped in a population-based Swedish-Norwegian sample comprising 831 TGCT case-parent triads, 474 dyads, 712 singletons and 3919 population controls. Seven hundred and thirty-four additional SNPs were imputed using reference haplotypes from the 1000 genomes project. SNP-TGCT association was investigated using a likelihood-based association test for nuclear families and unrelated subjects implemented in the software package UNPHASED. Forward stepwise regression within each gene was applied to determine independent association signals. Effect modifications by parent-of-origin and effect differences between histological subtypes were explored. We observed strong association between SNPs in all six genes and TGCT (lowest P-value per gene: ATF7IP 6.2 × 10(-6); BAK1 2.1 × 10(-10); DMRT1 6.7 × 10(-25); KITLG 2.1 × 10(-48); SPRY4 1.4 × 10(-29); TERT 1.8 × 10(-18)). Stepwise regression indicated three independent signals for BAK1 and TERT, two for SPRY4 and one each for DMRT1, ATF7IP and KITLG. A significant parent-of-origin effect was observed for rs10463352 in SPRY4 (maternal odds ratio = 1.72, paternal odds ratio = 0.99, interaction P = 0.0013). No significant effect differences between seminomas and non-seminomas were found. In summary, we validated previously reported genetic associations with TGCT in a Scandinavian population, and observed suggestive evidence of a parent-of-origin effect in SPRY4.

Subfertility among parents of men diagnosed with testicular cancer.

It is well known that men with testicular cancer also have reduced fertility before diagnosis. It is unclear, however, whether their parents also have reduced fertility. We performed a population-based record linkage study comparing parental fertility among 3711 testicular cancer cases and 371 100 control males. The cases were diagnosed from 1961 to 2001, and the data were analysed by logistic regression. Included indicators of parental fertility were number of children, rate of unlike-sex twins as a proxy for dizygotic twinning rate, and proportion of boys. The number of children was reduced across increasing sibship size among both mothers [odds ratio (OR) = 0.95, p(trend) = 0.003] and fathers [OR = 0.97, p(trend) = 0.057] of subjects with testicular cancer. The proportion of unlike-sex twins was also reduced among their mothers [(OR = 0.56, p = 0.049 (adjusted for year of birth)] and fathers [(OR = 0.56, p = 0.049 (adjusted for year of birth)]. The results were only marginally changed when also adjusting for respective parental age. Our study indicates that parents of testicular cancer cases have reduced fertility. This suggests that genetic factors are important in the association between testicular cancer and reduced fertility.

[Increased risk of testicular dysgenesis?]. / Økt forekomst av utviklingsfeil i testiklene?

The latest figures from the Cancer Registry of Norway show that Norway has the highest incidence rate of testicular cancer in the world. They also show that the incidence rate continues to increase, as it has for the last decades in the western world. The reasons for this increase, which might also be true for urogenital abnormalities in men and reduced sperm quality, are uncertain. Data suggest, however, that these anomalies originate in foetal life, and that contributing factors are genetic, pregnancy-related and environmental. The potential importance of environmental factors must be taken seriously, and the authorities must take action to strengthen the research in this area.

The RsaI polymorphism in the estrogen receptor-beta gene is associated with male infertility.

CONTEXT: Hypospadias, cryptorchidism, testicular cancer, and low semen quality have been proposed as being parts of the testicular dysgenesis syndrome (TDS) hypothetically due to changes in the androgen-estrogen balance in utero. Estrogens and estrogen receptors (ERs) play a role in regulating testicular function. ERbeta contains two silent polymorphisms, RsaI (G1082A) and AluI (G1730A). OBJECTIVE: We investigated the significance of these polymorphisms in the etiology of disorders being part of TDS. SETTING: The patients were recruited consecutively through university hospital clinics. PARTICIPANTS: Four groups of Caucasian patients were included: 106 men from infertile couples with a sperm concentration less than 5 x 10(6) spermatozoa/ml, 86 testicular cancer patients, 51 boys with hypospadias, and 23 cases with cryptorchidism. Military conscripts (n = 186) with sperm concentration higher than 5 x 10(6) spermatozoa/ml served as controls. MAIN OUTCOME MEASURES: ERbeta polymorphisms RsaI and AluI were determined by allele-specific PCR. In addition, reproductive hormone analyses were performed in controls and infertile men. RESULTS: Compared with the controls, the frequency of the heterozygous RsaI AG-genotype was three times higher in infertile men (13.2 vs. 4.3%; P = 0.01). The heterozygous RsaI AG genotype was associated with an approximately 20% reduction in LH concentration, compared with the wild-type RsaI GG genotype in both controls and infertile men. Subjects with testicular cancer, hypospadias, or cryptorchidism did not differ from controls regarding the frequency of any of the polymorphisms. CONCLUSIONS: Polymorphisms in ERbeta may have modulating effects on human spermatogenesis. The phenotype of TDS seems to be, at least partly, determined by the genotype.

Body Mass Index Is Associated with Impaired Semen Characteristics and Reduced Levels of Anti-Müllerian Hormone across a Wide Weight Range.

There is still controversy as to how body mass index (BMI) affects male reproduction. We investigated how BMI is associated with semen quality and reproductive hormones in 166 men, including 38 severely obese men. Standard semen analysis and sperm DNA integrity analysis were performed, and blood samples were analysed for reproductive hormones. Adjusted for age and time of abstinence, BMI was negatively associated with sperm concentration (B = -0.088, P = 0.009), total sperm count (B = -0.223, P = 0.001), progressive sperm motility (B = -0.675, P = 0.007), normal sperm morphology (B = -0.078, P = 0.001), and percentage of vital spermatozoa (B = -0.006, P = 0.027). A negative relationship was observed between BMI and total testosterone (B = -0.378, P < 0.001), sex hormone binding globulin (B = -0.572, P < 0.001), inhibin B (B = -3.120, P < 0.001) and anti-Müllerian hormone (AMH) (B = -0.009, P < 0.001). Our findings suggest that high BMI is negatively associated with semen characteristics and serum levels of AMH.

Linkage between cryptorchidism, hypospadias, and GGN repeat length in the androgen receptor gene.

Although sufficient androgen receptor (AR) function is crucial for normal male sexual differentiation, single-point mutations in the AR gene are infrequent in the two most common male congenital malformations, hypospadias and cryptorchidism. Because polymorphic CAG and GGN segments regulate AR function, we investigated whether there was any association between these polymorphisms and mentioned malformations. Genotyping was performed by direct sequencing of DNA from patients diagnosed with hypospadias (n = 51) and cryptorchidism (n = 23) and controls (n = 210). The subjects with hypospadias were divided into subgroups of glanular, penile, and penoscrotal hypospadias. Median GGN lengths were significantly higher (24 vs. 23) among both subjects with cryptorchidism, compared with controls (P = 0.001), and those with penile hypospadias, compared with either controls (P = 0.003) or glanular and penoscrotal hypospadias combined (P = 0.018). The frequency of cases with GGN 24 or more vs. GGN = 23, differed significantly among those with cryptorchidism (65/35%), compared with controls (31/54%) (P = 0.012), and among subjects with penile hypospadias (69/31%), compared with either controls (P = 0.035) or glanular or penoscrotal hypospadias combined (32/55%) (P = 0.056). There were no significant differences in CAG lengths between the cases and controls. Our findings indicate an association between GGN length and the risk of cryptorchidism and penile hypospadias, both conditions considered consequences of low androgenicity.

Is there an association between maternal weight and the risk of testicular cancer? An epidemiologic study of Norwegian data with emphasis on World War II.

Since registration started in the 1950s, the incidence of testicular cancer (TC) in the Western world has increased, which is also the case in Norway. Men born in Norway during World War II (WWII), however, have a lower TC incidence than men born in the years before or after WWII. Increased fetal exposure to estrogen during the first trimester of pregnancy has been proposed as a risk factor for the development of TC later in life. Increased maternal weight is associated with higher insulin levels, leading to lower sex hormone-binding globulin levels and thereby increased levels of bioavailable estrogens for transplacental transfer from mother to fetus. The aim of the present study was therefore to examine whether there was an association between maternal weight and the incidence of TC among those who were born in a time period where the nutritional conditions changed, i.e., around the time of WWII. We compared data for a random sample of women giving birth in Oslo, Norway, in the years 1931 to 1955 with the TC incidence among men born in the whole country in the same time period. Maternal weight at delivery was used as a proxy for first-trimester weight. We found a correlation (Spearman's rho = 1.00, p < 0.01; Pearson's r = 0.95, p = 0.02) between the TC incidence and maternal weight adjusted for birth weight and maternal age. Although one cannot draw firm conclusions from ecologic correlations, these findings suggest that the increase in TC incidence over the past decades could be at least partly attributed to the increased maternal body weight observed in most populations in the relevant time period since TC is thought to be associated with in utero conditions.