Risk Of Testicular Germ Cell Tumors Research Articles

Genetic variation in AKT1, PTEN and the 8q24 locus, and the risk of testicular germ cell tumor

Is there an association between testicular germ cell tumor (TGCT) and genetic polymorphisms in AKT1, PTEN and the 8q24 locus? Our findings suggest that genetic variation in PTEN may influence the risk of TGCT. There is strong evidence that genetic variation influences the risk of TGCT. The oncogene, AKT1, the tumor suppressor gene, PTEN and the chromosome 8q24 locus play important roles in cancer development in general. We have conducted a population-based Norwegian-Swedish case-parent study, based on cases diagnosed in 1990-2008, including 831 triads (TGCT case and both parents), 474 dyads (TGCT case and one parent) and 712 singletons (only the TGCT case). In addition we expanded the study to include 3922 unrelated male controls from the TwinGene project. We genotyped 26 single nucleotide polymorphisms (SNPs) in AKT1, PTEN and the 8q24 locus. First, triads and dyads were included in a likelihood-based association test. To increase the statistical power, case singletons and controls from the TwinGene project were included in a single test for association. We examined if the allelic effect on TGCT risk differed by histological subgroup, country of origin or parent of origin. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated with Bonferroni correction (P bonf) for multiple testing. In the case-parent analyses, none of the 26 SNPs were significantly associated with TGCT. Of the 23 SNPs investigated in the combined study, one SNP in PTEN (rs11202586) remained associated with TGCT risk after adjusting for multiple testing (OR = 1.16, 95% CI = 1.06-1.28, P bonf = 0.040). We found no difference in risk according to histological subgroup, parent of origin or between countries. Our study is strengthened by the population-based design and large sample size, which gives high power to detect risk alleles. The reported association was not highly significant, and although it was based on an a priori hypothesis of this tumor suppressor gene being implicated in the etiology of TGCT, replication studies, as well as functional studies of this polymorphism, are warranted. We report, to our knowledge, a novel association between TGCT and a marker in the tumor suppressor gene PTEN. Previous studies have linked PTEN to TGCT etiology, and there is also a link between PTEN and KITLG, which contains TGCT susceptibility loci revealed through recent genome-wide studies.

Second to fourth digit ratio, handedness and testicular germ cell tumors

BackgroundResearch on early life exposures and testicular germ cell tumors (TGCT) risk has focused on a possible perinatal etiology with a well-known hypothesis suggesting that hormonal involvement during fetal life is associated with risk. Second-to-fourth digit ratio (2D:4D) and left-hand dominance have been proposed as markers of prenatal hormone exposure. AimTo evaluate associations between 2D:4D digit ratio, right minus left 2D:4D (ΔR−L), and left-hand dominance and TGCT in the U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study. MethodsA total of 246 TGCT cases and 236 non-testicular cancer controls participated in the current study, and completed a self-administered questionnaire. Associations between digit ratio, hand dominance and TGCT were estimated using unconditional logistic regression adjusting for identified covariates. ResultsRight 2D:4D was not associated with TGCT [odds ratio (OR) for a one-standard deviation (SD) increase in right-hand 2D:4D: 1.12, 95% confidence interval (CI): 0.93–1.34]. The results were consistent when evaluating the association based on the left hand. The difference between right and left-hand 2D:4D was also not associated with TGCT risk [OR for a one-SD increase in ΔR−L: 1.03, 95% CI: 0.87–1.23]. Compared to men who reported right-hand dominance, ambidexterity [OR (95% CI)=0.65 (0.30–1.41)] and left-hand dominance [OR (95% CI)=0.79 (0.44–1.44)] were not associated with risk. ConclusionsThese results do not support the hypothesis that prenatal hormonal imbalance is associated with TGCT risk. Given the limited sample size, further evaluation of the relationship between TGCT and prenatal hormonal factors using digit ratio, ΔR−L, or left-hand dominance and larger sample size are warranted.

Abstract 1348: Association between genetic variation at the AKT1 and PTEN genes, and in the 8q24 locus, and the risk of testicular germ cell tumor.

Abstract Background There is strong evidence that genetic variation influences the risk of testicular germ cell tumor (TGCT). The oncogene AKT1, tumor suppressor gene PTEN and the 8q24 locus play important roles in cancer development, and investigation of their role in TGCT is warranted. Methods We investigated the association between risk of TGCT and genetic variation in the AKT1 and PTEN genes, and the 8q24 locus in a Norwegian-Swedish case-parent study. We included 831 triads, 474 dyads and 712 singletons, and 26 single nucleotide polymorphisms (SNPs) were genotyped. First, triads and dyads were included in a likelihood-based association test. To increase the statistical power, case singletons and 3922 unrelated controls from the Swedish TwinGene project were included in a single test for association. Interaction terms were included in the statistical model to examine if the allelic effect on TGCT risk was modified by histological subgroup, country of origin or parent of origin. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated and Bonferroni correction (Pbonf) was used to adjust for multiple testing. Results In the case-parent triad analyses, none of the 26 SNPs were significantly associated with TGCT. Of the 23 SNPs investigated in the combined study, one SNP in the PTEN gene, the rs11202586, remained associated with TGCT risk after adjusting for multiple testing (OR=1.16, 95% CI=1.06-1.28, Pbonf=0.040). We found no difference in risk according to histological subgroup, parent of origin or between countries. Conclusions Our findings suggest that genetic variation in the PTEN gene influences the risk of TGCT. Table. Odds ratios (ORs) for associations between polymorphisms in AKT1, PTEN and 8q24 locus and TGCT risk in the combined case-parent/case-control study. Gene Gene name SNP Allele1* Allele2 Genomic position CHR OR 95% CI P Pbonf# AKT1 v-akt murine thymoma viral oncogene homolog 1 rs2494731 C G 104308725 14 0.93 0.86–1.01 0.071 1.000 rs2494739 C T 104318034 0.96 0.83–1.11 0.594 1.000 rs2494752 A G 104334653 0.95 0.81–1.11 0.502 1.000 rs4983387 A G 104339273 1.07 0.95–1.22 0.283 1.000 PTEN phosphatase and tensin homolog rs1234212 C T 89598872 10 0.99 0.92–1.07 0.824 1.000 rs11202586 C T 89602004 1.16 1.06–1.28 0.002 0.040 rs1234221 A C 89606459 0.97 0.89–1.06 0.537 1.000 rs1234220 A G 89635453 1.16 1.03–1.31 0.018 0.414 rs1234219 A G 89639557 1.09 0.95–1.25 0.221 1.000 rs2299939 A C 89647130 1.04 0.95–1.15 0.386 1.000 rs12357281 C G 89690651 1.05 0.91–1.20 0.534 1.000 rs2248293 C T 89697245 0.95 0.88–1.03 0.233 1.000 rs926091 C T 89711392 0.91 0.82–1.02 0.105 1.000 8q24 locus rs7008482 G T 126336812 8 0.91 0.84–0.99 0.029 0.674 rs13254738 A C 128173525 1.02 0.94–1.10 0.707 1.000 rs6983561 A C 128176062 0.98 0.80–1.19 0.815 1.000 rs16901979 A C 128194098 0.94 0.78–1.15 0.566 1.000 rs6983267 G T 128482487 0.98 0.91–1.05 0.548 1.000 rs7000448 C T 128510352 0.97 0.90–1.05 0.424 1.000 rs1447295 A C 128554220 0.99 0.88–1.11 0.864 1.000 rs4242382 A G 128586755 1.00 0.89–1.13 0.986 1.000 rs7017300 A C 128594450 0.94 0.85–1.05 0.266 1.000 rs7837688 G T 128608542 1.06 0.94–1.19 0.333 1.000 * Reference allele # Bonferroni correction (P multiplied by the number of total SNPs analyses, n = 23). Citation Format: Kristine E. Andreassen, Wenche Kristiansen, Robert Karlsson, Elin L. Aschim, Olav Dahl, Sophie D. Fosså, Hans-Olov Adami, Fredrik Wiklund, Trine B. Haugen, Tom Grotmol. Association between genetic variation at the AKT1 and PTEN genes, and in the 8q24 locus, and the risk of testicular germ cell tumor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1348. doi:10.1158/1538-7445.AM2013-1348

Abstract 1346: Investigation of six testicular germ cell tumor susceptibility genes reveals a parent-of-origin effect in SPRY4.

Abstract BACKGROUND: Testicular germ cell tumor (TGCT) is the most common malignancy in young men. Genetic components and conditions during pregnancy are known to play an etiologic role. Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with 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 two major histological subtypes, seminoma and nonseminoma. METHODS: 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 3922 population controls. 734 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 modification by parent-of-origin and effect differences between histological subtypes were explored. RESULTS: 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 independent signals for SPRY4, and one independent signal 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 were found between seminoma and nonseminoma. CONCLUSION: Previously reported genetic associations with TGCT were validated in a Scandinavian population. A genetic variant in SPRY4 only influenced TGCT risk when inherited maternally. The simplest interpretation of this parent-of-origin effect is that the SPRY4 (tumor suppressor) gene is silenced, by imprinting or some other epigenetic mechanism, in the fathers of TGCT cases. Parent-of-origin effects have to our knowledge not been reported before in the development of this cancer form. Citation Format: Tom Grotmol, Robert Karlsson, Kristine Andreassen, Wenche Kristiansen, Elin Aschim, Roy Bremnes, Olav Dahl, Sophie Fosså, Olbjørn Klepp, Carl Langberg, Arne Solberg, Steinar Tretli, Patrik Magnusson, Hans-Olov Adami, Trine Haugen, Fredrik Wiklund. Investigation of six testicular germ cell tumor susceptibility genes reveals a parent-of-origin effect in SPRY4. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1346. doi:10.1158/1538-7445.AM2013-1346

A Big Catch for Germ Cell Tumour Research

A Big Catch for Germ Cell Tumour Research

Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23

Genome-wide association studies (GWASs) have identified multiple common genetic variants associated with an increased risk of testicular germ cell tumors (TGCTs). A previous GWAS reported a possible TGCT susceptibility locus on chromosome 1q23 in the UCK2 gene, but failed to reach genome-wide significance following replication. We interrogated this region by conducting a meta-analysis of two independent GWASs including a total of 940 TGCT cases and 1559 controls for 122 single-nucleotide polymorphisms (SNPs) on chromosome 1q23 and followed up the most significant SNPs in an additional 2202 TGCT cases and 2386 controls from four case-control studies. We observed genome-wide significant associations for several UCK2 markers, the most significant of which was for rs3790665 (PCombined = 6.0 × 10(-9)). Additional support is provided from an independent familial study of TGCT where a significant over-transmission for rs3790665 with TGCT risk was observed (PFBAT = 2.3 × 10(-3)). Here, we provide substantial evidence for the association between UCK2 genetic variation and TGCT risk.

Cryptorchidism and testicular germ cell tumors: comprehensive meta-analysis reveals that association between these conditions diminished over time and is modified by clinical characteristics

Introduction: Risk of testicular germ cell tumors (TGCT) is consistently associated with a history of cryptorchidism (CO) in epidemiologic studies. Factors modifying the association may provide insights regarding etiology of TGCT and suggest a basis for individualized care of CO. To identify modifiers of the CO-TGCT association, we conducted a comprehensive, quantitative evaluation of epidemiologic data.Materials and Methods: Human studies cited in PubMed or ISI Web of Science indices through December 2011 and selected unpublished epidemiologic data were reviewed to identify 35 articles and one unpublished dataset with high-quality data on the CO-TGCT association. Association data were extracted as point and 95% confidence interval estimates of odds ratio (OR) or standardized incidence ratio (SIR), or as tabulated data. Values were recorded for each study population, and for subgroups defined by features of study design, CO and TGCT. Extracted data were used to estimate summary risk ratios (sRR) and evaluate heterogeneity of the CO-TGCT association between subgroups.Results: The overall meta-analysis showed that history of CO is associated with four-fold increased TGCT risk [RR = 4.1(95% CI = 3.6–4.7)]. Subgroup analyses identified five determinants of stronger association: bilateral CO, unilateral CO ipsilateral to TGCT, delayed CO treatment, TGCT diagnosed before 1970, and seminoma histology.Conclusions: Modifying factors may provide insight into TGCT etiology and suggest improved approaches to managing CO. Based on available data, CO patients and their parents or caregivers should be made aware of elevated TGCT risk following orchidopexy, regardless of age at repair, unilateral vs. bilateral non-descent, or position of undescended testes.

Population‐based case‐control study of recreational drug use and testis cancer risk confirms an association between marijuana use and nonseminoma risk

BACKGROUND: Testicular germ cell tumor (TGCT) incidence increased steadily in recent decades, but causes remain elusive. Germ cell function may be influenced by cannabinoids, and 2 prior epidemiologic studies reported that the use of marijuana may be associated with nonseminomatous TGCT. Here, the authors evaluate the relation between TGCTs and exposure to marijuana and other recreational drugs using a population-based case-control study. METHODS: In total, 163 patients who were diagnosed with TGCT in Los Angeles County from December 1986 to April 1991 were enrolled, and 292 controls were matched on age, race/ethnicity, and neighborhood. Participants were asked about drug use by a structured, in-person interview. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression analysis adjusted for history of cryptorchidism; education; religiosity; and reported use of marijuana, cocaine, and amyl nitrite. RESULTS: Compared with never use, ever use of marijuana had a 2-fold increased risk (OR, 1.94; 95% CI, 1.02-3.68), whereas ever use of cocaine had a negative association with TGCT (OR, 0.54; 95% CI, 0.32-0.91). Stratification on tumor histology revealed a specific association of marijuana use with nonseminoma and mixed histology tumors (OR, 2.42; 95% CI, 1.08-5.42). CONCLUSIONS: A specific association was observed between marijuana use and the risk of nonseminoma and mixed tumors. To the authors’ knowledge, this is the first report of a negative association between cocaine use and TGCT risk. The current results warrant mechanistic studies of marijuana’s effect on the endocannabinoid system and TGCT risk and caution that recreational and therapeutic use of cannabinoids by young men may confer malignant potential to testicular germ cells. Cancer 2012;000:000–000. V C 2012 American Cancer Society.

Population‐based case‐control study of recreational drug use and testis cancer risk confirms an association between marijuana use and nonseminoma risk

Testicular germ cell tumor (TGCT) incidence increased steadily in recent decades, but causes remain elusive. Germ cell function may be influenced by cannabinoids, and 2 prior epidemiologic studies reported that the use of marijuana may be associated with nonseminomatous TGCT. Here, the authors evaluate the relation between TGCTs and exposure to marijuana and other recreational drugs using a population-based case-control study. In total, 163 patients who were diagnosed with TGCT in Los Angeles County from December 1986 to April 1991 were enrolled, and 292 controls were matched on age, race/ethnicity, and neighborhood. Participants were asked about drug use by a structured, in-person interview. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression analysis adjusted for history of cryptorchidism; education; religiosity; and reported use of marijuana, cocaine, and amyl nitrite. Compared with never use, ever use of marijuana had a 2-fold increased risk (OR, 1.94; 95% CI, 1.02-3.68), whereas ever use of cocaine had a negative association with TGCT (OR, 0.54; 95% CI, 0.32-0.91). Stratification on tumor histology revealed a specific association of marijuana use with nonseminoma and mixed histology tumors (OR, 2.42; 95% CI, 1.08-5.42). A specific association was observed between marijuana use and the risk of nonseminoma and mixed tumors. To the authors' knowledge, this is the first report of a negative association between cocaine use and TGCT risk. The current results warrant mechanistic studies of marijuana's effect on the endocannabinoid system and TGCT risk and caution that recreational and therapeutic use of cannabinoids by young men may confer malignant potential to testicular germ cells.

Surveillance or adjuvant treatments in stage 1 testis germ-cell tumours

All patients with stage 1 testicular germ-cell tumours (TGCT) can expect to be permanently cured with currently available management approaches. Orchidectomy alone cures 80% of pure seminomas and 70%-75% of nonseminomatous and combined seminoma plus nonseminomatous germ-cell tumours of the testis (NSGCTT). Currently there are well-validated criteria for estimating recurrence risk in NSGCTT. The presence of vascular invasion (VI+) in the testicular primary identifies a group with a recurrence risk approaching 50%. In VI-cases, the risk is ≤20%. Adjuvant chemotherapy with two cycles of bleomycin, etoposide, and cisplatin (BEP) is increasingly recommended in VI+ cases, and when offered is selected in place of surveillance by many VI- patients. In seminomatous germ-cell testicular tumours (SGCTT), there are no validated criteria for estimating recurrence risk. Concerns about second cancers complicating adjuvant radiotherapy are reducing its popularity and the absence of tumour markers, the need for frequent scans, long follow-up and evidence of poor compliance argue against surveillance. Single-dose carboplatin is well tolerated, cheap, reduces recurrence rates to <5% and also the risk of second primary TGCT. There remain concerns about long-term toxicity although evidence is accumulating to allay these. This article discusses the relevant issues affecting decision-making and choice in these intriguing, curable cancers.

Evaluation of genes associated with undescended testes as predictors of TGCT susceptibility.

1539 Background: Testicular germ cell tumors (TGCTs) are highly heritable. Cryptorchidism (undescended testes; UDT) is a strong risk factor for TGCT, with increased risk to both the ipsilateral and contralateral testes. However, recent genome-wide association studies (GWAS) identifying genetic variants associated with TGCT susceptibility have not found differences in genotype carriage between TGCT patients with and without UDT. We investigated the role of potential risk variants for UDT as risk factors for TGCT. Methods: 1300 SNPs in and around 25 gene regions with published associations with UDT were evaluated in 474 TGCT cases (45 with UDT) and 919 controls. Genotype information was available from the Affymetrix Genome-Wide Human SNP Array 6.0. Statistical analysis was performed using PLINK, and statistical significance was assessed by Fisher's Exact test. Results: Comparing TGCT cases with and without UDT, variants in the region of four genes (EPHB2, ESR1, SEMA3C, TGFBR3) were suggestively associated with UDT. When TGCT cases with UDT were compared with unaffected controls, the associations all met the required level of significance (p &lt; 4 x 10-5). Only variation at ESR1 approached significance (P=0.0004) when TGCT cases and unaffected controls were compared. Conclusions: We identified variants at three genetic loci - SEMA3C, TGFBR3 and EPHB2 - that were significantly associated with UDT, but not with TGCT. The association of variation in EPHB2 and SEMA3C with UDT are novel findings. While associated with UDT, variation at ESR1 is also potentially associated with TGCT risk. These data continue to suggest that genetic risk factors for UDT are largely independent of those for TGCT. Thus, screening for TGCT could be targeted in a UDT population to those with genetic risk factors. Further studies should be done to investigate the genetic link between UDT and TGCT.

Bilateral testicular germ cell tumors (TGCT) prevalence: The 24-year-long single-center experience.

e15031 Background: Theetiology andreliable biomarkers for the risk of bilateral TGCT are still under investigation. Long-term relapse risks of up to 20 years after the therapy in contralateral testes demand a specific model of surveillance. Due to the rarity of the tumor type, reports of national experiences of bilateral TGCT are of a crucial significance for a future global database. Methods: The study was conducted during the treatment of 1 823 patients with TGCT in a single center from 1987-2011. Their mean age was 24 years at the time of diagnosis. Results: Out of 1 823 patients diagnosed with TGCT, 33 developed the bilateral disease (1.81%), 11 of them had synchronous tumors (33%). In the rest of patients the second testicular tumor was diagnosed 1 to 17 years after the initial diagnosis. The mean age of patients with bilateral TGCT was 28. According to the histological type: 11 were seminoma, 14 non-seminoma and 8 mixed seminoma and non-seminoma. Seven patients with bilateral tumor had a seminoma component at initial diagnosis. Compared to 5 patients out of 11 with synchronous tumor, the yolk sac component was detected only in 2 out of 22 metachronous patients. Conclusions: The presented findings of bilateral TGCT prevalence (1.8%) are in concordance with similar previous studies. As this type of tumor may be effectively treated, the risk assessment of metachronous tumor development should in future be facilitated by new biomarkers based on omics techniques. Thus, the investigation of karyotyping, c-KIT and transcriptome specificities will contribute to elucidation which pathways contribute to germ cell neoplasms. The stem cell markers for pluripotency maintenance may in future become potential diagnostic markers used as predictors for metastatic germ cell tumors. The development of a global database on these rare tumors will be of a crucial importance.

Abstract 4468: Pre-diagnostic steroid hormone levels and risk of testicular germ cell tumors

Abstract Background: Testicular germ cell tumors (TGCT), the most commonly occurring cancer among young men in the U.S., are thought to be endocrine-related tumors. The relationship between steroid hormone levels and development of TGCT, however, has been difficult to study given the rarity of the tumor in the general population and the paucity of pre-diagnostic serum from young men. The U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) study, however, was able to overcome these obstacles by enrolling military servicemen who had previously donated serum specimens to the Department of Defense Serum Repository. Methods: STEED participants were enrolled between 2002 and 2005. The associations between TGCT risk and log-transformed serum concentrations of testosterone, free testosterone, estradiol, free estradiol, 3α-androstanediol glucuronide (3α-diol-G), an indicator of peripheral androgen action, and sex hormone-binding globulin (SHBG) were examined in 517 case and 790 control participants. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models, adjusting for date of serum donation, age, race/ethnicity, family history of testicular cancer, history of cryptorchidism, height, and body mass index. Results: The analysis found that while testosterone was not significantly associated with TGCT risk, there was an inverse association between 3α-diol-G and risk (OR=0.80, 95%CI=0.63-0.99). In addition, there was a significant inverse association with TGCT and the ratio of 3α-diol-G to testosterone (OR=0.76, 95%CI=0.61-0.93). There was also a significant direct association between estradiol and TGCT risk (OR=1.41, 95%CI=1.06-1.87). The relationships between the free forms of testosterone and estradiol and risk were the same as the relationships between the total forms of each hormone and risk. There was no association between TGCT and SHBG. Conclusion: These results suggest that the hormone metabolism of men who subsequently develop TGCT may vary from that of other men. In men who develop TGCT, more testosterone may be converted to estradiol and less to dihydrotestosterone, the most potent form of androgen, than in men who do not develop TGCT. Further examination of metabolites, both upstream and downstream in the steroid hormone pathway, may help elucidate the mechanism by which these exposures are related to development of TGCT. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4468. doi:1538-7445.AM2012-4468

Abstract 4470: Pre-diagnostic gonadotropin levels and development of testicular germ cell tumors

Abstract INTRODUCTION: Testicular germ cell tumors (TGCT) are the most common cancer among young men (20-45 years of age). The pathogenesis of TGCT remains largely unknown; however, there is evidence that TGCT is related to other male reproductive disorders namely infertility and genitourinary malformations (cryptorchidism and hypospadias). It is generally assumed that the development of TGCT is under endocrine control and it has been hypothesized that gonadotropin dysregulation may be one potential cause of TGCT, as the testes are primary target organs for the gonadotropins, follicle-stimulating hormone (FSH) and luteinzing hormone (LH). FSH stimulates spermatogenesis via binding to receptors in Sertoli cells, while LH stimulates the Leydig cells to produce testosterone. Data support the role of primary LH deficiency in cryptorchidism, and also support the role of gonadotropin deficiency in infertility. It is currently not known whether FSH and LH levels are associated with TGCT risk. Thus, we assessed associations of pre-diagnostic serum FSH and LH concentrations and risk of TGCT among participants in the U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) Study. METHODS: TGCT cases diagnosed between 2002 and 2005 (n=517) were matched on age, race and serum draw date to at least one control (n=790). Associations between pre-diagnostic serum FSH and LH levels and TGCT were estimated using conditional logistic regression with further adjustment for prior cryptorchidism, family history of testicular cancer, height, body mass index and serum testosterone. Associations stratified on histology (seminoma, nonseminoma) were also examined. RESULTS: Overall, TGCT was associated with increased levels of FSH and decreased levels of LH. Men had an increased risk of TGCT if they were in the highest quartile of FSH [Q4 vs. Q1: OR 2.17, 95% CI 1.35-3.48] and in the lowest quartile of LH [Q1 vs. Q4: OR 1.99, 95% CI 1.25-3.16]. These associations were independent of one another and independent of serum testosterone concentration. In analyses stratified by histologic subtype the increased risk of TGCT with high FSH [Q4 vs. Q1: OR 2.86, 95% CI 1.33-6.18] and low LH [Q1 vs. Q4: OR 2.55, 95% CI 1.18, 5.49] was consistent for seminomas. Among nonseminomas, the ORs were indicative of elevated TGCT risk with high FSH [Q4 vs. Q1: OR 1.81, 95% CI 0.96-3.43] and low LH [Q1 vs. Q4: OR 1.80, 95% CI 0.97-3.36], albeit the results did not attain statisitical significance. DISCUSSION: Our findings of associations of TGCT with FSH and LH suggest that gonadotropin disruption may be a critical event in development of TGCT. LH deficiency has previously been associated with risk factors for TGCT, cryptorchidism and infertility, while high levels of FSH may indicate a defect in Sertoli cell production of inhibin B, a negative feedback regulator of FSH. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4470. doi:1538-7445.AM2012-4470

Gene variations in sex hormone pathways and the risk of testicular germ cell tumour: a case–parent triad study in a Norwegian–Swedish population

Testicular germ cell tumour (TGCT) is the most common cancer in young men, and an imbalance between the estrogen and androgen levels in utero is hypothesized to influence TGCT risk. Thus, polymorphisms in genes involved in the action of sex hormones may contribute to variability in an individual's susceptibility to TGCT. We conducted a Norwegian-Swedish case-parent study. A total of 105 single-nucleotide polymorphisms (SNPs) in 20 sex hormone pathway genes were genotyped using Sequenom MassArray iPLEX Gold, in 831 complete triads and 474 dyads. To increase the statistical power, the analysis was expanded to include 712 case singletons and 3922 Swedish controls, thus including triads, dyads and the case-control samples in a single test for association. Analysis for allelic associations was performed with the UNPHASED program, using a likelihood-based association test for nuclear families with missing data, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. False discovery rate (FDR) was used to adjust for multiple testing. Five genetic variants across the ESR2 gene [encoding estrogen receptor beta (ERβ)] were statistically significantly associated with the risk of TGCT. In the case-parent analysis, the markers rs12434245 and rs10137185 were associated with a reduced risk of TGCT (OR = 0.66 and 0.72, respectively; both FDRs <5%), whereas rs2978381 and rs12435857 were associated with an increased risk of TGCT (OR = 1.21 and 1.19, respectively; both FDRs <5%). In the combined case-parent/case-control analysis, rs12435857 and rs10146204 were associated with an increased risk of TGCT (OR = 1.15 and 1.13, respectively; both FDRs <5%), whereas rs10137185 was associated with a reduced risk of TGCT (OR = 0.79, FDR <5%). In addition, we found that three genetic variants in CYP19A1 (encoding aromatase) were statistically significantly associated with the risk of TGCT in the case-parent analysis. The T alleles of the rs2414099, rs8025374 and rs3751592 SNPs were associated with an increased risk of TGCT (OR = 1.30, 1.30 and 1.21, respectively; all FDRs <5%). We found no statistically significant differences in allelic effect estimates between parental inherited genetic variation in the sex hormone pathways and TGCT risk in the offspring, and no evidence of heterogeneity between seminomas and non-seminomas, or between the Norwegian and the Swedish population, in any of the SNPs examined. Our findings provide support for ERβ and aromatase being implicated in the aetiology of TGCT. Exploring the functional role of the TGCT risk-associated SNPs will further elucidate the biological mechanisms involved.

Case-control study of anthropometric measures and testicular cancer risk

The etiology of testicular germ cell tumors (TGCTs) is poorly understood. Recent epidemiological findings suggest that, TGCT risk is determined very early in life, although the available data are still conflicting. The rapid growth of the testes during puberty may be another period of vulnerability. Body size has received increasing attention as possible risk factor for TC. To clarify the relation of body size and its anthropometric variables to TGCT risk, the authors analyzed data from 272 cases and 382 controls with regard to height (cm), weight (Kg), and body mass index (BMI; kg/m2). Overall, participants in the highest quartile of height were more likely to be diagnosed with TGCTs than participants in the lowest quartile of height, OR 2.22 (95% confidence intervals (CI): 1.25–3.93; adjusted; ptrend = 0.033). Moreover, histological seminoma subgroup was significantly associated with tallness, very tall men (>182 cm) having a seminoma TGCT risk of OR = 2.44 (95% confidence intervals (CI): 1.19–4.97; adjusted; ptrend = 0.011). There was also a significant inverse association of TGCT with increasing BMI (ptrend = 0.001; age-adjusted analysis) and this association was equally present in both histological subgroups. These preliminary results indicate that testicular cancer (TC) is inversely associated with BMI and positively associated with height, in particular with seminoma subtype. Several studies have reported similar findings on body size. As adult height is largely determined by high-calorie intake in childhood and influenced by hormonal factors at puberty, increased attention to postnatal exposures in this interval may help elucidate the etiology of TGCTs.

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

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)=2.38, 95% confidence interval (95% CI)=1.81-3.12; OR=2.43, 95% CI=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.

Heterogenous effect of androgen receptor CAG tract length on testicular germ cell tumor risk: shorter repeats associated with seminoma but not other histologic types

Increasing rates of testicular germ cells tumors (TGCTs) overtime suggest that environmental factors are involved in disease etiology, but familial risk and genome-wide association studies implicate genetic factors as well. We investigated whether variation in the functional CAG(n) polymorphism in the androgen receptor (AR) gene is associated with TGCT risk, using data from a population-based family study. We estimated odds ratios (OR) and 95% confidence intervals (CI) for the association of CAG repeat length and TGCT risk using matched pairs logistic regression. Analyses of 273 TGCT case-mother pairs revealed no association between AR CAG repeat length and overall TGCT risk. However, risk of seminoma was significantly associated with shorter CAG repeat length [CAG 20-21 versus CAG ≤ 19: OR = 0.82 (95% CI: 0.43-1.58), CAG 22-23 versus CAG ≤ 19: OR = 0.39 (95% CI: 0.19-0.83) and CAG ≥ 24 versus CAG ≤ 19: OR = 0.42 (95% CI: 0.20-0.86)], with a highly significant trend over these four categories of decreasing CAG repeat length (P(trend) = 0.0030). This is the first report of a statistically significant association between AR CAG repeat length and seminoma risk, suggesting that increased AR transactivation may be involved in development of seminoma and/or progression of carcinoma in situ/intratubular germ cell neoplasia unclassified to seminoma. This result provides a rationale whereby androgenic environmental compounds could contribute to increases in TGCT incidence, and identifies for the first time a potential biological pathway influencing whether TGCTs achieve seminomatous versus nonseminomatous histology, a clinically and biologically important distinction.

Genome‐wide association studies provide new insights into the genetic basis of testicular germ‐cell tumour

Testicular germ-cell tumour (TGCT) is the most common cancer in young men, and genetic epidemiological studies suggest that the disease has a strong genetic basis. Until 2009, very little of this genetic component had been explained. Genome-wide association studies have since identified eight SNPs at six loci which together account for approximately 15% of the genetic risk of TGCT and offer novel biological insights into testicular germ-cell oncogenesis. In this review, we summarize the genetic epidemiology of TGCT, detail the contribution genome-wide association studies have made to our understanding of the genetic basis of TGCT and reflect on how future technological advances may assist in revealing the remaining genetic factors underlying TGCT susceptibility.

Risk of metachronous contralateral testicular germ cell tumors: A population‐based study of 7,102 Norwegian patients (1953–2007)

The purpose of the study was to identify overall incidence and risk of developing a metachronous contralateral testicular germ cell tumor (TGCT) and compare the risk for patients treated before and after 1980 (cisplatin became available for patients with metastatic TGCT). Our hypothesis was that the risk of metachronous TCGT would be reduced for patients with metastatic disease diagnosed after 1980. We included 7,102 men with unilateral TGCT, recorded in the Cancer Registry of Norway. Allowing for competing risk, cumulative incidence and adjusted hazard ratio (HR) were estimated for different subgroups, and the diagnostic periods 1953-1979 (I) and 1980-2007 (II). Relative risks were assessed by standardized incidence ratio (SIR). In Period I and Period II, 38 and 137 males, respectively, were diagnosed with metachronous contralateral TGCT. Corresponding 20-year cumulative incidences were 1.9% and 3.9%. In Period II, risk of a second TGCT was halved [HR = 0.5, 95% confidence interval (95% CI) = 0.33-0.77] for patients with metastatic compared to localized disease. For patients presenting with localized and metastatic disease, the SIRs for Period I were 14.6 (95% CI = 9.6-21.2) and 25.3 (95% CI = 12.1-46.5), respectively. In Period II, the corresponding numbers were 19.0 (95% CI = 15.6-22.9) and 9.8 (95% CI = 6.4-14.5). In conclusion, the risk of metachronous contralateral TGCT was halved for patients with metastatic compared to localized disease in Period II, whereas this protective effect of extent of disease lacked significance for Period I. These findings support our hypothesis that cisplatin-based chemotherapy reduced the risk of a second TGCT for patients with metastatic TGCT diagnosed after 1980.