CEBP CTRC-AACR San Antonio Breast Cancer Symposium 2008 Conference on Cancer Prevention - Washington, D.C.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Cancer Epidemiology Biomarkers & Prevention 16, 77-83, January 1, 2007. doi: 10.1158/1055-9965.EPI-06-0573
© 2007 American Association for Cancer Research
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Purdue, M. P.
Right arrow Articles by McGlynn, K. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Purdue, M. P.
Right arrow Articles by McGlynn, K. A.

A Case-Control Investigation of Immune Function Gene Polymorphisms and Risk of Testicular Germ Cell Tumors

Mark P. Purdue1, Lori C. Sakoda1, Barry I. Graubard1, Robert Welch2, Stephen J. Chanock2, Isabel A. Sesterhenn3, Mark V. Rubertone4, R. Loren Erickson5 and Katherine A. McGlynn1

1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, Maryland; 2 National Cancer Institute Core Genotyping Facility, NIH, Department of Health and Human Services, Gaithersburg, Maryland; 3 Armed Forces Institute of Pathology, Washington, District of Columbia; 4 U.S. Army Center for Health Promotion and Preventive Medicine; Washington, District of Columbia and 5 Walter Reed Army Institute of Research, Forest Glen, Maryland

Requests for reprints: Mark P. Purdue, Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, EPS-8009, 6120 Executive Boulevard, Rockville, MD 20892-7234. Phone: 301-451-5036; Fax: 301-402-1819. E-mail: purduem{at}mail.nih.gov


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
There is reason to suspect that testicular germ cell tumor (TGCT) development may be influenced by cytokines, secreted proteins that modulate tumor immune surveillance activity as well as a variety of processes in the testis. To address this hypothesis, we conducted a case-control analysis (508 cases, 608 controls) of 32 putatively functional single-nucleotide polymorphisms (SNP) in 16 immune function genes among non-Hispanic Caucasian participants in the U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study. The TGFB1 Ex5–73C>T variant was positively associated with TGCT (CT/TT versus CC: odds ratio, 1.73; 95% confidence interval, 1.01-2.95; Ptrend = 0.05); additionally, haplotypes of the assessed TGFB1 SNPs (–509C>T, 327C>T, Ex1–282C>G, and Ex5–73C>T) differed in frequency between cases and controls (all TGCT, P 0.07; seminoma, P 0.04; nonseminoma, P 0.11). We also observed excess frequencies among TGCT cases versus controls of LTA 252G (Ptrend = 0.08) and of the TNF variants –1042C (Ptrend = 0.06), –1036T (Ptrend = 0.07), and –238G (Ptrend = 0.09). Analyses of haplotypes for LTA-TNF SNPs (LTA –91C>A, LTA 252A>G, TNF –863C>A, TNF –857C>T, TNF –308G>A, and –238G>A) were similarly suggestive of an association with TGCT (P = 0.06) and nonseminoma (P = 0.04), but not seminoma (P = 0.21). Polymorphisms in other genes were found to be associated only with seminoma (IL2) or nonseminoma (IFNGR2 and IL10). However, none of the associations remained noteworthy after applying the false discovery rate method to control for multiple testing. In conclusion, our findings suggest that polymorphisms in TGFB1 and LTA/TNF, and possibly other immune function genes, may influence susceptibility to TGCT. (Cancer Epidemiol Biomarkers Prev 2007;16(1):77–83)


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The etiology of testicular germ cell tumors (TGCT), the most common type of testicular cancer diagnosed among adolescent and young adult males, remains largely unknown; the only well-described risk factors are cryptorchism, Caucasian ethnicity, and family history and personal history of TGCT (1). Epidemiologic findings suggest various factors that may influence TGCT development, including exposure to high maternal estrogen levels in utero, low androgen levels, mechanisms underlying infertility, and viral infection (1). However, these hypotheses remain tentative.

There is evidence that immunologic factors may influence the development of TGCT. Studies of acquired immune deficiency syndrome patients and kidney transplant recipients suggest that immunosuppressed men have an increased risk of seminoma (2-5), a common histologic subtype of TGCT. The elevated risk may be the result of an unchecked viral infection, although no such agents have been identified to date. Another explanation that has been proposed is impaired tumor immune surveillance (4); this hypothesis is supported by evidence that the extent of lymphocyte infiltration in seminomas is associated with a reduced risk of disease recurrence (6).

The study of cytokines may yield insight into the etiology of TGCT. Cytokines are secreted proteins that play a critical role in regulating the immune system; they modulate various activities of target cells, such as cell division, differentiation, and apoptosis. Cytokines may promote or inhibit tumorigenesis through their effects in modulating inflammation and tumor immune surveillance activity (7). Additionally, cytokines expressed in the testis, most notably interleukin (IL)-1, IL-2, IL-4, tumor necrosis factor-{alpha} (TNF-{alpha}), and transforming growth factor-ß (TGF-ß), are known to influence a variety of testicular processes (e.g., inflammation, steroidogenesis, spermatogenesis, and testis development; ref. 8) and may affect TGCT development on this basis. Evidence that levels of cytokine gene expression are altered by common genetic polymorphisms (9-11) has led to considerable interest in investigating the etiologic relevance of such variants for a wide variety of diseases.

To explore whether cytokines influence TGCT development, we investigated the relationship between putatively functional single-nucleotide polymorphisms (SNP) in cytokine genes and TGCT risk within a population-based case-control study, the U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
A detailed description of the study methods is provided elsewhere (12). Briefly, the U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study is a case-control study of TGCT conducted within the population of men who served in the Army and Navy between 1989 and 2002, and have at least one serum sample stored in the Department of Defense Serum Repository (Silver Spring, MD). Using a person-specific ID, specimens in the Department of Defense Serum Repository computerized database were linked to the Defense Medical Surveillance System (13) and to other military medical databases to determine which military personnel had developed medical conditions. Cases and controls were asked to complete a telephone interview, donate a buccal cell sample collected in mouthwash, grant permission to use the Department of Defense Serum Repository serum specimen, and to sign an informed consent document. In addition, each participant was asked for permission to contact his mother to enroll her in the study. The study was approved by Institutional Review Boards of the National Cancer Institute (Rockville, MD) and the Walter Reed Army Institute for Research (Forest Glen, MD).

All men with a sample in the Department of Defense Serum Repository who subsequently developed TGCT while on active duty and who were of ages ≤45 years at diagnosis were eligible to participate as cases. Diagnoses of TGCT were limited to classic seminoma or nonseminoma (embryonal carcinoma, yolk sac carcinoma, choriocarcinoma, teratomas, mixed germ cell tumor). The diagnoses were based on the original pathology reports. In instances where the original reports were unclear (6.5%), the diagnosis was confirmed by one of the coauthors (I.A.S.). Nine hundred sixty-one eligible case participants were initially identified. Of these men, 76 could not be traced, 27 had died, 3 were deployed to a combat zone, 2 were found to be ineligible, 22 did not complete study enrollment before the cutoff date, and 77 refused to participate. Of the remaining 754 men who were enrolled as cases, 590 provided buccal cell samples. Five hundred seventy-seven of these cases were successfully genotyped.

Men with a sample in the Department of Defense Serum Repository who did not subsequently develop TGCT were eligible to participate as controls. The study was designed as a pair-matched case-control study, although additional controls were initially identified due to the transient nature of the military population. Using the computerized Defense Medical Surveillance System database, all available controls were identified for each potential case participant. From the list of possible controls, four individuals who matched each case on age (within 1 year), race (white, black, other), and date of serum collection (within 30 days) were chosen at random as the control set. The first man on the list was designated as the primary control. Every attempt was made to enroll this man for 30 days (average number of attempted contacts = 90). The effort included tracing attempts, multiple letters, and telephone calls. If the man could not be traced, was deployed to a combat zone, deceased, refused to participate, or could not be contacted within a 30-day period, attempts began to enroll the next possible control in the set.

Among the controls, 2,579 were evaluated for inclusion. Three hundred eighty-five men could not be traced, 18 had died, 64 were deployed to a combat zone, 2 were found to be ineligible, 32 did not complete study enrollment before the cutoff date, 928 were lost because they did not respond to attempts to contact them within 30 days, and 222 refused to participate. Of the remaining 928 controls who were successfully enrolled, 712 provided buccal cell samples. Seven hundred eight of these controls were successfully genotyped. Among the 577 cases and 708 controls with genotyping data, there were 547 matched case-control pairs.

Genotyping and Quality Control
Buccal cell specimens were mailed directly to BBI Biotech Research Laboratories, Inc. (Gaithersburg, MD) for DNA extraction using the Gentra AutoPure system (Gentra Systems, Inc., Minneapolis, MN). Genotype analysis was done at the National Cancer Institute Core Genotyping Facility (Gaithersburg, MD). All TaqMan assays (Applied Biosystems, Inc., Foster City, CA) were optimized on the ABI 7900 HT detection system with 100% concordance with sequence analysis of 102 individuals listed on the SNP500Cancer website (14).6

We selected 32 SNPs in 16 genes encoding cytokines or cytokine receptors that may influence tumor immune surveillance and/or processes in the testis (Table 1 ). The SNPs were selected if they possessed a minor allele frequency ≥0.05 and satisfied one of the following criteria: laboratory evidence of functional relevance or a previously reported association with human disease (Supplementary Table S1).


View this table:
[in this window]
[in a new window]

  		Table 1. Genes and SNPs evaluated

 
Genotyping success rates ranged between 98% and 100%. Duplicate samples from 99 study subjects were interspersed throughout each batch for all genotyping assays. The concordance rates for QC samples were 96% to 100% for all assays. Two SNPs were found to deviate from Hardy-Weinberg equilibrium among Caucasian controls (IL6 –236C>G, P = 0.01; IL6 –600A>G, P = 0.005); the quality control data were rechecked and the accuracy of these assays was confirmed (100% concordance for each SNP).

Statistical Analysis
The analysis was restricted to non-Hispanic Caucasians (508 cases, 608 controls, and 481 matched case-control pairs; 87% of study subjects). All statistical analyses were conducted using SAS version 8.2 (SAS Institute, Cary, NC). All statistical tests were two sided with an {alpha} level of 0.05. The {chi}2 test was used to identify departures from Hardy-Weinberg equilibrium among controls.

Odds ratios (OR) and 95% confidence intervals (CI) were calculated to estimate the relative risk of TGCT in relation to SNP genotype. Data for homozygotes and heterozygotes were combined if the former consisted of fewer than five subjects. For each SNP, tests for trend were conducted by assigning the ordinal values 1, 2, and 3 to homozygous wild-type, heterozygous, and homozygous variant genotypes, respectively, and by modeling these scores as a continuous variable. The risk estimates for TGCT were calculated using unconditional logistic regression, adjusting for age at reference date (case's date of diagnosis) and date of serum sample collection, a study design variable. Both of these variables were modeled as continuous covariates. These unconditional models provided estimates similar to conditional logistic regression models for individually matched pairs (data not shown). Additional adjustment for cryptorchism did not affect the results (data not shown). Separate analyses for seminoma and nonseminoma were also conducted to investigate the existence of subtype-specific effects. To assess heterogeneity across these subtypes, we conducted case-case comparisons for each variant (analyzed assuming the additive model). Analyses of nonseminomas excluding mixed germ cell tumors (N = 21) yielded virtually identical findings.

Haplotype analyses were conducted for genes with multiple polymorphisms assessed. The interrelationships of polymorphisms were assessed via the linkage disequilibrium measures D' and R2 using Haploview,7 and haplotypes were reconstructed using the estimation-maximization algorithm in SAS/Genetics (SAS Institute). The effects of individual haplotypes were estimated by fitting an additive model (15), adjusting for age and serum collection date. The overall difference in haplotype frequencies between cases and controls was assessed using the likelihood ratio test.

We assessed the robustness of our findings for individual SNP loci by applying the false discovery rate method (16) to the P values from genotype comparisons made assuming the additive model. The 32 comparisons with all TGCT were assessed as one set, and the 64 subtype-specific comparisons were assessed as a separate set. We considered findings that met a false discovery rate criterion of 20% to be robust.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Table 1 provides a list of the genes and SNPs that were evaluated. A summary of the findings for all of the assessed polymorphisms is provided in Supplementary Table S2. Polymorphisms in TGFB1, LTA/TNF, IL2, IFNGR2, and IL10 were associated with TGCT or one of its histologic subtypes.

The results for TGFB1 variants are presented in Table 2 . One of the four SNPs assessed, Ex5–73C>T, was significantly associated with TGCT, with the T allele more frequent among cases than controls (CT/TT versus CC: OR, 1.73; 95% CI, 1.01-2.95; Ptrend = 0.05). This association was stronger for seminoma (OR, 2.09; 95% CI, 1.07-4.05) than for nonseminoma (OR, 1.53; 95% CI, 0.81-2.90), although a test of heterogeneity was not significant. We also observed weaker evidence of association with other polymorphisms; the Ex1–282C allele was associated with a reduced risk of seminoma (Ptrend = 0.08) whereas a positive association with nonseminoma risk was observed for –509T (Ptrend = 0.06). When we analyzed haplotypes of the TGFB1 SNPs (–509C>T, Ex1–327T>C, Ex1–282G>C, and Ex5–73C>T), a global test of haplotype frequencies was statistically significant for seminoma (P = 0.04) and approached statistical significance for all TGCT (P = 0.07) and for nonseminoma (P = 0.11). The risk estimates of individual haplotypes seemed to be largely explained by the observed associations for TGFB1 SNP genotypes.


View this table:
[in this window]
[in a new window]

  		Table 2. Genetic polymorphisms in TGFB1 and risk of TGCT, both overall and by subtype (seminoma and nonseminoma)

 
The findings for variants in LTA and TNF, which lie adjacent to one another on 6q21, are presented in Table 3 . Among cases, we observed excess frequencies of LTA 252G (Ptrend = 0.08) and of the TNF variants –1042C (Ptrend = 0.06), –1036T (Ptrend = 0.07), and –238G (Ptrend = 0.09). We did not observe any clear differences between seminomas and nonseminomas with regard to these relationships. For most polymorphisms, slightly stronger associations were observed for nonseminomas than for seminomas, although these differences were not statistically significant. We analyzed haplotypes for the six LTA-TNF SNPs (LTA Ex1+49C>A, LTA 252A>G, TNF –1042C>A, TNF –1036C>T, TNF –487G>A, and TNF –238G>A). Global haplotype tests were of borderline statistical significance for all TGCT (P = 0.06) and nonseminoma (P = 0.04), but not seminoma (P = 0.21). Haplotypes positively associated with TGCT or a subtype included A-A-C-T-G-G (all TGCT, P = 0.04; seminoma, P = 0.04) and C-G-C-C-G-G (seminoma, P = 0.04). The C-A-C-C-G-A haplotype was underrepresented among nonseminomas (P = 0.02).


View this table:
[in this window]
[in a new window]

  		Table 3. Genetic polymorphisms in LTA/TNF and risk of TGCT, both overall and by subtype (seminoma and nonseminoma)

 
Polymorphisms in IL2, IFNGR2, and IL10 were also found to be associated with seminoma or nonseminoma (Table 4 ). The IL2 IVS1–100G allele was associated with an increased risk of seminoma (GT: OR, 1.37; 95% CI, 0.98-1.64; GG: OR, 1.95; 95% CI, 1.13-3.36; Ptrend = 0.008), whereas IFNGR2 Ex7–128T was inversely associated with nonseminoma risk (CT: OR, 0.89; 95% CI, 0.65-1.23; TT: OR, 0.58; 95% CI, 0.39-0.88; Ptrend = 0.01). The IL10 variants –853T and –626A were also associated with decreased risk of nonseminoma (Ptrend = 0.04 and 0.07, respectively). Analyses of IL10 haplotypes (–3584T>A, –1116A>G, –853C>T, and –626C>A) were generally null, although the T-A-T-A was associated with reduced nonseminoma risk (P = 0.03).


View this table:
[in this window]
[in a new window]

  		Table 4. Genetic polymorphisms in IL2, IFNGR2, IL2, IL10 and risk of TGCT, both overall and by subtype (seminoma and nonseminoma)

 
We also observed that cases were less likely than controls to be heterozygous for the IL6 SNPs –600G>A and –236G>C (P = 0.01 and 0.01, respectively), although the prevalence of homozygous variant carriers did not differ between groups (Supplementary data). However, as we noted earlier, the genotype frequencies of both SNPs deviated from Hardy-Weinberg equilibrium among controls (IL6 –236, P = 0.01; IL6 –600, P = 0.005). To explore the sensitivity of these findings to the observed departures from Hardy-Weinberg equilibrium, we calculated crude ORs using the control genotype frequencies expected under Hardy-Weinberg equilibrium. After adjustment, we observed no association with –600 (OR, 0.83 and 0.83 for AG and GG, respectively) or –236 (OR, 0.86 and 0.86 for CG and CC respectively).

When we applied the false discovery rate method to assess the robustness of our findings, none of the observed associations met a false discovery rate criterion of ≤20%.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
A role for the immune system in TGCT development has previously been postulated on the basis of reports of increased incidence rates among immunosuppressed populations and evidence suggesting the possible importance of viral infections in the etiology of this malignancy (3, 4, 17-19). Previous studies of testicular cancer have investigated the etiologic relevance of variation in human leukocyte antigen genes, with mainly inconclusive results (summarized in ref. 20). We present, to our knowledge, the first report describing the relationship between polymorphisms in cytokine genes and TGCT risk. We analyzed 32 SNPs in 16 genes encoding cytokines and cytokine receptors among 508 cases and 608 controls. Our findings, although not robust on adjustment for multiple testing, suggest that genetic variants in TGFB1, LTA/TNF, IL2, IFNGR2, and IL10 may influence susceptibility to TGCT.

In our study, the TGFB1 variant Ex5–73T was associated with an increased risk of TGCT. We also observed weaker, subtype-specific associations, with Ex1–282G and –509T associated with elevated risks of seminoma and nonseminoma, respectively. Comparisons of haplotype (–509C>T, Ex1–327T>C, Ex1–282G>C, and Ex5–73C>T) frequencies between cases and controls approached statistical significance. The Ex5–73C>T polymorphism involves a nonsynonymous substitution at codon 263 of the polar threonine amino acid with apolar isoleucine, within a region of the TGF-ß proprotein that is cleaved from the active part at amino acid 278. It has been proposed that the Ex5–73T allele could affect the stability and activation process of TGF-ß and possibly lead to decreased levels of this cytokine (21), although no empirical evidence about function has been published. Conversely, the other risk alleles have been associated with increased TGF-ß activity. Ex1–282G>C corresponds to a change from arginine to proline at codon 25, with the –282G (25Arg) allele linked to increased TGF-ß expression in in vitro stimulated leukocytes (22). The –509T allele has been associated with increased circulating plasma TGF-ß concentration in a gene dose–dependent fashion (23).

TGF-ß affects a variety of processes in the testis, most notably the inhibition of primordial germ cell development and Leydig cell steroidogenesis (8). This cytokine has been shown to influence the development of many types of cancer, although the nature of this relationship is complex. Whereas TGF-ß is a potent inhibitor of cell proliferation and inducer of apoptosis in normal and transformed cell types, it also seems to promote the invasiveness and metastasis of tumors, possibly through the inhibition of antitumor immune responses (24). Expression of TGF-ß was detected in the majority of 26 TGCT specimens analyzed in an immunohistochemical study, with both a greater percentage of positive immunostained cells and stronger intensity of staining in tumor than in peritumor nonneoplastic testis tissue (25). These findings suggest an important role of TGF-ß in the development of TGCT, although the mechanism of action is unclear. A mutational analysis of TGF-ß pathway components among 20 seminomas found identical insertion mutants in a highly conserved residue of SMAD4 in two tumors (26). SMAD4, located on chromosome 18q21, is a critical member of the TGF-ß signal transduction pathway, with mutations in this gene found to disrupt growth inhibitory and apoptotic activities (27). The observation that chromosome 18q is frequently lost or deleted in TGCT further supports a role for the TGF-ß pathway in the development of these tumors (28-30).

We also found LTA 252G and the TNF variants –1042C, –1036T, and –238G to be weakly associated with increased TGCT risk in our study population. The LTA 252G allele has been linked to increased lymphotoxin-{alpha} production by phytohemagglutinin-activated mononuclear cells in vitro (31), whereas TNF –238G has been consistently associated with elevated antigen-stimulated production of TNF-{alpha} (32, 33). TNF –863A and –857T were found in two studies to be associated with increased TNF promoter activity (34) and lipopolysaccharide-induced TNF-{alpha} production (35), although contradictory findings have also been reported (36, 37). TNF-{alpha} and lymphotoxin-{alpha}, produced mainly by activated macrophages, are important mediators of local inflammatory processes. TNF-{alpha} has also been shown to possess both antitumor and tumor-promoting or proangiogenic effects in in vitro and mouse studies (7). In the testis, TNF-{alpha} has been shown to influence Leydig cell steroidogenesis and germ cell survival (8). Elevated levels of this cytokine have also been associated with experimental autoimmune orchitis (38) and male infertility (39, 40), a risk factor for TGCT.

Other polymorphisms were unrelated to overall TGCT risk, but associated with a particular subtype. Seminoma cases were more likely than controls to carry the IL2 IVS1–100G allele. The functional relevance of this variant is unclear; the G allele has been associated with increased promoter activity in a study of transfected Jurkat cells (41) and with decreased IL-2 expression in peripheral lymphocytes (11, 41). IL-2, a T-lymphocyte growth factor, has been shown to be a potent inhibitor of Leydig cell testosterone production (8, 42), and increased seminal plasma concentrations of this cytokine have been associated with male infertility (43). We also found the IFNGR2 Ex7–128T allele and the IL10 –3584T/–1116A/–853T/–626A haplotype to be associated with decreased risks of nonseminoma. The IFNGR2 Ex7–128T allele, located in the 3'-untranslated region, has also been reported to be associated with decreased risk of non-Hodgkin's lymphoma (44). IFN-{gamma}, an important effector of antitumor immune activity, has been reported to be highly expressed in TGCT; the significance of this expression is unclear, although the investigators speculated that it may affect stromal architecture, thereby facilitating metastasis and angiogenesis (45). IL-10 is an anti-inflammatory cytokine that is suspected to facilitate tumor immune evasion through local immunosuppression. The IL10 –1116A/–853T/–626A haplotype has been reported to be associated with low IL-10 production, and the GCC haplotype to be a "high-production" marker (46, 47). It is not clear whether IL-10 is commonly expressed in the testis, although this induction of this cytokine by testicular lymphocytes following lipopolysaccharide stimulation has been shown in a rat model (48).

Strengths of this study include its population-based design and relatively large sample size; the U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study is one of the largest case-control investigations of testicular cancer etiology conducted to date. However, our analysis also has some limitations. Despite its relatively large size, our study had limited statistical power to detect associations involving weak effects or rare variants, particularly for the analyses of seminoma and nonseminoma. Additionally, given that we assessed many SNPs and examined relationships both overall and by subtype, it is possible that at least some of our findings are due to chance. Indeed, none of the observed associations were found to be robust after applying the false discovery rate method to our findings. It is important for these findings to be replicated in other studies before meaningful inferences about their causal relevance can be drawn.

In conclusion, our results suggest that polymorphisms in TGFB1 and LTA/TNF, and possibly other immune function genes, may influence susceptibility to TGCT. Additional investigations are needed to replicate and extend these findings and to clarify the biological basis for these relationships.


   Footnotes
 
Grant support: Intramural Research Program of the NIH, National Cancer Institute.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Supplementary data for this article are available at Cancer Epidemiology, Biomarkers & Prevention Online (http://cebp.aacrjournals.org/).

6 http://snp500cancer.nci.nih.gov. Back

7 http://www.broad.mit.edu/personal/jcbarret/haploview/. Back

Received 7/10/06; revised 10/27/06; accepted 11/ 3/06.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. McGlynn KA. Environmental and host factors in testicular germ cell tumors. Cancer Invest 2001;19:842–53.[CrossRef][Medline]
  2. Goedert JJ, Cote TR, Virgo P, et al. Spectrum of AIDS-associated malignant disorders. Lancet 1998;351:1833–9.[CrossRef][Medline]
  3. Frisch M, Biggar RJ, Engels EA, Goedert JJ. Association of cancer with AIDS-related immunosuppression in adults. JAMA 2001;285:1736–45.[Abstract/Free Full Text]
  4. Powles T, Bower M, Daugaard G, et al. Multicenter study of human immunodeficiency virus-related germ cell tumors. J Clin Oncol 2003;21:1922–7.[Abstract/Free Full Text]
  5. Birkeland SA, Storm HH, Lamm LU, et al. Cancer risk after renal transplantation in the Nordic countries, 1964-1986. Int J Cancer 1995;60:183–9.[Medline]
  6. Parker C, Milosevic M, Panzarella T, et al. The prognostic significance of the tumour infiltrating lymphocyte count in stage I testicular seminoma managed by surveillance. Eur J Cancer 2002;38:2014–9.[Medline]
  7. Smyth MJ, Cretney E, Kershaw MH, Hayakawa Y. Cytokines in cancer immunity and immunotherapy. Immunol Rev 2004;202:275–93.[CrossRef][Medline]
  8. Gnessi L, Fabbri A, Spera G. Gonadal peptides as mediators of development and functional control of the testis: an integrated system with hormones and local environment. Endocr Rev 1997;18:541–609.[Abstract/Free Full Text]
  9. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW. Effects of a polymorphism in the human tumor necrosis factor {alpha} promoter on transcriptional activation. Proc Natl Acad Sci U S A 1997;94:3195–9.[Abstract/Free Full Text]
  10. Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV. An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 1997;24:1–8.[Medline]
  11. Hoffmann SC, Stanley EM, Darrin CE, et al. Association of cytokine polymorphic inheritance and in vitro cytokine production in anti-CD3/CD28-stimulated peripheral blood lymphocytes. Transplantation 2001;72:1444–50.[CrossRef][Medline]
  12. McGlynn KA, Sakoda LC, Rubertone MV, et al. Body size, dairy consumption, puberty and risk of testicular germ cell tumors. Am J Epidemiol. Epub 2006 Nov 16.
  13. Rubertone MV, Brundage JF. The Defense Medical Surveillance System and the Department of Defense serum repository: glimpses of the future of public health surveillance. Am J Public Health 2002;92:1900–4.[Abstract/Free Full Text]
  14. Packer BR, Yeager M, Burdett L, et al. SNP500Cancer: a public resource for sequence validation, assay development, and frequency analysis for genetic variation in candidate genes. Nucleic Acids Res 2006;34:D617–21.[Abstract/Free Full Text]
  15. Kraft P, Cox DG, Paynter RA, Hunter D, De Vivo I. Accounting for haplotype uncertainty in matched association studies: a comparison of simple and flexible techniques. Genet Epidemiol 2005;28:261–72.[CrossRef][Medline]
  16. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc, Ser B 1995;57:289–300.
  17. Newell GR, Mills PK, Johnson DE. Epidemiologic comparison of cancer of the testis and Hodgkin's disease among young males. Cancer 1984;54:1117–23.[CrossRef][Medline]
  18. Mueller N, Hinkula J, Wahren B. Elevated antibody titers against cytomegalovirus among patients with testicular cancer. Int J Cancer 1988;41:399–403.[Medline]
  19. Akre O, Lipworth L, Tretli S, et al. Epstein-Barr virus and cytomegalovirus in relation to testicular-cancer risk: a nested case-control study. Int J Cancer 1999;82:1–5.[CrossRef][Medline]
  20. Lutke Holzik MF, Rapley EA, Hoekstra HJ, Sleijfer DT, Nolte IM, Sijmons RH. Genetic predisposition to testicular germ-cell tumours. Lancet Oncol 2004;5:363–71.[CrossRef][Medline]
  21. Langdahl BL, Knudsen JY, Jensen HK, Gregersen N, Eriksen EF. A sequence variation: 713-8delC in the transforming growth factor-ß1 gene has higher prevalence in osteoporotic women than in normal women and is associated with very low bone mass in osteoporotic women and increased bone turnover in both osteoporotic and normal women. Bone 1997;20:289–94.[Medline]
  22. Awad MR, El Gamel A, Hasleton P, Turner DM, Sinnott PJ, Hutchinson IV. Genotypic variation in the transforming growth factor-ß1 gene: association with transforming growth factor-ß1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation 1998;66:1014–20.[CrossRef][Medline]
  23. Grainger DJ, Heathcote K, Chiano M, et al. Genetic control of the circulating concentration of transforming growth factor type ß1. Hum Mol Genet 1999;8:93–7.[Abstract/Free Full Text]
  24. Derynck R, Akhurst RJ, Balmain A. TGF-ß signaling in tumor suppression and cancer progression. Nat Genet 2001;29:117–29.[CrossRef][Medline]
  25. Cardillo MR, Petrangeli E, Ravenna L, Salvatori L, Di Silverio F. Transforming growth factor-ß expression in human testicular neoplasms. Anal Quant Cytol Histol 1998;20:461–9.[Medline]
  26. Bouras M, Tabone E, Bertholon J, et al. A novel SMAD4 gene mutation in seminoma germ cell tumors. Cancer Res 2000;60:922–8.[Abstract/Free Full Text]
  27. Miyaki M, Kuroki T. Role of Smad4 (DPC4) inactivation in human cancer. Biochem Biophys Res Commun 2003;306:799–804.[CrossRef][Medline]
  28. Murty VV, Bosl GJ, Houldsworth J, et al. Allelic loss and somatic differentiation in human male germ cell tumors. Oncogene 1994;9:2245–51.[Medline]
  29. Rothe M, Albers P, Wernert N. Loss of heterozygosity, differentiation, and clonality in microdissected male germ cell tumours. J Pathol 1999;188:389–94.[CrossRef][Medline]
  30. Summersgill B, Osin P, Lu YJ, Huddart R, Shipley J. Chromosomal imbalances associated with carcinoma in situ and associated testicular germ cell tumours of adolescents and adults. Br J Cancer 2001;85:213–20.[CrossRef][Medline]
  31. Messer G, Spengler U, Jung MC, et al. Polymorphic structure of the tumor necrosis factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-ß gene correlates with a variant amino acid in position 26 and a reduced level of TNF-ß production. J Exp Med 1991;173:209–19.[Abstract/Free Full Text]
  32. Kaluza W, Reuss E, Grossmann S, et al. Different transcriptional activity and in vitro TNF-{alpha} production in psoriasis patients carrying the TNF-{alpha} 238A promoter polymorphism. J Invest Dermatol 2000;114:1180–3.[CrossRef][Medline]
  33. Huizinga TW, Westendorp RG, Bollen EL, et al. TNF-{alpha} promoter polymorphisms, production and susceptibility to multiple sclerosis in different groups of patients. J Neuroimmunol 1997;72:149–53.[CrossRef][Medline]
  34. Higuchi T, Seki N, Kamizono S, et al. Polymorphism of the 5'-flanking region of the human tumor necrosis factor (TNF)-{alpha} gene in Japanese. Tissue Antigens 1998;51:605–12.[Medline]
  35. Soga Y, Nishimura F, Ohyama H, Maeda H, Takashiba S, Murayama Y. Tumor necrosis factor-{alpha} gene (TNF-{alpha}) –1031/–863, –857 single-nucleotide polymorphisms (SNPs) are associated with severe adult periodontitis in Japanese. J Clin Periodontol 2003;30:524–31.[CrossRef][Medline]
  36. Kaijzel EL, Bayley JP, van Krugten MV, et al. Allele-specific quantification of tumor necrosis factor {alpha} (TNF) transcription and the role of promoter polymorphisms in rheumatoid arthritis patients and healthy individuals. Genes Immun 2001;2:135–44.[CrossRef][Medline]
  37. Uglialoro AM, Turbay D, Pesavento PA, et al. Identification of three new single nucleotide polymorphisms in the human tumor necrosis factor-{alpha} gene promoter. Tissue Antigens 1998;52:359–67.[Medline]
  38. Lysiak JJ. The role of tumor necrosis factor-{alpha} and interleukin-1 in the mammalian testis and their involvement in testicular torsion and autoimmune orchitis. Reprod Biol Endocrinol 2004;2:9.[CrossRef][Medline]
  39. Hill JA, Haimovici F, Politch JA, Anderson DJ. Effects of soluble products of activated lymphocytes and macrophages (lymphokines and monokines) on human sperm motion parameters. Fertil Steril 1987;47:460–5.[Medline]
  40. Basu S, Aballa TC, Ferrell SM, Lynne CM, Brackett NL. Inflammatory cytokine concentrations are elevated in seminal plasma of men with spinal cord injuries. J Androl 2004;25:250–4.[Abstract/Free Full Text]
  41. Matesanz F, Fedetz M, Leyva L, Delgado C, Fernandez O, Alcina A. Effects of the multiple sclerosis associated –330 promoter polymorphism in IL2 allelic expression. J Neuroimmunol 2004;148:212–7.[CrossRef][Medline]
  42. Meikle AW, Cardoso de Sousa JC, Ward JH, Woodward M, Samlowski WE. Reduction of testosterone synthesis after high dose interleukin-2 therapy of metastatic cancer. J Clin Endocrinol Metab 1991;73:931–5.[Abstract]
  43. Paradisi R, Capelli M, Mandini M, Bellavia E, Focacci M, Flamigni C. Interleukin-2 in seminal plasma of fertile and infertile men. Arch Androl 1995;35:35–41.[Medline]
  44. Purdue MP, Lan Q, Kricker A, et al. Polymorphisms in immune function genes and risk of non-Hodgkin lymphoma: findings from the New South Wales non-Hodgkin lymphoma study. Carcinogenesis. Epub 2006 Oct 20.
  45. Schweyer S, Soruri A, Peters J, Wagner A, Radzun HJ, Fayyazi A. Malignant germ cell tumours of the testis express interferon-{gamma}, but are resistant to endogenous interferon-{gamma}. Br J Cancer 2003;89:915–21.[Medline]
  46. Crawley E, Kay R, Sillibourne J, Patel P, Hutchinson I, Woo P. Polymorphic haplotypes of the interleukin-10 5' flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthritis Rheum 1999;42:1101–8.[CrossRef][Medline]
  47. Hulkkonen J, Pertovaara M, Antonen J, Lahdenpohja N, Pasternack A, Hurme M. Genetic association between interleukin-10 promoter region polymorphisms and primary Sjogren's syndrome. Arthritis Rheum 2001;44:176–9.[CrossRef][Medline]
  48. O'Bryan MK, Gerdprasert O, Nikolic-Paterson DJ, et al. Cytokine profiles in the testes of rats treated with lipopolysaccharide reveal localized suppression of inflammatory responses. Am J Physiol Regul Integr Comp Physiol 2005;288:R1744–55.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Cancer Res.Home page
M. P. Purdue, B. I. Graubard, S. J. Chanock, M. V. Rubertone, R. L. Erickson, and K. A. McGlynn
Genetic Variation in the Inhibin Pathway and Risk of Testicular Germ Cell Tumors
Cancer Res., April 15, 2008; 68(8): 3043 - 3048.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Purdue, M. P.
Right arrow Articles by McGlynn, K. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Purdue, M. P.
Right arrow Articles by McGlynn, K. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online