Risk Of Testicular Germ Cell Tumors Research Articles

Occupational exposure to organic solvents and the risk of developing testicular germ cell tumors (TESTIS study): Effect of combined exposure assessment on risk estimation.

Etiological factors of testicular germ cell tumors (TGCT) remain largely unknown, but a causal role of occupational exposures to solvents has been suggested. Previous studies analyzing these exposures reported discordant results, potentially related to exposure assessment methods. The aim of this study was to investigate the role of occupational exposure to solvents on the risk of developing TGCT among young men. This study examined occupational exposures to solvents and TGCT risk based on the lifetime work histories of 454 cases and 670 controls, aged 18-45 years, of the French national TESTIS case-control study. Solvent exposure was estimated using: (i) exposure assignment by job-exposure matrix (JEM) and (ii) JEM combined with self-reported exposure data from specific questionnaires (SQ) and expert assessment (EA). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression models. Both approaches (JEM and JEM+SQ+EA) showed a consistent association between TGCT and trichloroethylene exposure (exposed versus not exposed; JEM=OR 1.80 [95% confidence interval (CI) 1.12-2.90] and JEM+SQ+EA= OR 2.59 (95% CI 1.42-4.72). Both approaches also observed positive associations with ketone esters and fuels & petroleum-based solvents. The results suggest that some organic solvents might be involved in the pathogenesis of TGCT among occupationally exposed men. The combined use of JEM+SQ+EA seemed to limit misclassification by considering individual exposure variability and is, therefore, an appealing approach to assess occupational exposures in epidemiological studies.

A Case Report on Familial Testicular Germ Cell Tumour

Familial testicular germ cell tumours (FTGCT) are testicular germ cell tumours (TGCT) diagnosed in at least two blood relatives and account for 1-2% of all cases of TGCT. Brothers and fathers of TGCT patients have an 8-10 and 4-6-fold increased risk of TGCT, respectively. We report a case of testicular germ cell tumour in two siblings.

Mitochondrial metabolism-related signature depicts immunophenotype and predicts therapeutic response in testicular germ cell tumors.

In recent years, there has been growing evidence linking mitochondrial dysfunction to the development and progression of cancer. However, the role of mitochondrial metabolism-related genes (MMRGs) in testicular germ cell tumor (TGCT) remains unclear. We downloaded clinical pathology, transcriptome, and somatic mutation data for TGCT from public databases and conducted univariate Cox regression analysis to investigate prognostic correlations. We also used consensus clustering to identify molecular subtypes, comparing differential expression genes, biological processes, Kyoto Encyclopedia of Genes and Genomes pathways, mutations, prognosis, immune infiltration, drug sensitivity, and immune therapeutic response between these subtypes. We constructed multi-gene risk features and nomograms for TGCT prognosis. Fifteen MMRGs were significantly correlated with progression-free survival in TGCT patients. Based on these genes, we identified 2 molecular subtypes which showed significant differences in somatic mutations, prognosis, and immune cell infiltration. These subtypes could also indicate drug sensitivity and immune therapeutic response; the subtype with poor prognosis showed a higher potential benefit from some drugs and immunotherapy. Abnormalities in immune-related biological processes and extracellular matrix as well as Kyoto Encyclopedia of Genes and Genomes pathways such as PI3K-AKT signaling pathway, pat5hways in cancer, primary immunodeficiency, and neutrophil extracellular trap formation were associated with significant differences in phenotypes among subtypes. Finally, we constructed an 8-gene TGCT risk feature based on differential expression genes between subtypes which performed well in TGCT patient prognostic evaluation. Our study elucidated the prognostic correlation between MMRGs and TGCT and established MMRG-derived molecular subtypes and risk features for personalized treatment of TGCT which have potential clinical application value.

Prediagnostic Hormone Levels and Risk of Testicular Germ Cell Tumors: A Nested Case-Control Study in the Janus Serum Bank.

It has been hypothesized that poorly functioning Leydig and/or Sertoli cells of the testes, indicated by higher levels of serum gonadotropins and lower levels of androgens, are related to the development of testicular germ cell tumors (TGCT). To investigate this hypothesis, we conducted a nested case-control study within the Janus Serum Bank cohort. Men who developed TGCT (n = 182) were matched to men who did not (n = 364). Sex steroid hormones were measured using LC/MS. Sex hormone binding globulin, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were quantified by direct immunoassay. Multivariable logistic regression was used to calculate ORs and 95% confidence intervals (CI) for associations between hormone levels and TGCT risk. Higher FSH levels [tertile (T) 3 vs. T2: OR = 2.89, 95% CI = 1.83-4.57] were associated with TGCT risk, but higher LH levels were not (OR = 1.26, 95% CI = 0.81-1.96). The only sex steroid hormone associated with risk was androstane-3α, 17β-diol-3G (3α-diol-3G; OR = 2.37, 95% CI = 1.46-3.83). Analysis by histology found that increased FSH levels were related to seminoma (OR = 3.55, 95% CI = 2.12-5.95) but not nonseminoma (OR = 1.19, 95% CI = 0.38-3.13). Increased levels of 3α-diol-3G were related to seminoma (OR = 2.29, 95% CI = 1.35-3.89) and nonsignificantly related to nonseminoma (OR = 2.71, 95% CI = 0.82-8.92). Higher FSH levels are consistent with the hypothesis that poorly functioning Sertoli cells are related to the development of TGCT. In contrast, higher levels of 3α-diol-3G do not support the hypothesis that insufficient androgenicity is related to risk of TGCT. Clarifying the role of sex hormones in the development of TGCT may stimulate new research hypotheses.

Parental occupational exposure to solvents and risk of developing testicular germ cell tumors among sons: a French nationwide case-control study (TESTIS study).

The etiology of testicular germ cell tumors (TGCT) is suspected to be related to prenatal environmental risk factors. Some solvents have potential endocrine disrupting or carcinogenic properties and may disrupt male genital development in utero. The aim of this study was to examine the association between parental occupational exposure to solvents and TGCT risk among their offspring. A French nationwide case-control study, TESTIS included 454 TGCT cases and 670 controls frequency-matched on region and 5-year age strata. Participants were interviewed via telephone and provided information on parental occupations at birth. Job-exposure matrices (JEM) developed in the French Matgéné program were used to assign exposure to five petroleum-based solvents, five solvents or groups of oxygenated solvents, and five chlorinated solvents. Odds ratios (OR) for TGCT and 95% confidence intervals (CI) were estimated using conditional logistic regression, adjusting for TGCT risk factors. Occupational exposure to at least one solvent during the year of their son's birth was 41% among fathers and 21% among mothers. Paternal exposure to at least one solvent showed OR 0.89 (95% CI 0.68-1.15). Exposure to perchloroethylene (OR 1.41, 95% CI 0.55-3.61), methylene chloride (OR 1.13, 95% CI 0.54-2.34) and diesel/kerosene/fuel oil (OR 1.17, 95% CI 0.80-1.73) disclosed OR >1 but with low precision. Our results suggest a possible modest increase in non-seminoma risk for sons whose fathers were highly exposed to trichloroethylene (OR 1.44, 95% CI 0.79-2.63). Maternal exposure to at least one solvent showed OR 0.90 (95% CI 0.65-1.24). When stratifying by birth year, men born in the 1970s experienced an increased TGCT risk following maternal exposure to fuels and petroleum-based solvents (OR 2.74, 95% CI 1.11-6.76). Overall, no solid association was found between parental occupational exposure to solvents and TGCT risk. The association found with maternal occupational exposure to fuels and petroleum solvents among older men needs further investigation.

Testicular germ cell tumour risk by occupation and industry: a French case–control study – TESTIS

ObjectiveTesticular germ cell tumours (TGCT) are the most common cancer in men of working age and its incidence has increased notably over the past 40 years. Several occupations have been...

Military occupation and testicular germ cell tumour risk among US Air Force servicemen

ObjectivesTesticular germ cell tumours (TGCTs) are the most commonly diagnosed malignancy among active duty US military servicemen. Occupational risk factors may play a role in TGCT aetiology, although the evidence...

Occupation and risk of testicular cancer: A case‐control study in France

BACKGROUND AND AIM. Testicular germ cell tumors (TGCT) are the most frequently diagnosed cancer in young men and their incidence rate has increased dramatically in recent decades. Occupational factors may play a role in testicular cancer etiology. This study aimed to further explore the association between occupation, industry, and the risk of TGCT in adulthood in France. METHODS. The TESTIS study included 454 histologically confirmed TGCT cases at ages 18-45 years. Controls (N=670) were frequency-matched to cases on 5-year age group and region. Occupational histories, with detailed description of each job, were ascertained through telephone interviews. Occupations were coded according to ISCO68, and industrial sectors according to NAF99. A manual backward stepwise selection procedure was performed to select the covariates to be included in our analyses. Odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for potential confounders, were estimated using conditional logistic regression. RESULTS. An increased risk of TGCT was observed for "machine fitters, machine assemblers" and "electrical fitters, electrical and electronic " workers (ISCO: 8-41; adjusted-OR = 2.46; 95% CI [1.08-5.62]/ISCO: 8-5; adjusted-OR = 1.80; 95% CI [1.11-2.91], respectively). Analyses by industry supported these findings. Moreover, an increased TGCT risk (adjusted-OR = 1.71; 95% CI [1.02-2.82]) and non-seminoma risk (adjusted-OR = 2.12; 95% CI [1.11-4.04]) was identified for "agricultural and animal husbandry workers” (ISCO: 6-2). CONCLUSIONS. Our results suggest that occupational exposures may be associated with an increased risk of TGCT in agricultural, machine, and electrical/electronic workers in this population. Our findings were consistent with previously published studies. Since these jobs may involve exposure to a variety of potential carcinogens/endocrine disruptors, such as pesticides and solvents, complementary studies with the application of job-exposure matrices will allow an in-depth evaluation of the role of the substances involved in the high-risk professions identified. KEYWORDS. Occupation, epidemiology, testicular cancer, agriculture

A Nested Case-Control Study of Serum Per- and Polyfluoroalkyl Substances and Testicular Germ Cell Tumor Risk in U.S. Air Force Personnel

A Nested Case-Control Study of Serum Per- and Polyfluoroalkyl Substances and Testicular Germ Cell Tumor Risk in U.S. Air Force Personnel

Genetics of testicular cancer: a review.

Testicular germ cell tumours (TGCTs) are the most common solid malignant cancer diagnosed in young males and the incidence is increasing. Understanding the genetic basis of this disease will help us to navigate the challenges of early detection, diagnosis, treatment, surveillance, and long-term outcomes for patients. TGCTs are highly heritable. Current understanding of germline risk includes the identification of one moderate-penetrance predisposition gene, checkpoint kinase 2 ( CHEK2 ), and 78 low-to-moderate-risk single nucleotide polymorphisms identified in genome-wide-associated studies, which account for 44% of familial risk. Biomarker research in TGCTs has been challenging for multiple reasons: oncogenesis is complex, actionable mutations are uncommon, clonal evolution unpredictable and tumours can be histologically and molecularly heterogeneous. Three somatic mutations have thus far been identified by DNA exome sequencing, exclusively in seminomas: KIT, KRAS and NRAS . Several genetic markers appear to be associated with risk of TGCT and treatment resistance. TP53 mutations appear to be associated with platinum resistance. MicroRNA expression may be a useful biomarker of residual disease and relapse in future. The biology of testicular germ cells tumours is complex, and further research is needed to fully explain the high heritability of these cancers, as well as the molecular signatures which may drive their biological behaviour.

Association Study between Polymorphisms in DNA Methylation-Related Genes and Testicular Germ Cell Tumor Risk.

Testicular germ cell tumors (TGCT), histologically classified as seminomas and nonseminomas, are believed to arise from primordial gonocytes, with the maturation process blocked when they are subjected to DNA methylation reprogramming. SNPs in DNA methylation machinery and folate-dependent one-carbon metabolism genes have been postulated to influence the proper establishment of DNA methylation. In this pathway-focused investigation, we evaluated the association between 273 selected tag SNPs from 28 DNA methylation-related genes and TGCT risk. We carried out association analysis at individual SNP and gene-based level using summary statistics from the Genome Wide Association Study meta-analysis recently conducted by the international Testicular Cancer Consortium on 10,156 TGCT cases and 179,683 controls. In individual SNP analyses, seven SNPs, four mapping within MTHFR, were associated with TGCT risk after correction for multiple testing (q ≤ 0.05). Queries of public databases showed that three of these SNPs were associated with MTHFR changes in enzymatic activity (rs1801133) or expression level in testis tissue (rs12121543, rs1476413). Gene-based analyses revealed MTHFR (q = 8.4 × 10-4), methyl-CpG-binding protein 2 (MECP2; q = 2 × 10-3), and ZBTB4 (q = 0.03) as the top TGCT-associated genes. Stratifying by tumor histology, four MTHFR SNPs were associated with seminoma. In gene-based analysis MTHFR was associated with risk of seminoma (q = 2.8 × 10-4), but not with nonseminomatous tumors (q = 0.22). Genetic variants within MTHFR, potentially having an impact on the DNA methylation pattern, are associated with TGCT risk. This finding suggests that TGCT pathogenesis could be associated with the folate cycle status, and this relation could be partly due to hereditary factors.

Proximity to endocrine-disrupting pesticides and risk of testicular germ cell tumors (TGCT) among adolescents: A population-based case-control study in California.

The incidence of testicular germ cell tumors (TGCT) is increasing steadily in the United States, particularly among Latinos. TGCT is thought to be initiated in utero and exposure to endocrine-disrupting chemicals, suspected contributors to TGCT pathogenesis, during this critical developmental period may contribute to the rise. To assess the relationship between fetal exposure to agricultural endocrine-disrupting pesticides (EDPs) and TGCT risk among adolescents in a diverse population in California. We conducted a registry-based case-control study of TGCT. Cases, diagnosed between 1997 and 2011, were 15-19 years of age (n=381). Controls were matched on birth year and race/ethnicity (n=762). Quantities (kilograms) of 33 pesticides applied within 3 km and 1 km radii of each individual's address before birth were estimated using the Pesticide Use Reporting database. Odds ratios (OR), 95% confidence intervals (CI), and population attributable risk (PAR) were calculated for each EDP (using log-2 transformed values). Risk models considered race/ethnicity, birth year, and neighborhood socioeconomic status. A doubling of nearby acephate applications (3km and 1km radii) and malathion applications (1km radius) was associated with increased risks of TGCT among Latinos only (OR=1.09; 95% CI:1.01-1.17; 1.30; 95% CI:1.08-1.57, and 1.19; 95% CI:1.01-1.39, respectively), whereas application of carbaryl within a 3km radius increased TGCT risk in non-Latinos only (OR=1.14, 95% CI:1.01-1.28). We estimate that acephate was associated with approximately 10% of the TGCT PAR, malathion with 3% and carbaryl with 1%. TGCT among adolescents in California was associated with prenatal residential proximity to acephate and malathion among Latinos, and with carbaryl among non-Latinos. These results suggest that the rise in TGCT risk among Latinos may be associated with exposure to these pesticides.

Parental occupational exposures in wood-related jobs and risk of testicular germ cell tumours in offspring in NORD-TEST a registry-based case–control study in Finland, Norway, and Sweden

ObjectiveWe assessed the association between parental prenatal exposures in wood-related jobs and risk of testicular germ cell tumours (TGCT) in offspring.MethodsNORD-TEST, a registry-based case–control study in Sweden, Finland and Norway, included 8112 TGCT cases diagnosed at ages 14–49 years between 1978 and 2012 with no history of prior cancer, and up to four controls matched to each case on year and country of birth. Parents of cases and controls were identified via linkages with the population registries and their occupational information was retrieved from censuses. The Nordic Occupational Cancer Study Job-Exposure Matrix was used to assign occupational exposures to each parent. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI).ResultsMaternal wood-related job was not associated with the risk of TGCT in offspring (OR 1.08, CI 0.55–2.14), while paternal wood-related job was associated with a decreased risk of TGCT in offspring (OR 0.85, CI 0.75–0.96). None of the specific wood-related jobs, such as upholsterers, sawyers, or construction carpenters, were significantly associated with a risk of TGCT. Only exception was observed in a sensitivity analysis which showed an increased risk in the small group of sons of fathers working as ‘cabinetmakers and joiners’ the year before conception (OR of 2.06, CI 1.00–4.25).ConclusionThis large-scale NORD-TEST analysis provided no evidence of an association between parental prenatal exposures in wood-related jobs and TGCT in sons.

Identification of 22 susceptibility loci associated with testicular germ cell tumors

Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95th percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation.

Genetically Inferred Telomere Length and Testicular Germ Cell Tumor Risk.

Studies evaluating the association between peripheral blood leukocyte telomere length (LTL) and testicular germ cell tumor (TGCT) risk have produced conflicting results. Using available genotype data from the Testicular Cancer Consortium (TECAC), polygenic risk score and Mendelian randomization analyses of genetic variants previously associated with LTL were used to assess potential etiologic associations between telomere length and TGCT risk. Genetically inferred telomere length was not associated with TGCT risk among 2,049 cases and 6,921 controls with individual-level genotype data (OR, 1.02; 95% confidence interval, 0.97-1.07). Mendelian randomization analyses using summary statistic data further indicated no evidence for an association between telomere length and TGCT risk among all available TECAC participants (3,558 cases and 13,971 controls). Our analyses in the largest molecular genetic testicular cancer study to date provide no evidence for an association between genetically inferred peripheral blood LTL and TGCT risk. The lack of evidence for an overall association indicates that peripheral blood LTL is likely not a strong biomarker for TGCT risk.

Serum polychlorinated biphenyl (PCB) levels and risk of testicular germ cell tumors: A population-based case-control study in Connecticut and Massachusetts.

The incidence rate of testicular germ cell tumors (TGCT) has continuously increased in Western countries over the last several decades. Some epidemiologic studies have reported that the endocrine disrupting polychlorinated biphenyls (PCBs) in serum may be associated with TGCT risk, but the evidence is inconsistent. Our goal was to investigate whether serum levels of PCBs are associated with the increase of TGCT risk. We conducted a population-based case-control study of 308 TGCT cases and 323 controls, all residents of Connecticut and Massachusetts. Serum levels of 56 PCBs congeners were measured using gas chromatography and unconditional logistic regression model was used to evaluate the risk of TGCT associated with total PCBs exposure, groups of PCBs categorized by Wolff's functional groups, and individual PCB congeners. The results showed that there was no association between total serum levels of PCBs and risk of TGCT overall (quartile 4 (Q4) vs. quartile 1 (Q1) odds ratio (OR) and 95% confidence interval (C.I.)=1.0 (0.6-1.9), ρ trend=0.9). However, strong positive association was observed between total serum levels of Wolff's Group 1 (potentially estrogenic) PCBs and risk of overall TGCT (Q4 vs. Q1 OR=2.5, 95% CI=1.3-4.7, ρ trend <0.05) as well as seminoma and non-seminoma subtypes. Wolff's Group 1 PCB congeners that showed an increased risk of TGCT included: 25, 44, 49, 52, 70, 101, 174, and 201/177. Considering the continuing increase of TGCT, these associations should be replicated in different populations with larger sample size.

Abstract PO-125: Prenatal proximity to agricultural use of endocrine-disrupting pesticides and risk of testicular germ cell tumor (TGCT) among Latino and non-Latino adolescents in California

Abstract BACKGROUND. Incidence of testicular germ cell tumors (TGCTs) has increased steadily in the United States in recent years, especially among Latinos. TGCT initiation is believed to occur during fetal development and to be related to endocrine disruption; the increasing prevalence of in utero exposures to endocrine- disrupting chemicals may have contributed to the rise in the disease’s incidence. METHODS. This registry-based case-control study included 381 California-born patients diagnosed with TGCT at age 15-19 years from 1997-2011 (336 non- seminomas, 41 seminomas) and 762 controls matched on birth year and race/ethnicity. We assessed the agricultural application of 22 endocrine-disrupting pesticides (EDPs) using California’s Pesticide Use Reporting (PUR) database for an area within a 3km radius of participants’ birth address in the year prior to birth; 15 high-volume EDPs (those to which 50 or more participants were potentially exposed) were included in statistical analyses. We used logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for log2-transformed continuous pesticide levels, and to calculate attributable risk (AR) for dichotomous exposure (zero and low application vs. high application). Analyses accounted for the timing of pesticide application, histologic subtype, race/ethnicity, birth year, and neighborhood socioeconomic status (SES). RESULTS. Overall, 48% of cases and 45% of controls lived within 3km of an EDP application in the year before birth. Nearby pesticide applications were greater among Latinos than non-Latinos for 13 of 15 EDPs; the median [interquartile range (IQR)] for total EDP application was 29 kg [5- 135] vs. 11 kg [1-80]. Application was also greater for those born after 1990 (the period of time with complete PUR reporting) than before 1990 for 14 of 15 EDPs (median [IQR] for total EDP application: 54 kg [10-229] vs. 13 kg [0.7-70]). Analyses of individual EDPs showed an increased risk of TGCT associated with acephate (OR [95%CI]: 1.1 [1.0-1.2] and 1.3 [1.0-1.7] for continuous and binary exposures, respectively). In analyses stratified by ethnicity, risk remained elevated for acephate application among Latinos (n=614, OR [95% CI] for continuous exposure model: 1.1 [1.0-1.2]) and for carbaryl and copper sulfate in non-Latinos (n=504, OR [95% CI]: 1.2 [1.0-1.3] and 1.1 [1.0-1.3], respectively). Overall there were no differences by PUR reporting period (before and after 1990) and application timing (preconception and trimesters), yet risk appeared to be higher for non-seminomas and among high SES participants. The population AR for high levels of acephate was 5.4% among Latinos, and &amp;lt;1% prior to 1990 vs. 10% after 1990 for all subjects combined. In non-Latinos, the AR for carbaryl was 4.8% and 2.5% for copper sulfate. CONCLUSIONS. Acephate, an organophosphate insecticide, was associated with an increased TGCT risk, possibly contributing 5-10% to the prevalence of TGCT among Latinos in California. Citation Format: Scott J. Swartz, Libby Morimoto, Todd Whitehead, Robert Gunier, Joseph Wiemels, Xiaomei Ma, Catherine Metayer. Prenatal proximity to agricultural use of endocrine-disrupting pesticides and risk of testicular germ cell tumor (TGCT) among Latino and non-Latino adolescents in California [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-125.

Lower abdominal and pelvic radiation and testicular germ cell tumor risk.

BackgroundTesticular germ cell tumor (TGCT) incidence has increased in recent decades along with the use and dose of diagnostic radiation. Here we examine the association between reported exposure to diagnostic radiation and TGCT risk.MethodsWe conducted a case-control study of men with and without TGCT recruited from hospital- and population-based settings. Participants reported on exposures to 1) x-ray or CT below the waist and 2) lower GI series or barium enema, which consists of a series of x-rays of the colon. We also derived a combined measure of exposure. We used logistic regression to determine the risk of developing TGCT according to categories of exposures (0, 1–2, or ≥3 exposures) and age at first exposure, adjusting for age, year of birth, race, county, body mass index at diagnosis, family history of TGCT, and personal history of cryptorchidism.ResultsThere were 315 men with TGCT and 931 men without TGCT in our study. Compared to no exposures, risk of TGCT was significantly elevated among those reporting at least three exposures to x-ray or CT (OR≥3 exposures, 1.78; 95% CI, 1.15–2.76; p = 0.010), lower GI series or barium enema (OR≥3 exposures, 4.58; 95% CI, 2.39–8.76; p<0.001), and the combined exposure variable (OR≥3 exposures, 1.59; 95% CI, 1.05–2.42; p = 0.029). The risk of TGCT was elevated for those exposed to diagnostic radiation at age 0–10 years, compared to those first exposed at age 18 years or later, although this association did not reach statistical significance (OR, 2.00; 95% CI, 0.91–4.42; p = 0.086).ConclusionsExposure to diagnostic radiation below the waist may increase TGCT risk. If these results are validated, efforts to reduce diagnostic radiation doses to the testes should be prioritized.

Serum polychlorinated biphenyl (PCB) levels and risk of testicular germ cell tumors: a population-based case-control study in Connecticut and Massachusetts

Background: The incidence of testicular germ cell tumors (TGCT) has continuously increased in Western countries over the last few decades. Some epidemiologic studies have reported that serum levels of endocrine disrupting polychlorinated biphenyls (PCBs) may be associated with TGCT risk, but the evidence is inconsistent.Methods: To evaluate whether serum levels of PCBs are associated with TGCT risk, we conducted a population-based case-control study of 308 TGCT cases and 323 controls, all residents of Connecticut and Massachusetts. Serum levels of 56 PCB congeners were measured using gas chromatography and unconditional logistic regression was used to evaluate associations with TGCT risk for concentrations of total PCBs, groups of PCBs categorized by functional characteristics, and individual PCB congeners.Results: There was no association between total serum levels of PCBs and risk of TGCT overall (quartile 4 (Q4) vs. quartile 1 (Q1) odds ratio (OR) and 95% confidence interval (C.I.) = 1.0 (0.6-1.9), ρ trend = 0.9). However, strong positive association was observed between total serum levels of Wolff Group 1 (potentially estrogenic) PCBs and risk of overall TGCT (Q4 vs. Q1 OR = 2.5, 95% CI = 1.3-4.7, ρ trend &lt;0.05) as well as seminoma and non-seminoma subtypes. Wolff Group 1 PCB congeners that showed an increased risk of TGCT included: 25, 44, 49, 52, 70, 101, 174, and 201/177.Conclusion: We found an increased risk of TGCT associated with Wolff Group 1 PCBs and specific PCB congeners. Considering the continuing increase of TGCT, these associations should be replicated in larger studies.

Abstract 1203: Identification of 22 novel loci associated with susceptibility to testicular germ cell tumors

Abstract Background: Testicular germ cell tumors (TGCT) are the most common cancers in young men of European ancestry aged 20 to 39 years. The incidence of TGCT has doubled over the past 20 years, yet no robust environmental risk factors for disease have been identified. Although TGCTs are treatable by surgery, radiation, and platinum-based chemotherapy, multiple long-term toxicities of treatment often occur impacting morbidity and mortality. Due to their high heritability and homogenous cell of origin, TGCTs are well suited to genome-wide association methods. The Testicular Cancer Consortium (TECAC) has brought together the largest genome-wise association study (GWAS) study of TGCT to date. Methods: We conducted a GWAS of 5,602 cases and 5,006 controls aggregated from 12 locations in the US and Europe. Logistic regression models adjusted for study center and genomic ancestry. Genotypes were imputed against the Human Haplotype Reference Consortium. Meta-analysis was performed to combine GWAS results with summary statistics from five previously published TGCT studies, UK Biobank, deCODE Genetics, and an independent set of cases and controls, for a total of 10,156 cases and 179,683 controls. Biologic function of loci was explored using PAINTOR annotated with ATAC-seq data of four TGCT cell lines, SPATIAL-seq data of the NTERA2 TGCT cell-line, and publicly available data from ENCODE. Polygenic risk scores (PRS) were computed using subject-level data from the 5,602 cases and 5,006 controls, and effect sizes of the novel hits derived from the meta-analysis. Results: 22 novel and 45 previously reported loci associated with TGCT surpassed genome-wide significance (p &amp;lt; 5e-08). We discovered additional markers in known susceptibility loci and identified novel regions associated with germ cell development and sex determination (e.g., BCL11, AR), immune function (e.g., TNXB, ITIH5), and for the first time identified genes associated with kinetochore activity (e.g., PPP2R5A, ANAPC2). All identified risk SNPs to date account for 42.3% of heritability. Men in the highest 1% of PRS had over a 15-fold increased risk of TGCT compared to those at the median PRS, and PRS overall had an AUC of 74.29%. Conclusions: Results from our TGCT meta-analysis continue to provide insights into biological pathways affecting germ cell specification, expression, and epigenetic reprogramming, and sex determination. Our results also uniquely place TGCT as the only cancer type in which inherited variants implicating kinetochore activity, critical for chromosomal segregation, have been identified. Citation Format: John Pluta, Louisa Pyle, Timothy Bishop, Javier Benitez, Victoria Cortessis, Alberto Ferlin, Jourik Gietema, Mark Greene, Thomas Grotmol, Ramneek Gupta, Robert Hamilton, Michelle Hildebrandt, Lambertus Kiemeney, Davor Lessel, Thorunn Rafnar, Lorenzo Richiardi, Rolf Skotheim, Clare Turnbull, Fredrik Wiklund, Tongzhang Zheng, Ewa Rajpert- De Meyts, Stephen Schwartz, Katherine McGlynn, Peter Kanetsky, Katherine Nathanson. Identification of 22 novel loci associated with susceptibility to testicular germ cell tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1203.