Ralph L. Erickson

Perinatal factors and the risk of testicular germ cell tumors.

Testicular germ cell tumors (TGCT) are the most common cancer among young men in the United States and Western Europe. Prior evidence suggests that TGCT may arise in perinatal life, although few risk factors have yet been identified. To study the etiology of TGCT, the US Servicemens Testicular Tumor Environmental and Endocrine Determinants (STEED) case‐control study enrolled participants and their mothers between 2002 and 2005. Five hundred twenty‐seven mothers of cases and 561 mothers of controls provided information on perinatal variables. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95%CI) associated with the candidate risk factors. Analyses were conducted for all TGCT together and for each histologic subgroup (seminoma and nonseminoma) separately. Young maternal age (<20 vs. 20–29 years, OR = 1.51, 95%CI: 1.09–2.10), young paternal age (<25 vs. 25–29 years, OR = 1.45, 95%CI: 1.08–1.94), maternal parity (3 vs. 1, OR = 0.63, 95%CI: 0.44–0.90) and breech birth (OR = 1.92, 95%CI: 1.03–3.56) were associated with risk of TGCT. For seminoma, young maternal age (<20 vs. 20–29 years, OR = 1.67, 95%CI: 1.10–2.54), young paternal age (<25 vs. 25–29 years, OR = 1.53, 95%CI: 1.03–2.27), maternal parity (3 vs. 1, OR = 0.58, 95%CI: 0.35–0.96) and low birth weight (<2,500 g vs. 2,500–4,000 g, OR = 1.82, 95%CI: 1.00–3.30) were risk factors. Nonseminoma was associated with breech birth (OR = 2.44, 95%CI: 1.25–4.78) and Cesarean section (OR = 2.10, 95%CI: 1.25–3.54). These results support the hypothesis that TGCT may originate in very early life.

Polychlorinated Biphenyls and Risk of Testicular Germ Cell Tumors

Exposure to endocrine-disrupting chemicals, such as polychlorinated biphenyls (PCB), may alter hormonal balance and thereby increase risk of testicular germ cell tumors (TGCT). To study the relationship of PCBs to TGCT, prediagnostic serum samples from 736 cases and 913 controls in the Servicemens Testicular Tumor Environmental and Endocrine Determinants study were analyzed. Adjusted odds ratios and 95% confidence intervals were estimated using logistic regression. PCB levels were examined in association with all TGCT and, separately, with each histologic type (seminoma and nonseminoma). Risks associated with seven functional groupings of PCBs, as well as sum of PCBs, were also examined. There were significantly decreased risks of TGCT in association with eight PCBs (PCB-118, PCB-138, PCB-153, PCB-156, PCB-163, PCB-170, PCB-180, and PCB-187) and no association with the remaining three (PCB-99, PCB-101, and PCB-183). The same eight congeners were significantly associated with decreased risk of nonseminoma, whereas five (PCB-138, PCB-153, PCB-156, PCB-163, and PCB-170) were associated with decreased risk of seminoma. All functional groupings of PCBs were also associated with decreased risk of TGCT and of nonseminoma, whereas six of the seven functional groups were associated with decreased risk of seminoma. Sum of PCBs was significantly associated with decreased risk of TGCT (P(trend) = 0.006), nonseminoma (P(trend) = 0.007), and seminoma (P(trend) = 0.05). Overall, these data do not support the hypothesis that PCB exposure increases the risk of TGCT.

Maternal Smoking and Testicular Germ Cell Tumors

Testicular germ cell tumors (TGCT) are the most common cancer among men ages 15 to 35 years in the United States. The well-established TGCT risk factors cryptorchism, prior diagnosis of TGCT, and family history of testicular cancer indicate that exposures in early life and/or in the familial setting may be critical to determining risk. Previous reports of familial clustering of lung cancer in mothers and testicular cancers in sons suggest that passive smoking in childhood may be such an exposure. To clarify the relationship of passive smoking exposure to TGCT risk, data from 754 cases and 928 controls enrolled in the Servicemens Testicular Tumor Environmental and Endocrine Determinants study were analyzed. Data from 1,086 mothers of the cases and controls were also examined. Overall, there was no relationship between maternal [odds ratio (OR), 1.1; 95% confidence interval (95% CI), 0.9-1.3] or paternal smoking (OR, 1.0; 95% CI, 0.8-1.3) and TGCT risk. Although living with a nonparent smoker was marginally related to risk (OR, 1.4; 95% CI, 1.0-2.1), there was no relationship with number of smokers, amount smoked, or duration of smoking. Responses from both case-control participants and mothers also revealed no relationship between either maternal smoking while pregnant or while breast-feeding. Results did not differ by TGCT histology (seminoma, nonseminoma). These results do not support the hypothesis that passive smoking, either in utero or in childhood, is related to risk of TGCT. Other early life exposures, however, may explain the familial clustering of lung cancer in mothers and TGCT in sons. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1820–4)

Risk of cancer in first- and second-degree relatives of testicular germ cell tumor cases and controls

Risk factors for testicular germ cell tumors (TGCT) have not been well identified; however, data suggest that risks of cancer in family members of men with TGCT is elevated. Using family history data from 738 cases and 904 controls enrolled in the U.S. Servicemens Testicular Tumor Environmental and Endocrine Determinants (STEED) Study from 2002 to 2005, the risk of cancer in first‐ and second‐degree family members of these men was examined. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, adjusting for reference age of case or control, race/ethnicity of case or control, sex of family member and lineage (maternal vs. paternal). An increased risk of all cancer among first‐degree relatives of cases compared to controls was observed (RR = 1.17, 95% CI: 1.01–1.35). There were suggestions of differences in risk when stratifying all relatives by lineage. For maternal relatives, there was a statistically significant increased risk of all cancer (RR = 1.16, 95% CI: 1.04–1.30), digestive tract (RR = 1.52, 95% CI: 1.15–2.00) and male genital organ cancer (RR = 1.70, 95% CI: 1.15–2.51); there was also a suggestion of increased risks of hematopoetic cancers, cancers in the female genital organs and nonmelanoma skin cancer. For paternal relatives, there was a statistically significant association only with decreased risk of lung cancer (RR = 0.69, 95% CI: 0.51–0.94). Thus, this study suggests that there may be aggregation of cancer among families of men diagnosed with TGCT. Published 2008 Wiley‐Liss, Inc.

Genetic Variation in the Inhibin Pathway and Risk of Testicular Germ Cell Tumors

Gene-knockout studies in mice suggest that INHA, encoding a subunit of gonadotropin-regulating proteins known as inhibins, is a tumor suppressor for testicular stromal cell tumors. It is not known whether genetic variation in the inhibin pathway also influences susceptibility to testicular germ cell tumors (TGCT), the most common testicular cancer in young men. To address this question, we conducted a case-control analysis (577 cases; 707 controls) of single-nucleotide polymorphisms (SNP) in genes in the inhibin pathway among participants in the U.S. Servicemens Testicular Tumor Environmental and Endocrine Determinants Study. Thirty-eight tagging SNPs in six genes (INHA, INHBA, INHBB, INHBC, INHBE, and SMAD4) were genotyped. Odds ratios (OR) and 95% confidence intervals (CI) relating variant genotypes to TGCT risk were calculated using unconditional logistic regression. Among White subjects, an elevated risk of TGCT was observed for carriers of the T allele of the INHA variant rs2059693 (CT genotype: OR, 1.33; 95% CI, 1.04-1.71; TT: OR, 1.60; 95% CI, 1.01-2.52; P(trend) = 0.008). The association with rs2059693 was stronger for nonseminomas, and for teratomas and teratocarcinomas in particular (N = 58; CT: OR, 1.63; 95% CI, 0.89-2.99; TT: OR, 4.54; 95% CI 2.00-10.3; P(trend) = 0.0008). We found no evidence of association with variants in the other investigated genes. These findings suggest that genetic variation in the INHA locus influences TGCT development.

Sexual functioning among testicular cancer survivors: A case–control study in the U.S.

OBJECTIVE Sexual function among testicular cancer survivors is a concern because affected men are of reproductive age when diagnosed. We conducted a case-control study among United States military men to examine whether testicular cancer survivors experienced impaired sexual function. METHODS A total of 246 testicular cancer cases and 236 ethnicity and age matched controls were enrolled in the study in 2008-2009. The Brief Male Sexual Function Inventory (BMSFI) was used to assess sexual function. RESULTS Compared to controls, cases scored significantly lower on sex drive (5.77 vs. 5.18), erection (9.40 vs. 8.63), ejaculation (10.83 vs. 9.90), and problem assessment (10.55 vs. 9.54). Cases were significantly more likely to have impaired erection (OR 1.72; 95% CI 1.11-2.64), ejaculation (OR 2.27; 95% CI 1.32-3.91), and problem assessment (OR 2.36; 95% CI 1.43-3.90). In histology and treatment analysis, nonseminoma, chemotherapy and radiation treated cases risk of erectile dysfunction, delayed ejaculation, and/or problem assessment were greater when compared to controls. CONCLUSION This study provides evidence that testicular cancer survivors are more likely to have impaired sexual functioning compared to demographically matched controls. The observed impaired sexual functioning appeared to vary by treatment regimen and histologic subtype.

Insulin-like Growth Factor 1, Insulin-like Growth Factor-Binding Protein 3, and Testicular Germ-Cell Tumor Risk

Studies have consistently shown that taller men are at increased risk of testicular germ-cell tumors. Thus, it is plausible that factors associated with height may also influence risk of these tumors. The authors examined associations between testicular germ-cell tumor risk and circulating concentrations of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3) among 517 cases and 790 controls from the US Servicemens Testicular Tumor Environmental and Endocrine Determinants (STEED) Study (2002-2005). Odds ratios and 95% confidence intervals were estimated using logistic regression models, adjusting for age, race/ethnicity, height, and body mass index. All tests of significance were two-sided. Overall, there were no associations between IGF-1 or IGFBP-3 concentrations and risk of testicular germ-cell tumors (p > 0.05). However, when cases were separated by histologic type, there was a suggestion of a reduction in seminoma risk associated with the highest concentrations of IGF-1 as compared with the lowest concentrations (odds ratio = 0.66, 95% confidence interval: 0.40, 1.09). Although there were no overall associations with insulin-like growth factor, contrary to expectation, there was a suggestion that IGF-1 concentrations may be inversely associated with risk of seminoma.

Risk of Testicular Germ Cell Tumors and Polymorphisms in the Insulin-Like Growth Factor Genes

Because taller men are at increased risk of developing testicular germ cell tumors (TGCT), it is conceivable that factors that influence adult height could be related to risk of TGCT. Because common genetic variation in genes of the insulin-like growth factor (IGF) pathway could influence somatic growth, 43 single nucleotide polymorphisms in four IGF genes (IGF-1, IGF-1R, IGF-2, and IGFALS) were genotyped in 577 case and 707 control participants from the U.S. Servicemens Testicular Tumor Environmental and Endocrine Determinants Study to assess relationships with TGCT risk; additionally, associations between polymorphisms and adult height were examined. Relationships between polymorphisms and adult height were assessed using adjusted linear regression models, and associations between polymorphisms and TGCT risk were determined by adjusted logistic regression models estimating odds ratios. Although four IGF-1R polymorphisms (rs907806, rs3743258, rs229765, and rs9282714) were associated with height (Ptrend < 0.05), there were no relationships with any other polymorphism. Overall, there were no associations among polymorphisms or haplotypes in the IGF genes and TGCT risk, with odds ratios ranging from 0.55 to 1.50. Similarly, there was no association among the polymorphisms and risk of specific TGCT histologies (seminoma and nonseminoma). There was a suggestion, however, that adult height may modify the relationship between an IGF-1 haplotype and TGCT risk. These results suggest that, in aggregate, genetic variation in IGF loci is not associated with TGCT risk. (Cancer Epidemiol Biomarkers Prev 2008;17(3):721–6)

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

BACKGROUND Research 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. AIM To evaluate associations between 2D:4D digit ratio, right minus left 2D:4D (ΔR-L), and left-hand dominance and TGCT in the U.S. Servicemens Testicular Tumor Environmental and Endocrine Determinants Study. METHODS A 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. RESULTS Right 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. CONCLUSIONS These 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.

Trends in testicular germ cell tumors among U.S. military servicemen, 1990-2003.

OBJECTIVE To determine the incidence of testicular germ cell tumors among active duty males and compare it with the incidence in the general U.S. population. METHODS The Automated Cancer Tumor Registry and the Surveillance, Epidemiology, and End Results Program data from 1990 to 2003 were analyzed for men aged between 20 and 59 years by histology and stage at diagnosis. Rates were age adjusted using the male active duty military population as the standard. RESULTS Nonseminoma incidence was significantly lower in the military than in the general population (incidence rate ratio = 0.90, 95% confidence interval = 0.82-0.98). Trends in incidence tended to be similar in both the populations. Increases were observed for both histologic types but were only significant for seminoma (Automated Cancer Tumor Registry: 21% and Surveillance, Epidemiology, and End Results program: 16%; p < 0.05). Increases in incidence were only observed for localized tumors of both histologic types. CONCLUSIONS The lower incidence of nonseminoma in the military and the increased incidence of localized tumors in both populations remain unexplained.