The Epidemiology and Genetics of Sporadic and Hereditary Testicular Germ Cell Tumors

David J. Vaughn

Peter A. Kanetsky

Katherine L. Nathanson

INTRODUCTION TO TESTICULAR GERM CELL TUMORS

Biology of Testicular Germ Cell Tumors

Germ cell tumors (GCTs) are the most common solid tumor in men between the ages of 15 and 35 years. Approximately 90% of GCT arise in the testicle (and are thus called testicular GCT [TGCT] or “testicular cancer”). Approximately 10% of GCT are extragonadal, arising in the mediastinum or retroperitoneum. Ninety-five percent of testicular neoplasms are GCT, with the remainder non-germ cell neoplasms such as sex cord stromal tumors or lymphoma. TGCT are classified as classic or pure seminomas (about 55% of new cases); nonseminomatous GCT, which contains any of the nonseminomatous histologies including embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma (about 44% of new cases); and spermatocytic seminomas (about 1% of new cases). This chapter addresses the epidemiology and genetics of sporadic and hereditary TGCT.

Most TGCT (the exception is spermatocytic seminoma) are derived from testicular intratubular germ cell neoplasia undifferentiated (ITGCNU), also referred to as carcinoma in situ. Testicular ITGCNU likely arises from the fetal gonocyte that has not undergone normal differentiation. The transformation of the gonocyte to ITGCNU occurs early in fetal development. The factors that influence the development of ITGCNU and the subsequent transformation of ITGCNU to TGCT have not been fully elucidated. Clearly, both genetic factors and environmental factors must play an important role in this process.

TGCT Incidence

In 2010, an estimated 8,480 American men will be diagnosed with TGCT, resulting in 350 deaths (http://ww2.cancer.org/downloads/STT/Cancer_Facts_and_Figures_2010.pdf). For reasons not well understood, the incidence of GCT is increasing. Despite the increasing incidence, there has been a remarkable decrease in mortality from GCT. This decrease is in large part related to the development of cisplatin-based chemotherapy for patients with metastatic disease, most of whom will become long-term survivors of this disease.

There is a striking geographical variation in the incidence of GCT. The highest reported incidence is in Scandinavia, Switzerland, and Germany. The lowest is in Africa and Asia. The United States is intermediate. For example, in Denmark, the incidence is 9.2/100,000, whereas in Egypt, the incidence is 0.5/100,000 (1). There is a higher incidence of GCT in countries with greater economic development. The geographic and socioeconomic variation in GCT incidence is in part because most men diagnosed with this disease are white. In the United States, there is a striking disparity in the incidence of TGCT between white and black men. However, a recent study based upon the SEER database demonstrated that the incidence of TGCT in black men in the United States increased 100% from 1973 to 2001, with the incidence of seminoma increasing twice as much as nonseminoma (124% and 64%, respectively) (2).

EPIDEMIOLOGY OF TESTICULAR GERM CELL TUMORS

Medical Conditions Associated with TGCT

Undescended Testis

Undescended testis (UDT), also called cryptorchidism (“hidden testicle”), is the most common congenital birth defect in men that occurs in 2 to 4 per 100 male births (3,4). This condition is a strong and robust risk factor for TGCT. A meta-analysis of 20 case-control studies undertaken between 1976 and 2003 found a near fivefold risk (pooled odds ratio [OR] = 4.8, 95% CI 4.0, 5.7) associated with UDT (5). Subsequent case-control studies, however, have found slightly attenuated odds of UDT in the range of three- to fourfold. (6,7) Further, two recent large cohort studies among men with UDT demonstrated slightly lower risk estimates (relative risk [RR] = 2.75, 95% CI 2.08, 3.57 and RR = 3.71, 95% CI 3.29, 4.19) of developing TGCT (8,9).

Given the striking disparity in incidence of TGCT between white and black men in the United States, one might also expect to find a similar disparity in the occurrence of UDT. However, this is not the case. Rates of UDT were found to be more similar than TGCT rates in these groups, leading some researchers to posit that the strong link between UDT and TGCT observed among white men is attenuated among black men, and thus UDT cannot greatly account for the observed cancer disparity (10).

The degree to which UDT predisposes to TGCT or whether UDT shares a common genetic or environmental etiology with TGCT (see Testicular Dysgenesis Syndrome [TDS]) remains a point of continued scientific discussion. An indication of the underlying mechanism can be inferred from studies investigating the association between laterality of UDT and laterality of TGCT. A recent meta-analysis of 1 cohort and 11 case-control studies indicates a substantial risk of TGCT to the UDT itself (pooled RR = 6.33, 95% CI 4.30, 9.31) and a more modest
risk of TGCT to the contralateral testis (pooled RR = 1.74, 95% CI 1.01, 2.98) (11). The strong risk for ipsilateral disease supports the concept that the physical location of the UDT mediates risk of disease and that UDT is an intermediate on the causal pathway for TGCT; however, the notion of a common factor mediating risk in both testes, possibly from prenatal exposures, is supported—perhaps only weakly—by the increased risk of contralateral disease.

Age at surgical correction of UDT and risk of TGCT provides another means for assessing the mechanism linking UDT to TGCT. In a meta-analysis of five studies, the pooled estimate indicated that later age at orchiopexy (age 11 or older, or never corrected) increased risk of TGCT 3.5-fold (OR = 3.4, 95% CI 0.7, 17.7) compared to an earlier age at orchiopexy (prior to age 11) (12). Similarly, a large retrospective cohort study in Sweden followed nearly 17,000 men who underwent orchiopexy to correct for UDT and found that those who had surgery before age 13 were at decreased risk (RR = 2.23, 95% CI 1.58, 3.06) of TGCT compared to those who had surgery at 13 years of age or older (RR = 5.40, 95% CI 3.20, 8.53) (8). However, a Danish study using similar methods found similar risks of TGCT for various strata of age at orchiopexy (13). Thus, the preponderance of epidemiological evidence on age of orchiopexy points to UDT as an intermediate step through which the carcinogenic process progresses.

Impaired Fertility

Combining the results from seven published case-control studies, a recent systematic review of impaired fertility and TGCT noted an aggregate 68% increased odds (summary OR = 1.68, 95% CI 1.22, 2.30) of impaired fertility comparing men with TGCT to those without (14). There was little evidence of heterogeneity across the studies, and sensitivity analysis among studies with similar characteristics did not affect inferences. Two cohort studies also were reviewed; each that followed a group of men with known semen quality for outcomes including TGCT. Both studies indicated a statistically significant positive association between impaired fertility and TGCT (14).

Testicular Dysgenesis Syndrome

In 2001, the term TDS was fashioned to describe a constellation of genitourinary conditions including TGCT, UDT, hypospadius, and impaired fertility all of which are the downstream result of a common in utero environmental exposure layered atop of possible genetic factors resulting in impaired development of the testes (15). Recent opinion, however, has questioned the notion of a shared etiological factor for the four clinical component of TDS (16,17). Several components of TDS appeared better explained by likely cause-effect relationship, in particular the connection between UDT and impaired fertility and between UDT and TGCT, rather than an associative relationship in line with the common risk factor hypothesis of TDS. In response to this criticism, the originators of the TDS hypothesis note that, as with other clinical syndromes, it is not necessary for any given individual to display phenotypes of all the component conditions of TDS, rather a spectrum of TDS phenotypes is likely with the least severely affected men displaying reduced fertility only (18).

Recently, the heritability of TDS was accessed in a large Danish cohort that examined risk of TGCT among relatives of men with UDT or hypospadius (9). Evidence of heritability of TGCT among first- or second-degree relatives of men with either of these two conditions was not observed. Another investigation by the same researchers focused on heritability of UDT and hypospadius (19). Again, no evidence was found for increased risk of UDT given a family history of hypospadius or increased risk of hypospadius given a family history of UDT. Taken together, these findings suggest that while there are associative relations, some strong, at the individual level (e.g., men with TGCT are more likely to have a personal history of UDT), the notion of a familial factor that can account for the observed constellation of TDS conditions is unlikely.

Prior History of TGCT

A history of TGCT is the single most significant risk factor for the development of a TGCT (20,21,22). The presentation of a patient with bilateral synchronous GCT is rare. Approximately, 1% to 3% of patients with a history of TGCT develop a metachronous TGCT. In a patient with TGCT, the RR of developing a metachronous TGCT is approximately 25. The median time between the diagnosis of the initial TGCT and the metachronous GCT is approximately 5 years. Patients with bilateral TGCT are commonly included in studies of familial TGCT.

Disorders of Sex Development and Genetic Syndromes Associated with TGCT

There are numerous case reports of testicular or other GCT occurring in men with Klinefelter (47,XXY genotype) or mosaic Klinefelter (e.g., 46,XY/47,XXY and 46,XX/47,XXY) syndrome. Because of its affect on the testis including infertility, decreased testosterone and increased gonadotropin levels, the connection between testicular and other GCT and Klinefelter syndrome is biologically plausible (23). Two cohort studies, one from Denmark (24) and one from England and Wales (25) have assessed cancer incidence in men with Klinefelter syndrome. The smaller, among 707 Danish men, noted one TGCT, which was less than the number of TGCT expected based on national rates, and four mediastinal GCT, which was much greater that that expected (RR = 67, 95% CI 18, 171). In contrast, the larger study observed no cases of either testicular or mediastinal GCT among the 4,806 British men under investigation. Thus, the contribution of infertility, testosterone levels, or gonadotropin levels to TGCT risk is not supported in these data.

Similarly, numerous case reports can be found describing men with persistent Mullerian duct syndrome who have TGCT (26,27,28,29,30). In males, persistent Mullerian duct syndrome is a condition in which a karyotypically and externally intact 46,XY male retains (internal) Mullerian duct derivatives including uterus, cervix and fallopian tubes. As case reports are not useful in unraveling associations between two conditions, the observed tracking of these two conditions will need to be replicated using more robust study methodologies, though this will be challenging given the rarity of the condition.

Down syndrome (trisomy 21) is yet another condition for which presentation with TGCT in affected males appears in excess of what might be expected (31). Two cohort studies, one in Finland (32) and the other in Norway and Sweden (33), looked prospectively at the risk of developing TGCT among persons with Down syndrome. In two of the three countries, there was statistically significant evidence of a fivefold increased risk of TGCT (standardized incident ratio [SIR] = 4.8, 95% CI 1.8, 10 among Finnish males, and SIR = 5.5, 95% CI 1.8, 13 among Norwegian males). The SIR among Swedish males was not statistically significant and was not given.

Familial Risk of TGCT

Investigations of families with multiple TGCT members often are a first line inquiry seeking to support the idea that common genetic and/or shared environmental factors underlie the disease of interest. Studies of heritability have noted that genetic effects can account for 25% of TGCT, and that shared environmental exposures, particularly in childhood, can account for 17% of TGCT. Considering all sources of shared effects, TGCT ranks second only behind thyroid cancer (34).

TABLE 29.1 SUMMARY OF FAMILIAL RISKS OF TGCT AMONG BROTHERS, FATHERS, AND SONS

Authors	Year	Location	Brothers	Fathers	Sons	First Degree (Combined)	Ref
Forman et al.	1992	UK	8.0 (1.1, 355)	4.0 (0.4, 197)	—	—	(159)
Heimdal et al.	1996	Norway and southern Sweden	10.2 (6.2, 16)	4.3 (1.6, 9.3)	5.7 (0.65, 23)	7.6 (5.1, 11)	(91)
Westergaard et al.	1996	Denmark	12 (3.3, 32)	2.0 (1.0, 3.4)	—	—	(160)
Sonneveld et al.	1999	Netherlands	13 (6.4, 23) for estimated 0.5 brothers per proband 8.5 (4.3,15) for estimated 0.75 brothers per proband	1.8 (0.64, 3.8)	—	—	(161)
Spermon et al.	2001	Netherlands	5.9 (2.2, 13)	0.96 (0.01, 5.4)	0 (0.01, 61)	3.3 (1.4, 6.9)	(162)
Bromen et al.	2004	Germany	19 (3.1, 110)	2.1 (0.16, 27)	—	6.6 (2.4, 19)	(163)
Gundy et al.	2004	Hungary	12 (1.4, 256)	—	—	—	(164)
Hemminki and Chen et al.	2006	Sweden	7.6 (5.1, 11)	3.8 (1.9, 6.6)	—	—	(165)
Chia et al.	2009	USA	4.8 (0.99, 23)	3.7 (0.39, 36)	—	4.5 (1.2, 17)	(166)

Familial risk of TGCT repeatedly has been shown to increase risk of disease among first degree relatives of affected men, with risk to brothers being stronger than risk to fathers. Table 29.1 summarizes reported risk to brother, fathers, and sons. Point estimates among brothers range from 5- to 19-fold, while that for fathers range from 2- to 4-fold, although one study failed to demonstrate an elevated risk for fathers.

Studies of twins also provide invaluable information as to potential genetic and environmental effects associated with TGCT. A meta-analysis of seven twin studies, including six cohort and one case-control study, reported a 30% to 40% increased risk of TGCT among monozygotic (SIR = 1.4, 95% CI 1.2, 1.8) or dizygotic (SIR = 1.3, 95% CI 1.0, 1.7) twins of brothers with TGCT. This meta-analysis does not suggest a strong genetic effect as the risk to monozygotic and dizygotic twins was similar. However, two studies among twins did report such findings, one of which showed very strong risk of TGCT among monozygotic (SIR = 77, 95% CI 11, 518) and dizygotic twins (SIR = 36, 95% CI 5.2, 245) but was not included in the meta-analysis because data were not abstractable in the required format (35,36).

Given the observed heritability of TGCT—and in the absence of known genetic markers of risk which have only recently come to light (see section on “Genome Wide Association Studies”)—insight into the possible mode of transmission can be gleaned from segregation analyses. While not definitive, an autosomal recessive model best fit the pattern of observed transmission in an investigation of men with TGCT and their family members living in Norway and southern Sweden (37). Similarly, a recessive model best fit the data derived from bilateral and familial cases of TGCT, and data from the general population of the UK (38).

Prenatal and Postnatal Risk Factors Associated with TGCT

Transformation of the arrested gonocyte into testicular ITGCNU occurs during fetal development. Several prenatal risk factors have been investigated as potentially associated with the development of TGCT. Despite extensive investigation, the picture is not clear. The mechanisms involved in the progression of ITGCNU to invasive TGCT also have not been fully determined. Postnatal risk factors hypothesized to potentially play a role in this transformation are reviewed below.

Prenatal Risk Factors

Tobacco.

It has been hypothesized that maternal smoking during pregnancy increases the offspring’s risk of TGCT. Indirect evidence supporting this comes from one Swedish study that identified 40 cases of TGCT in almost 13,000 male offspring of mothers subsequently diagnosed with lung cancer resulting in a SIR of 1.90 (95% CI 1.35, 2.58) (39). However, several subsequent studies have refuted this hypothesis. McGlynn et al. reported a case-control study demonstrating no relationship between maternal or paternal smoking and risk of TGCT. A meta-analysis of seven epidemiological studies (2,149 cases and 2,762 controls) using indirect measures of tobacco exposure demonstrated no increased risk of TGCT (odds ratio [OR] = 1.0, 95% CI 0.88, 1.12) (40). A population-based case-control study from Sweden found no association between maternal smoking and TGCT risk (41). A nested case-control study that directly measured maternal first trimester cotinine levels demonstrated no statistically significant association between cotinine levels and risk of TGCT (OR = 0.68, 95% CI 0.35, 1.34) (40). In sum, there is no conclusive evidence that maternal tobacco use increases the risk of TGCT in offspring.

Estrogen Exposure.

One hypothesis on TGCT etiology relates to high levels of maternal estrogens. Although several studies have addressed this question, no definitive conclusion can be made. An early study of men exposed in utero to diethylstilbestrol (DES) demonstrated overall cancer rates that were similar to nonexposed men. The RR for TGCT in DES exposed men was 3.05 (95% CI 0.65, 22). The authors concluded that DES exposure had an uncertain effect on TGCT risk. The Collaborative Perinatal Project examined maternal estrogen levels in 150 black and 150 white mothers. The authors hypothesized that since TGCT is much more commonly seen in whites, that these mothers would have higher estrogen levels. However, the black mothers rather than the white mothers had significantly higher first trimester estradiol levels (p = 0.05) (42). A Danish case-control study examined whether clinical indicators of increased perinatal estrogen exposure including birth weight, twin status, and preeclampsia were more likely to be present in TGCT cases compared to age-matched controls. The results provided no evidence to support the “estrogen exposure” hypothesis (43). A second study examining prenatal
and perinatal clinical risk factors that were possibly linked to maternal estrogen levels (e.g., nausea, preterm delivery, birth weight) demonstrated that extreme nausea during the first trimester was associated with an increased TGCT risk (OR = 2.0, 95% CI 1.0, 3.9) (44). A recent nested case-referent study of Finnish, Swedish, and Icelandic mothers evaluated early pregnancy endogeneous steroid levels (dehydroepiandrostene sulfate [DHEA], androstenedione, testosterone, estradiol, estrone, and sex hormone binding globulin) and TGCT risk. Offspring of mothers with a high DHEA level had a significantly decreased risk of TGCT. However, offspring of mothers with high androstenedione and estradiol levels did demonstrate an increased risk of TGCT (45). In sum, studies are inconclusive concerning the role of maternal endogeneous estrogen in TGCT etiology. Additional study of this question is needed.

Birth Order and Sibship Size.

A nested case-control study from Sweden also demonstrated that birth order and sibship size had an inverse association with TGCT risk (46). A Danish case-control study demonstrated a decreasing risk of TGCT with increasing birth order (p = 0.020) (47). Numerous studies have examined additional risk factors and the association with TGCT risk.

Birth Weight.

A recently published systemic review and metaanalysis examined the association between birth weight and TGCT risk. Thirteen studies including 5,663 TGCT patients were analyzed. Men weighing less than 2,500 g at birth had an increased risk of TGCT compared to normal (2,400-4,000 g) birth weight men (OR = 1.12, 95% CI 1.01, 1.38). Interestingly, men with birth weight greater than 4,000 g also had a higher risk of subsequent TGCT (OR = 1.12, 95% CI 1.02, 1.22). Low birth weight was most associated with the future development of seminoma (49).

Other Maternal Factors.

The US Servicemen Testicular Tumor Environmental and Endocrine Determinants (STEED) casecontrol study examined prenatal risk factors among 527 TGCT cases and 561 controls. Young maternal age, young paternal age, maternal parity, and breech birth were associated with an increased risk of TGCT. When examined by histology, risk of seminoma was associated with young maternal age, young paternal age, maternal parity, and low birth weight. Risk of nonseminoma was associated with breech birth and Cesarean section (50). A recent meta-analysis of maternal characteristics and the risk of TGCT in offspring found that maternal bleeding during pregnancy, birth order, and sibship size were associated with TGCT risk. Risk factors with no association included maternal age, maternal nausea, maternal hypertension, preeclampsia, and breech delivery. When the meta-analysis was restricted to United States studies, Cesarean section was associated with TGCT risk (48). The authors concluded that this study supports the hypothesis of TGCT originating early in life.

Other prenatal risk factors have been studied. One casecontrol study reported that severe gestational hypertension was strongly associated with a decreased risk of TGCT, but mild gestational hypertension resulted in an increased risk (51). Chemical exposures have been examined. One cohort study from Norway reported that specific fertilizer regimens used on rural farms were associated with an increased incidence of TGCT, especially nonseminomas (52). A second study examined whether in utero exposure to organic pollutants was associated with an increased TGCT risk but was not conclusive (53). A United States case-control study concluded that parental occupation was not associated with TGCT risk when all histologies were considered (54). One nested case-control study examined whether maternal viral infections were associated with TGCT risk in offspring. High levels of maternal Epstein-Barr Virus IgG were associated with a significantly increased risk of TGCT in offspring, but serological evidence of cytomegalovirus was associated with a decreased TGCT risk. This study has not been confirmed (55).

Postnatal Risk Factors

Body Size.

Multiple studies have examined the association between body size and TGCT risk. More recent studies will be discussed. Investigators from STEED study described above compared 767 cases and 928 controls with respect to body size. Increased height was associated with an increased risk of TGCT (OR = 83, 95% CI 1.36, 45). Body mass index (BMI) was not associated with an increased risk (OR = 1.06, 95% CI 0.66, 1.69) (7). A large Norwegian cohort study demonstrated a decreased TGCT risk with increased BMI. A moderate increase in risk of seminoma was associated with increasing height (56). A large Swedish case-control study demonstrated a positive association between height at 18 years of age and TGCT risk. No association was demonstrated between birthweight and TGCT risk (57). A German case-control study reported no significant associations with BMI or weight. Interestingly, height was significantly associated with the TGCT risk where subjects with a body height of ≥185 cm was associated with an OR of 2.11 (95% CI 1.25, 3.55) compared to a height of 175 to 179 cm (58). These studies demonstrate that height but not BMI is associated with TGCT risk. A recent German case-control study of almost 8,500 TGCT patients examined BMI categories and TGCT risk adjusted for age. While overall the frequency of BMI categories did not differ between cases and controls, in men aged 18 to 29 years, increased BMI categories were more frequently seen in the TGCT cases (59).

Nutrition.

Diets high in fat and calories have been associated with an increased risk of TGCT (60). A second study did not demonstrate an association between diet and TGCT risk (61). Dairy foods have also been associated with an increase TGCT risk (62,63). No association was noted between dietary phytoestrogens and TGCT risk (64).

Exposures.

Numerous studies have investigated whether exposure to chemicals is associated with an increased risk of TGCT. Organochlorines have been demonstrated to have antiandrogenic properties. One case-control study did not identify a relationship between serum levels of organochloride pesticide residues and TGCT risk (65). One study did not demonstrate a positive association between tobacco use and TGCT risk (66). One recent case-control study suggested an association between marijuana use and NSGCT (67).

Occupation.

A number of studies have examined whether occupation is associated with the risk of TGCT. Some studies have identified an increased risk of TGCT in several occupations including firefighting (68,69,70), metal work (71), military (72,73,74), and farming (75). A case-control study identified an association between professional employment such as administrators or teachers and seminoma and between production work employment and other germ cell malignancies. However, no specific occupation was identified as a risk factor (76).

Infection.

Recent reports have identified an increased risk of TGCT in men infected with HIV, suggesting a viral etiology for the disease. The predominant histology is seminoma (77,78,79). The herpes viruses Epstein-Barr virus and cytomegalovirus have also been associated with an increased risk of TGCT (80).

Physical Activity.

In one case-control study, a moderate to high level of recreational physical activity was inversely associated with TGCT (81). A large population based cohort study from
Norway did not demonstrate an association between physical activity and TGCT risk (82). A more recent Canadian study suggested that the extent of moderate or strenuous physical activity in adolescence increased the risk of TGCT (83).

Other Factors.

Exposure to electromagnetic fields related to electric blankets (84), residential exposure to high voltage overhead electrical lines, and occupational exposure to electromagnetic fields did not increase the risk of TGCT (85,86). In a large cohort study of over 73,000 men, vasectomy did not increase the risk of TGCT (87).

GENETICS OF TESTICULAR GERM CELL TUMORS

Based on the high heritability and RRs to family members, underlying genetic variation has long been thought to play an important role in susceptibility to TGCT. As with most cancers, genetic susceptibility studies in TGCT have progressed from family based to candidate gene and finally to genome wide association studies (GWAS). For this disease, it is only with GWAS that we have begun to have a more complete understanding of the genes involved in TGCT susceptibility.

Family Based Studies

High risk cancer susceptibility syndromes are generally characterized by the cosegregation of multiple cancer types, in particular otherwise rare cancers, or other phenotypes, bilateral disease and early age of cancer onset. While familial TGCT is generally characterized by the presence of two affected men, studies have been done to establish if there are other associated phenotypes. Case reports and an analysis of SEER data suggest that familial clustering of ovarian GCTs and TGCT exists and thus may be part of the familial TGCT phenotype (88,89,90). Given the extreme rarity of ovarian GCTs, however, a common susceptibility gene would be very difficult to definitely identify. Bilateral TGCT appears to be more common in multiple case families (9.8% vs. 2.8% in sporadic cases), consistent with other types of cancer susceptibility syndromes (91). A younger age of onset is observed in men with familial TGCT, with the mean age of diagnosis 2.5 years earlier than for sporadic cases across histologies (92). However, UDT is not more common in familial than in sporadic cases of TGCT (93). Testicular microlithiasis has been postulated to be associated with an increased risk of familial TGCT, and potentially that copredisposition exists for both conditions. Interestingly, while testicular microlithiasis appears to be associated with TGCT in the presence of other risk factors such as infertility, prior history of TGCT and UDT, it is not significantly associated with family history (RR 1.19, 95% CI 0.83, 1.71) (94,95,96). Thus, it remains unclear whether microlithiasis is associated with family history positive cases of TGCT, or TGCT in general. In summary, these studies support a phenotype associated with familial TGCT, similar to other cancers with familial clustering due to inherited susceptibility genes, including earlier age of onset, bilaterality, and potentially ovarian GCTs.

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