Best Pract Res Clin Endocrinol Metab 24(3): 503-513

PMID: 20833340

Familial Testicular Germ Cell Tumors

Introduction

Familial testicular germ cell tumors (FTGCT) are defined as testicular germ cell tumors (TGCT) that arise in more than one blood relative of the same family. Similar to the sporadic form of TGCT, pure seminoma and a group termed collectively as nonseminoma are the two main subclasses of FTGCT. It is generally believed that TGCT arise from primordial germ cells that are blocked in maturation. This process is thought to be initiated during fetal development and caused by both genetic and environmental factors (Figure 1). A non-invasive stage (intratubular germ-cell neoplasia unclassified (IGCNU) or carcinoma in situ) precedes progression to TGCT.¹ TGCT are highly curable, with current cure rates exceeding 95%.

An external file that holds a picture, illustration, etc.
Object name is nihms-172038-f0001.jpg

Fig. 1

Model illustrating factors involved in the pathogenesis of testicular germ cell tumors (TGCT)

TGCT arise from primordial germ cells that are disturbed in differentiation. This defect is due to both environmental factors and genetic susceptibility factors. The same factors may also lead to abnormalities frequently associated with TGCT, such as cryptorchidism, infertility, and microlithiasis. Cryptorchidism may also directly contribute to TGCT development. Somatic events characterize the progression to TGCT. During this process, TGCT go through a phase called intratubular germ-cell neoplasia unclassified (IGCNU). Notably, somatic events (such as KIT and RAS mutations) affect, at least in part, the same pathways that are altered by inherited susceptibility factors (e.g., polymorphisms near KITLG).

The following review uses data from three sources: (1) the peer-reviewed scientific literature, (2) the International Testicular Cancer Linkage Consortium, and (3) the NCI Clinical Genetics Branch multidisciplinary etiologic study of FTGCT (NCI Protocol 02-C-0178; NCT 00039598).

Epidemiology of Testicular Germ Cell Tumors

Although TGCT account for only approximately 1% of all neoplasms in males (American Cancer Society, 2009), these malignancies are the most common cancers in young men in the United States, where 8400 new cases of TGCT are predicted to occur in 2009.² An increasing incidence of TGCT within the last fifty years has been documented in several epidemiologic studies.³5 Between 1973 and 1995, the incidence of TGCT increased by 50% in the United States. This increase in incidence correlates with the year in which patients were born, indicating a birth cohort effect.⁶ There are 3 incidence peaks of TGCT in males, the first occurring in childhood (mainly mature or immature teratoma/yolk-sac tumor), the second (and largest) appearing between ages 20 and 35 years (seminoma and non-seminoma histologies), and the third manifesting in older men, and comprises primarily of spermatocytic seminoma.⁷ The lifetime risk of TGCT in Caucasian men is estimated to be one in 234. The risk is substantially less in African Americans (1 in 1,160).⁸11

Several observations indicate that heritable factors influence TGCT risk: (1) Approximately 1.4% of men with newly-diagnosed TGCT report a positive family history for this cancer;¹² (2) Sons of men with TGCT have a 4-6 fold increase in TGCT risk, and brothers of men with TGCT have an 8-10 fold increased risk.¹³14 (Notably, the familial relative risks for most of the common adult cancers are in the range of 1.5 to 2.5, for first-degree relatives of cases.); (3) A 37-fold/76.5-fold elevated risk of TGCT in dizygotic/monozygotic twin brothers of men with TGCT has been reported;¹⁵ and (4) 2-5% of patients develop cancer of the contralateral testicle and contralateral testicular cancer is one established risk factor for TGCT.¹⁶17

In addition to a positive personal history or family history for this tumor, cryptorchidism represents another important TGCT risk factor.¹⁸ The risk of TGCT in men with undescended testis (UDT) is elevated two to eight times and a history of UDT is reported in 5-10% of all men with TGCT.¹⁹20 Notably, in patients with a history of unilateral UDT, TGCT can arise in both testes, suggesting that (1) UDT itself increases the TGCT risk, and that (2) UDT and TGCT share a common (genetic and/or environmental) etiology (reviewed in ²¹). Infertility is another increasingly-established risk factor for TGCT²²25, supporting the idea that TGCT arise from (developmentally) disturbed germ cells. Additional risk factors include testicular microlithiasis²⁶27, persistent Müllerian duct syndrome²⁸, testicular atrophy²⁹30, testicular intraepithelial neoplasia (“TIN”)³⁰32, mixed gonadal dysgenesis³³34, Klinefelter syndrome³⁵, and testicular dysgenesis syndrome (TDS)³⁶. (The term TDS was coined in 2001 to describe a constellation of features encompassing impaired spermatogenesis, undescended testis, hypospadias, and testicular cancer.³⁷ The term TDS implies that unifying causal factors are responsible for all its manifestations; however, an ongoing debate challenges this widely accepted concept because of inconsistent non-causal associations and the possibility that the defining features of TDS have different causes.²¹) Less well established risk factors for TGCT include inguinal hernia and hydrocele,²⁹ polythelia (accessory nipples),³⁸in utero exposure to diethylstilbestrol (DES),³⁸39 gynecomastia,⁴⁰ and occupational exposure to polyvinyl chloride.⁴¹

Inheritance Pattern and Phenotypic Characteristics

A recent report by the International Testicular Cancer Linkage Consortium (ITCLC, an organization created to collect a large number of genetically-informative, multiple-case TGCT families to facilitate mapping and cloning potential testicular cancer susceptibility genes) analyzing 985 FTGCT cases from 461 families showed that the vast majority (88%) of families consisted of two affected family members; ^{the maximum number of affected members observed in a single family was 5, and there were only two such kindred. Multiple potential patterns of inheritance were seen from family-to-family, including those consistent with autosomal recessive (49% are sibling pairs), autosomal dominant (father/son, Grandfather/father/son: 19%), X-linked inheritance (absence of male-to-male transmission), as well as more complex patterns involving aunts, uncles and cousins. In a subset of ITCLC families (drawn from centers with large numbers of families and the availability of a national cancer registry), age-at-diagnosis was statistically significantly younger for FTGCT cases from North America (P = 0.024), the United Kingdom (P<0.0001), and Australia/New Zealand (P = 0.0033) compared with general population cases. When stratified by histology, the difference in age-at-diagnosis distribution between familial and population cases was observed for seminoma cases from North America (P = 0.002) and the United Kingdom (P<0.0001), and nonseminoma cases from the United Kingdom (P = 0.029) and Australia/New Zealand (P = 0.0023). Overall, the mean age at FTGCT diagnosis was about 2.5 years younger than that observed for sporadic TGCT from the same country.}⁴³

Approximately 6.5% of FTGCT cases reported in the ITCLC series had bilateral disease, a prevalence that is marginally higher than that observed in sporadic TGCT. The prevalence of cryptorchidism (21% of families; 14% of familial cases) was similar to that seen in sporadic TGCT, and there were no correlations in tumor subtype (seminoma versus non-seminoma), either within families or between testes in patients with bilateral disease.⁴² However, when examined by histology of the first diagnosis among those with metachronous bilateral disease, the second tumor histology was more likely to be of the same histology in patients whose first tumor was a seminoma, but not in patients whose first tumor was a nonseminoma.⁴²

Recently, it has been recognized that testicular microlithiasis has a particularly strong association with FTGCT. Microlithiasis is gaining acceptance as a risk factor for sporadic testicular cancer,⁴⁴ although its precise role in this context has yet to be fully defined.²⁷ Its potential association with FTGCT has been reported recently by both UK⁴⁵ and US⁴⁶ investigators using the same microlithiasis definition i.e., either “classic” (>5 microliths), or “limited” (<5 microliths). The UK group analyzed both familial and sporadic TGCT patients as well as unaffected male relatives and healthy male controls (total=328 subjects). Testicular microlithiasis was detected more frequently in TGCT cases than controls (36.7% versus 17.8%; p<0.0001) and in unaffected male relatives than controls (34.5 versus 17.8%; p=0.02). TGCT cases and matched relative pairs were significantly concordant for microlithiasis (p=0.05). The US study targeted 81 men (48 with, 33 without TGCT) from 31 extended multiple-case families.⁴⁶ Testicular microlithiasis was more frequently observed in the contralateral testicles of affected men than in those without cancer (48% versus 24%; p=0.04). Testicular microlithiasis was bilateral in 87% of the unaffected men with microlithiasis. Ten of the 31 families accounted for a majority (61%) of microlithiasis cases. The presence of microlithiasis was not correlated with tumor histology, cryptorchidism, inguinal hernia, history of testicular injury or infection, or treatment of TGCT.

In summary, these two studies suggest that testicular microlithiasis is significantly more common among FTGCT family members than in the general population (range 0.6% to 9.0%), and among FTGCT cases versus their unaffected blood relatives. It also appeared to cluster in certain families. These findings suggest both a familial predisposition to testicular microlithiasis and an association between microlithiasis and FTGCT.

Genetic Susceptibility Loci Involved in the Development of Testicular Germ Cell Tumors

Two groups from the UK⁴⁷ and the US⁴⁸ recently independently reported genome-wide association studies (GWAS) for susceptibility to TGCT. The UK study included 730 cases (165 of which were familial cases) and 1,435 controls, while the US study analyzed 277 cases (including 30 familial cases) and 919 controls. Both groups replicated results in independent cohorts. These studies showed three robust associations with risk of TGCT. SNPs which showed significant associations were in regions containing KITLG (ligand for the tyrosine kinase KIT) and SPRY4 (an inhibitor of the mitogen-activated protein kinase pathway acting downstream of KITLG-KIT), findings that were confirmed by both groups. A third genomic region - in an intron of the pro-apoptotic gene BAK1 (also downstream of KITLG) - was reported only in the UK study. The calculated perallele odds ratio for variants in the region of KITLG is the highest reported for any malignancy to date.⁴⁹

In the UK study, the relative risk for individuals homozygous for the high-risk allele in the KITLG region was approximately 6, and that for the variants in the region of SPRY4 and BAK1 were approximately two. Moreover, the predicted risk for individuals at highest-risk (males who were homozygous for all the high-risk alleles in the region of KITLG, SPRY4 and BAK1, (~0.7% of the population) was 40 times the risk of those who were homozygous for all the low-risk alleles.⁴⁷ The UK investigators estimated that these three susceptibility loci accounted for ~7% of the risk to siblings and ~10% of the risk to offspring of individuals with TGCT.⁴⁷ Notably, the risk allele affecting KITLG was less common in individuals of African ancestry in the U.S., providing a possible explanation for the lower incidence of TGCT in blacks.⁴⁸

KITLG belongs to the family of short-chain helical cytokines. Two isoforms have been identified, consisting of soluble and transmembrane versions of this protein. KITLG initiates multiple cellular responses by activating its cognate receptor, KIT. The biologic functions of the KIT signaling pathway are broad, and include roles in the development of hematopoietic cells, melanocytes, and germ cells (reviewed in ⁵⁰). Recent investigations in mice show that Kitl governs multiple aspects of primordial germ cell biology, such as midline cell death, proliferation and migration.⁵¹ Moreover, Kitl controls primordial germ cell survival and motility, and provides a continuous niche throughout their migration.⁵²

Germline mutations in KIT and KITLG have been shown previously to be etiologically associated with several human diseases. Germline KITLG mutations cause familial progressive hyperpigmentation,⁵³ while KIT germline mutations are associated with familial gastrointestinal stromal tumors⁵⁴ and familial diffuse cutaneous mastocytosis.⁵⁵ Furthermore, somatic mutations of the KIT oncogene are detected at various frequencies in several neoplasms, including both familial and sporadic TGCT.⁵⁶57

In a murine model, on the other hand, loss of the transmembrane Kitl isoform increases susceptibility to TGCT (see below).⁵⁸ Moreover, administration of the tyrosine kinase inhibitor imatinib (which includes KIT among its ligands) has resulted in complete response in pretreated disseminated testicular seminoma patient whose tumor displayed KIT overexpression.⁵⁹ Finally, results of a loss of heterozygosity study, published in 1992, are consistent with a germline deletion of KITLG in a patient with TGCT; this patient's tumor (a seminoma) harbored a homozygous deletion in this gene.⁶⁰

Revealing the mechanisms through which the recently-identified polymorphisms in KITLG, SPRY4 and BAK1 contribute to TGCT development has now emerged as a major scientific priority. Functional SNPs will need to be uncovered (by fine sequencing), and it is conceivable that these functional variants will be found to deregulate the signaling pathway (e.g., by altered gene expression) and/or that they render testicular germ cells more susceptible to somatic mutations required for neoplastic transformation.

Linkage Analysis in the ITCLC Family Set

The facts that most FTGCT families have only two affected family members and that multiple-case multi-generation pedigrees are uncommon result in reductions in the statistical power of classical linkage analysis as a gene-finding strategy. The rarity of such multiple-case TGCT families represents a major constraint on what linkage analysis can accomplish. Therefore, it is not surprising that linkage analysis has not resulted in any single, high-penetrance gene in this disorder. Moreover, the possibility remains that there truly is no rare, highly-penetrant FTGCT susceptibility locus. Instead, it is quite conceivable that FTGCT will prove to be a complex genetic trait that is, at least in part, influenced by multiple genes of variable effect size that can be altered by various genetic or epigenetic mechanisms. The results of the GWAS studies outlined above, and the results from various candidate gene studies (see below) strongly support this idea. Lastly, in a spontaneous mouse model of TGCT, this cancer appears to be a genetically complex trait; several loci that modify the frequency of TGCT in these mice have been identified (see below).

The first linkage analysis⁶¹ in FTGCT reported a strong linkage signal at chromosome Xq27. This study included 134 families with ≥ 2 TGCT, 99 of which were consistent with an X-linkage mode of inheritance. The odds in favor of linkage (i.e., the HLOD score) in this subset was 2.01 and, if X-linked families which contained at least one family member with bilateral TGCT were targeted, the HLOD score rose to 4.70. This finding led to a major effort aimed at recruiting additional families, in order to validate this observation.

In 2003, a second report expanded this series to 178 families (including the original 134)⁶², and yielded an HLOD score of 2.05 for chromosome 12q12-q13, the same region that commonly displays somatic cytogenetic rearrangements in testicular tumor tissue.

The most recent Consortium analysis included a further expansion of the study set to 237 families, of which 163 families were compatible with X-linkage. In that analysis, the HLOD score at the Xq27 locus fell to 1.01⁶³, substantially weakening the putative association between Xq27 and FTGCT. This analysis also found modest linkage signals (HLOD > 1.0) at a number of loci, including 2p23; 3p12; 3q26; 12p13-q21; and 18q21-q23. The authors of this linkage studies concluded it seemed likely that the combined effects of multiple common alleles, each conferring modest risk, might explain the familial aggregation of TGCT.⁶³

Candidate Gene Association Studies

Candidate gene analysis has also been employed to look for potential genes involved in FTGCT. Following the first linkage study⁶², three genes residing in the Xq27 locus were studied in this fashion by investigators at the Institute of Cancer Research in the United Kingdom, but no germline mutation was identified.⁶³KIT was also chosen for analysis, based on the frequent detection of somatic KIT mutations in sporadic TGCT. DNA samples from 240 multiple-case testicular cancer families were screened; no germline mutation was detected.⁵⁶ Based on a previous finding that germline mutations in Dnd1 caused testicular tumors in strain 129 inbred mice,⁶⁴ ITCLC investigators analyzed DND1, the human ortholog of this gene, in 434 familial and 671 sporadic human TGCT subjects.⁶⁵ Only a single rare variant was found, indicating that DDND1 could at best make only a minimal contribution to the genetic etiology of FTGCT.

Recognizing that male infertility is an established risk factor for sporadic testicular cancer, and that the E gr/gr deletion is the most commonly-identified genetic cause of male infertility,⁶⁶ the Y chromosome gr/gr deletion has been studied as an TGCT risk factor. This ~1.6 Mb deletion deletes parts of the AZoospermia Factor c (AZFc) region of the Y chromosome, but the breakpoints vary among patients. The AZFc locus contains several multi-copy genes which are biologically plausible candidates for modulators of germ cell differentiation and spermatogenesis, e.g., DAZ, CDY1, BPY2) (reviewed in ⁶⁷). The gr/gr deletion was detected in 13 of 431 (3.0%) familial TGCT, 28 of 1,376 (2.0%) sporadic TGCT cases, and 33 of 2,599 (1.3%) male controls, corresponding to threefold (95% CI 1.5-6.7) and twofold (95% CI 1.3-3.6) increases in TGCT risk, respectively. These findings indicate that the chromosome Y gr/gr microdeletion is an uncommon low-penetrance TGCT susceptibility allele for both the familial and sporadic forms of TGCT. Nevertheless, considering the fact that the human Y chromosome is extremely complex genetically, and thus difficult to analyze, a follow-up study is needed to confirm these results.

The most recent candidate gene study related to FTGCT targeted phosphodiesterase gene called PDE11A,⁶⁸ a regulator of cyclic AMP (cAMP) signaling in adrenal and other steroidogenic tissues, which is highly expressed in the normal human testis. Pde11a null mice are infertile,⁶⁹ and germline variations in this gene have been implicated in adrenal gland neoplasia.⁷⁰ We sequenced the PDE11A gene in 95 TGCT patients from 64 unrelated multiple-case kindreds, and identified 8 nonsynonymous substitutions (4 of which were unique to FTGCT subjects) in 20 patients from 15 families. The prevalence of all PDE11A-gene variants (combined) was significantly higher among patients with TGCT (p = 0.0002) than controls; they were detected in 19% of the families studied. Functional studies showed that all these mutations decreased phosphodiesterase activity, and that PDE11A protein expression was reduced or undetectable in TGCT tumor tissue from subjects carrying these variants.⁶⁸ We concluded that PDE11A-inactivating sequence variants appear to modify the risk of familial TGCT. This gene has not been evaluated in sporadic TGCT.

Somatic Genetic Changes in Testicular Germ Cell Tumors

A full discussion of the somatic events in TGCT is beyond the scope of this report; however, this issue has recently been addressed in several reviews.¹677173 Interestingly, some of the somatic changes detected in TGCT affect the KIT-KITLG signaling pathway, indicating that germline variations in this pathway may pave the way for somatic alterations. Specifically, activating somatic mutations (or amplification) are found at various frequencies in the KIT, KRAS, and BRAF oncogenes. We hypothesize that germline variants deregulate KIT-KITLG signaling, creating a microenvironment in the developing testis in which the acquisition of somatic mutations confers a selective growth advantage to primordial germ cells. This hypothesis, however, needs to be evaluated with functional studies and in genetic analyses correlating germline and somatic events.

Among the large number of known cytogenetic abnormalities, alterations affecting chromosome 12p are the only recurrent structural changes in TGCT; most tumors are characterized by one or several copies of isochromosme 12p (i(12p)).⁷¹7475 Although several appealing candidate genes have been named, the relevant genes on chromosome 12p that contribute to TGCT progression remain unknown.

Of note, spermatocytic seminoma, which occurs typically in older men and which has not been reported in FTGCT, has been recently shown to originate from mutations in FGFR3 and HRAS. These strongly activating mutations arise in the male germline and mutation levels increase with paternal age. Interestingly, moderately activating mutations in the same genes also occur in the male germline and can lead to rare developmental syndromes (e.g., Apert and Costello syndromes) in the offspring.⁷⁶

Mouse Models of Testicular Germ Cell Tumors

Studying mouse models of TGCT represents a complementary strategy to elucidate the biology of these tumors. In mice, spontaneous (pediatric-type) TGCT occurs on the 129 inbred background. TGCT susceptibility in 129/Sv is a genetically complex trait and the susceptibility genes remain unknown (reviewed in ⁷⁷). However, several known genetic variants act as modifiers of TGCT susceptibility on the 129/Sv background. Variants that increase the risk of TGCT in 129/Sv mice include Dnd1^Ter (point mutation in Dnd1), Kit^Sl, Kitl^SlJ, and Kitl^Slgb (different deletions of Kitl), while the A^y variant (a contiguous deletion affecting the three genes Raly, Eif2s2 and Agouti) decreases TGCT incidence.⁵⁸77 Recently, it has been determined that Eif2s2 is the relevant gene in this deletion.⁷⁸ Finally, it has been shown that genetic variants may act epistatically to modulate TGCT susceptibility in the 129/Sv strain.⁷⁹ As demonstrated by the observation that KITLG modifies TGCT risk in both humans and mice, these mouse models are of great value because they will help us to better understand the biology of this complex disease.

Psychosocial and Behavioral Factors Related to Testicular Cancer Families

As the genetic causes of TGCT are being uncovered in research that is moving at increasingly rapid pace, psychosocial and behavioral issues related to membership in a multiple-case TGCT family are becoming increasingly relevant. Information on psychosocial and behavioral factors related to FTGCT is important in order to more effectively develop and implement future studies and counseling protocols for this unique population when risk assessment tools for FTGCT become available. The NCI Clinical Genetics Branch Familial Testicular Cancer study recently showed that the majority (66%) of 229 participants (64 affected men, 66 unaffected men, and 99 women) from 47 multiple-case FTGCT families expressed interest in having a genetic test within 6 months, should such a test become available. Participants were more likely to be interested in genetic testing if they were younger and had higher levels of family support, a physician's recommendation supporting testing, cancer distress, and a need for information to inform the health care of their children.⁸⁰

A separate analysis aimed at determining baseline levels of TGCT and genetics knowledge and identifying factors associated with these knowledge levels among 258 male and female participants from families with FTGCT, including TGCT survivors, blood relatives and spouses, showed that knowledge levels were generally low, with genetic knowledge lower than TGCT knowledge.⁸⁰ Men with a personal TGCT history scored higher than unaffected family members on testicular cancer knowledge, while gender, age and education influenced genetics knowledge levels, particularly among unaffected relatives. Based on this study, we recommend tailoring FTGCT genetic education to the different informational needs of TGCT survivors, their spouses and relatives, in preparation for the day when clinical susceptibility testing may be available.⁸¹ In another report, we analyzed factors associated with testicular self-examination (TSE) behaviors among unaffected men from multiple-case testicular cancer families.⁸² For men in our sample, 46% (n = 46) reported performing TSE regularly and 51% (n = 50) reported not regularly performing TSE. Factors associated with regularly performing TSE were physician recommendation and testicular cancer worry. The findings suggest that, even in this high-risk setting, TSE practices are sub-optimal. Our data provide a basis for further exploring psychosocial issues that are specific to men with a family history of TGCT, and formulating genetic counseling and other clinical intervention strategies aimed at improving adherence to TSE practices.

Concluding remarks

Existing data suggest that the combined effects of multiple common alleles, each conferring modest risk, might underlie the genetic component of TGCT, which, in conjunction with poorly-defined environmental factors, predispose to TGCT. Candidate gene studies have implicated the chromosome Y gr/gr deletion and PDE11A gene mutations as genetic modifiers of FTGCT. Two GWAS have implicated the KITLG, SPRY4 and BAK1 genes as TGCT risk modifiers. All 5 loci are involved in normal testicular development and/or male infertility (Figure 1). It is possible that sporadic TGCT and familial TGCT are caused by the same spectrum of genetic and environmental factors. We hypothesize that patients with familial and/or bilateral TGCT have a higher risk score (e.g., a larger number out of known risk factors) (Figure 2). This hypothetical model would explain the occurrence of several TGCT in the same family, as well as the heterogeneous pattern of inheritance observed in patients with FTGCT. Thus far, only a proportion of the genetic factors have been identified. However, the fact that these factors influence, a least in part, identical biologic pathways provides a guide for future studies aiming at the identification of the remaining TGCT loci. The translation of robust genetic findings into improved patient care and tailoring counseling strategies to the specific needs of FTGCT family members represent ongoing challenges.

An external file that holds a picture, illustration, etc.
Object name is nihms-172038-f0002.jpg

Fig. 2

Hypothetical risk model of testicular germ cell tumors (TGCT)

Multiple genetic susceptibility factors in conjunction with environmental factors are necessary to initiate TGCT development. In rare individuals, the risk scores are very high and lead to the familial subtype of TGCT (FTGCT) and/or bilateral disease.

Practice Points

Personal history and family history of TGCT are well-recognized TGCT risk factors;
The majority of families with familial TGCT consist of only two affected family members;
Testicular microlithiasis is more common among familial TGCT family members than in the general population;
Several genetic susceptibility loci involved in the development of TGCT have been identified: KITLG, SPRY4,BAK1, PDE11A, and the gr/gr region on chromosome Y. These loci control the development of germ cells; and
Information on psychosocial and behavioral factors related to FTGCT is important in order to develop and implement counseling protocols and risk management strategies.

Research Agenda

Identifying additional genetic factors contributing to TGCT;
Identifying the functional variants in KITLG, SPRY4, and BAK1;
Confirming the role of PDE11A and the chromosome Y gr/gr deletion in TGCT;
Clarifying the complex interplay between germline and somatic genetics in TGCT;
Assessing the role of epigenetic changes and other mechanisms such as copy number variations in the pathogenesis of TGCT; and
Translating genetic findings into better patient care.

Acknowledgements

This work was supported by the Intramural Research Program of the US National Cancer Institute, National Institutes of Health, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc., Rockville, MD.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20852, USA

^{Corresponding author. Tel.: +1 301-594-7641}vog.hin.liam@meneerg (M.H. Greene)

Publisher's Disclaimer

Abstract

In this review, we define familial testicular germ cell tumors (FTGCT) as testicular germ cell tumors (TGCT) diagnosed in at least two blood relatives, a situation which occurs in 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, and an even higher elevated risk of TGCT in twin brothers of men with TGCT has been observed, suggesting that genetic elements play an important role in these tumors. Nevertheless, previous linkage studies with multiple FTGCT families did not uncover any high-penetrance genes and it has been concluded that the combined effects of multiple common alleles, each conferring modest risk, might underlie FTGCT. In agreement with this assumption, recent candidate gene association analyses have identified the chromosome Y gr/gr deletion and mutations in the PDE11A gene as genetic modifiers of FTGCT risk. Moreover, two genomewide association studies of predominantly sporadic but also familial cases of TGCT have identified three additional susceptibility loci, KITLG, SPRY4 and BAK1. Notably, all five loci are involved in the biology of primordial germ cells, representing the cell of origin of TGCT, suggesting that the tumors arise as a result of disturbed testicular development.

Keywords: Familial testicular cancer germ cell tumors, genetic susceptibility, KITLG-KIT signaling

Abstract

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Conflict of Interest

The authors have no conflict of interest.

Footnotes

References

1. Horwich A, Shipley J, Huddart RTesticular germ-cell cancer. Lancet. 2006;367:754–765.[PubMed][Google Scholar]
2. Society AC Cancer Facts & Figures 2009. American Cancer Society; Atlanta: 2009. [PubMed][Google Scholar]
3. Huyghe E, Matsuda T, Thonneau PIncreasing incidence of testicular cancer worldwide: a review. Journal of Urology. 2003;170:5–11.[PubMed][Google Scholar]
4. Purdue MP, Devesa SS, Sigurdson AJ, McGlynn KAInternational patterns and trends in testis cancer incidence. International Journal of Cancer. 2005;115:822–827.[PubMed][Google Scholar]
5. Holmes L, Jr., Escalante C, Garrison O, et al Testicular cancer incidence trends in the USA (1975-2004): plateau or shifting racial paradigm? Public Health. 2008;122:862–872.[Google Scholar]
6. McKiernan JM, Goluboff ET, Liberson GL, Golden R, Fisch HRising risk of testicular cancer by birth cohort in the United States from 1973 to 1995. Journal of Urology. 1999;162:361–363.[PubMed][Google Scholar]
7. Aggarwal N, Parwani AVSpermatocytic seminoma. Archives of Pathology and Laboratory Medicine. 2009;133:1985–1988.[PubMed][Google Scholar]
8. SEER . SEER Cancer Statistics Review: 1973-1990, No. 93-2789. National Cancer Institute: National Institutes of Health; Bethesda, Maryland: 1993. [PubMed]
9. Swerdlow AJThe epidemiology of testicular cancer. European Urology. 1993;23(Suppl 2):35–38.[PubMed][Google Scholar]
10. Shah MN, Devesa SS, Zhu K, McGlynn KATrends in testicular germ cell tumours by ethnic group in the United States. International Journal of Andrology. 2007;30:206–213. discussion 213-204. [[PubMed][Google Scholar]
11. SEER . SEER Cancer Statistics Review, 1975-2006. National Cancer Institute; Bethesda, MD: 2009. < >, based on November 2008 SEER data submission, posted to the SEER web site.
12. Dieckmann KP, Pichlmeier UThe prevalence of familial testicular cancer: an analysis of two patient populations and a review of the literature. Cancer. 1997;80:1954–1960.[PubMed][Google Scholar]
13. Dong C, Hemminki KModification of cancer risks in offspring by sibling and parental cancers from 2,112,616 nuclear families. International Journal of Cancer. 2001;92:144–150.[PubMed][Google Scholar]
14. Hemminki K, Li XFamilial risk in testicular cancer as a clue to a heritable and environmental aetiology. British Journal of Cancer. 2004;90:1765–1770.[Google Scholar]
15. Swerdlow AJ, De Stavola BL, Swanwick MA, Maconochie NERisks of breast and testicular cancers in young adult twins in England and Wales: evidence on prenatal and genetic aetiology. Lancet. 1997;350:1723–1728.[PubMed][Google Scholar]
16. Wanderas EH, Fossa SD, Tretli SRisk of a second germ cell cancer after treatment of a primary germ cell cancer in 2201 Norwegian male patients. European Journal of Cancer. 1997;33:244–252.[PubMed][Google Scholar]
17. Fossa SD, Chen J, Schonfeld SJ, et al. Risk of contralateral testicular cancer: a population-based study of 29,515 U.S. men. Journal of the National Cancer Institute. 2005;97:1056–1066.[PubMed]
18. Swerdlow AJ, Higgins CD, Pike MCRisk of testicular cancer in cohort of boys with cryptorchidism. BMJ. 1997;314:1507–1511.[Google Scholar]
19. Toppari J, Kaleva MMaldescendus testis. Hormone Research. 1999;51:261–269.[PubMed][Google Scholar]
20. Dieckmann KP, Pichlmeier UClinical epidemiology of testicular germ cell tumors. World Journal of Urology. 2004;22:2–14.[PubMed][Google Scholar]
21. Akre O, Richiardi LDoes a testicular dysgenesis syndrome exist? Human Reproduction. 2009;24:2053–2060.[PubMed][Google Scholar]
22. Moller HTrends in sex-ratio, testicular cancer and male reproductive hazards: are they connected? APMIS. 1998;106:232–238. discussion 238-239. [[PubMed][Google Scholar]
23. Jacobsen R, Bostofte E, Engholm G, et al Risk of testicular cancer in men with abnormal semen characteristics: cohort study. BMJ. 2000;321:789–792.[Google Scholar]
24. Walsh TJ, Croughan MS, Schembri M, Chan JM, Turek PJIncreased risk of testicular germ cell cancer among infertile men. Archives of Internal Medicine. 2009;169:351–356.[Google Scholar]
25. Hotaling JM, Walsh TJMale infertility: a risk factor for testicular cancer. Nat Rev Urol. 2009[PubMed][Google Scholar]
26. de Gouveia Brazao CA, Pierik FH, Oosterhuis JW, Dohle GR, Looijenga LH, Weber RFBilateral testicular microlithiasis predicts the presence of the precursor of testicular germ cell tumors in subfertile men. Journal of Urology. 2004;171:158–160.[PubMed][Google Scholar]
27. DeCastro BJ, Peterson AC, Costabile RAA 5-year followup study of asymptomatic men with testicular microlithiasis. Journal of Urology. 2008;179:1420–1423. discussion 1423. [[PubMed][Google Scholar]
28. Duenas A, Saldivar C, Castillero C, Flores G, Martinez P, Jimenez MA case of bilateral seminoma in the setting of persistent mullerian duct syndrome. Revista de Investigacion Clinica. 2001;53:193–196.[PubMed][Google Scholar]
29. Moller H, Prener A, Skakkebaek NETesticular cancer, cryptorchidism, inguinal hernia, testicular atrophy, and genital malformations: case-control studies in Denmark. Cancer Causes and Control. 1996;7:264–274.[PubMed][Google Scholar]
30. Dieckmann KP, Loy VPrevalence of contralateral testicular intraepithelial neoplasia in patients with testicular germ cell neoplasms. Journal of Clinical Oncology. 1996;14:3126–3132.[PubMed][Google Scholar]
31. Skakkebaek NE, Berthelsen JG, Muller JCarcinoma-in-situ of the undescended testis. Urologic Clinics of North America. 1982;9:377–385.[PubMed][Google Scholar]
32. Berthelsen JG, Skakkebaek NE, von der Maase H, Sorensen BL, Mogensen PScreening for carcinoma in situ of the contralateral testis in patients with germinal testicular cancer. British Medical Journal (Clinical Research Ed.) 1982;285:1683–1686.[Google Scholar]
33. Kulkarni JN, Kamat MR, Borges AMBilateral synchronous tumors in testes in unrecognized mixed gonadal dysgenesis: a case report and review of literature. Journal of Urology. 1990;143:362–364.[PubMed][Google Scholar]
34. Chemes H, Muzulin PM, Venara MC, Mulhmann Mdel C, Martinez M, Gamboni MEarly manifestations of testicular dysgenesis in children: pathological phenotypes, karyotype correlations and precursor stages of tumour development. APMIS. 2003;111:12–23. discussion 23-14. [[PubMed][Google Scholar]
35. Smyth CM, Bremner WJKlinefelter syndrome. Archives of Internal Medicine. 1998;158:1309–1314.[PubMed][Google Scholar]
36. Skakkebaek NE, Holm M, Hoei-Hansen C, Jorgensen N, Rajpert-De Meyts EAssociation between testicular dysgenesis syndrome (TDS) and testicular neoplasia: evidence from 20 adult patients with signs of maldevelopment of the testis. APMIS. 2003;111:1–9. discussion 9-11. [[PubMed][Google Scholar]
37. Skakkebaek NE, Rajpert-De Meyts E, Main KMTesticular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Human Reproduction. 2001;16:972–978.[PubMed][Google Scholar]
38. Goedert JJ, McKeen EA, Javadpour N, Ozols RF, Pottern LM, Fraumeni JF., JrPolythelia and testicular cancer. Annals of Internal Medicine. 1984;101:646–647.[PubMed][Google Scholar]
39. Weir HK, Marrett LD, Kreiger N, Darlington GA, Sugar LPre-natal and peri-natal exposures and risk of testicular germ-cell cancer. International Journal of Cancer. 2000;87:438–443.[PubMed][Google Scholar]
40. Olsson H, Bladstrom A, Alm PMale gynecomastia and risk for malignant tumours--a cohort study. BMC Cancer. 2002;2:26.[Google Scholar]
41. Hardell L, Ohlson CG, Fredrikson MOccupational exposure to polyvinyl chloride as a risk factor for testicular cancer evaluated in a case-control study. International Journal of Cancer. 1997;73:828–830.[PubMed][Google Scholar]
42. Mai PL, Friedlander M, Tucker K, et al The International Testicular Cancer Linkage Consortium: A clinicopathologic descriptive analysis of 461 familial malignant testicular germ cell tumor kindred. Urol Oncol. 2009[Google Scholar]
43. Mai PL, Chen BE, Tucker K, et al Younger age-at-diagnosis for familial malignant testicular germ cell tumor. Fam Cancer. 2009 In Press. DOI 10.1007/s10689-10009-19264-10686. [Google Scholar]
44. Parenti GC, Zago S, Lusa M, Campioni P, Mannella PAssociation between testicular microlithiasis and primary malignancy of the testis: our experience and review of the literature. Radiol Med. 2007;112:588–596.[PubMed][Google Scholar]
45. Coffey J, Huddart RA, Elliott F, et al Testicular microlithiasis as a familial risk factor for testicular germ cell tumour. British Journal of Cancer. 2007;97:1701–1706.[Google Scholar]
46. Korde LA, Premkumar A, Mueller C, et al Increased prevalence of testicular microlithiasis in men with familial testicular cancer and their relatives. British Journal of Cancer. 2008;99:1748–1753.[Google Scholar]
47. Rapley EA, Turnbull C, Al Olama AA, et al A genome-wide association study of testicular germ cell tumor. Nature Genetics. 2009;41:807–810.[Google Scholar]
48. Kanetsky PA, Mitra N, Vardhanabhuti S, et al Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer. Nature Genetics. 2009;41:811–815.[Google Scholar]
49. Chanock SHigh marks for GWAS. Nature Genetics. 2009;41:765–766.[Google Scholar]
50. Ashman LKThe biology of stem cell factor and its receptor C-kit. International Journal of Biochemistry and Cell Biology. 1999;31:1037–1051.[PubMed][Google Scholar]
51. Runyan C, Schaible K, Molyneaux K, Wang Z, Levin L, Wylie CSteel factor controls midline cell death of primordial germ cells and is essential for their normal proliferation and migration. Development. 2006;133:4861–4869.[PubMed][Google Scholar]
52. Gu Y, Runyan C, Shoemaker A, Surani A, Wylie CSteel factor controls primordial germ cell survival and motility from the time of their specification in the allantois, and provides a continuous niche throughout their migration. Development. 2009;136:1295–1303.[PubMed][Google Scholar]
53. Wang ZQ, Si L, Tang Q, et al Gain-of-function mutation of KIT ligand on melanin synthesis causes familial progressive hyperpigmentation. American Journal of Human Genetics. 2009;84:672–677.[Google Scholar]
54. Nishida T, Hirota S, Taniguchi M, et al Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nature Genetics. 1998;19:323–324.[PubMed][Google Scholar]
55. Tang X, Boxer M, Drummond A, Ogston P, Hodgins M, Burden ADA germline mutation in KIT in familial diffuse cutaneous mastocytosis. Journal of Medical Genetics. 2004;41:e88.[Google Scholar]
56. Rapley EA, Hockley S, Warren W, et al Somatic mutations of KIT in familial testicular germ cell tumours. British Journal of Cancer. 2004;90:2397–2401.[Google Scholar]
57. Coffey J, Linger R, Pugh J, et al Somatic KIT mutations occur predominantly in seminoma germ cell tumors and are not predictive of bilateral disease: report of 220 tumors and review of literature. Genes, Chromosomes and Cancer. 2008;47:34–42.[PubMed][Google Scholar]
58. Heaney JD, Lam MY, Michelson MV, Nadeau JHLoss of the transmembrane but not the soluble kit ligand isoform increases testicular germ cell tumor susceptibility in mice. Cancer Research. 2008;68:5193–5197.[Google Scholar]
59. Pedersini R, Vattemi E, Mazzoleni G, Graiff CComplete response after treatment with imatinib in pretreated disseminated testicular seminoma with overexpression of c-KIT. Lancet Oncol. 2007;8:1039–1040.[PubMed][Google Scholar]
60. Murty VV, Houldsworth J, Baldwin S, et al Allelic deletions in the long arm of chromosome 12 identify sites of candidate tumor suppressor genes in male germ cell tumors. Proceedings of the National Academy of Sciences of the United States of America. 1992;89:11006–11010.[Google Scholar]
61. Rapley EA, Crockford GP, Teare D, et al Localization to Xq27 of a susceptibility gene for testicular germ-cell tumours. Nature Genetics. 2000;24:197–200.[PubMed][Google Scholar]
62. Rapley EA, Crockford GP, Easton DF, Stratton MR, Bishop DTLocalisation of susceptibility genes for familial testicular germ cell tumour. APMIS. 2003;111:128–133. discussion 133-125. [[PubMed][Google Scholar]
63. Crockford GP, Linger R, Hockley S, et al Genome-wide linkage screen for testicular germ cell tumour susceptibility loci. Human Molecular Genetics. 2006;15:443–451.[PubMed][Google Scholar]
64. Youngren KK, Coveney D, Peng X, et al The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours. Nature. 2005;435:360–364.[Google Scholar]
65. Linger R, Dudakia D, Huddart R, et al Analysis of the DND1 gene in men with sporadic and familial testicular germ cell tumors. Genes, Chromosomes and Cancer. 2008;47:247–252.[Google Scholar]
66. Nathanson KL, Kanetsky PA, Hawes R, et al The Y deletion gr/gr and susceptibility to testicular germ cell tumor. American Journal of Human Genetics. 2005;77:1034–1043.[Google Scholar]
67. Krausz C, Looijenga LHGenetic aspects of testicular germ cell tumors. Cell Cycle. 2008;7:3519–3524.[PubMed][Google Scholar]
68. Horvath A, Korde L, Greene MH, et al Functional phosphodiesterase 11A mutations may modify the risk of familial and bilateral testicular germ cell tumors. Cancer Research. 2009;69:5301–5306.[Google Scholar]
69. Wayman C, Phillips S, Lunny C, et al Phosphodiesterase 11 (PDE11) regulation of spermatozoa physiology. International Journal of Impotence Research. 2005;17:216–223.[PubMed][Google Scholar]
70. Horvath A, Boikos S, Giatzakis C, et al A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia. Nature Genetics. 2006;38:794–800.[PubMed][Google Scholar]
71. Oosterhuis JW, Looijenga LHTesticular germ-cell tumours in a broader perspective. Nat Rev Cancer. 2005;5:210–222.[PubMed][Google Scholar]
72. McIntyre A, Gilbert D, Goddard N, Looijenga L, Shipley JGenes, chromosomes and the development of testicular germ cell tumors of adolescents and adults. Genes, Chromosomes and Cancer. 2008;47:547–557.[PubMed][Google Scholar]
73. Goddard NC, McIntyre A, Summersgill B, Gilbert D, Kitazawa S, Shipley JKIT and RAS signalling pathways in testicular germ cell tumours: new data and a review of the literature. International Journal of Andrology. 2007;30:337–348. discussion 349. [[PubMed][Google Scholar]
74. Atkin NB, Baker MCSpecific chromosome change, i(12p), in testicular tumours? Lancet. 1982;2:1349.[PubMed][Google Scholar]
75. Looijenga LH, Zafarana G, Grygalewicz B, et al Role of gain of 12p in germ cell tumour development. APMIS. 2003;111:161–171. discussion 172-163. [[PubMed][Google Scholar]
76. Goriely A, Hansen RM, Taylor IB, et al Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nature Genetics. 2009;41:1247–1252.[Google Scholar]
77. Heaney JD, Nadeau JHTesticular germ cell tumors in mice: new ways to study a genetically complex trait. Methods in Molecular Biology. 2008;450:211–231.[PubMed][Google Scholar]
78. Heaney JD, Michelson MV, Youngren KK, Lam MY, Nadeau JHDeletion of eIF2beta suppresses testicular cancer incidence and causes recessive lethality in agouti-yellow mice. Human Molecular Genetics. 2009;18:1395–1404.[Google Scholar]
79. Lam MY, Heaney JD, Youngren KK, Kawasoe JH, Nadeau JHTransgenerational epistasis between Dnd1Ter and other modifier genes controls susceptibility to testicular germ cell tumors. Human Molecular Genetics. 2007;16:2233–2240.[PubMed][Google Scholar]
80. Peters JA, Vadaparampil ST, Kramer J, et al Familial testicular cancer: interest in genetic testing among high-risk family members. Genet Med. 2006;8:760–770.[PubMed][Google Scholar]
81. Peters JA, Beckjord EB, Banda Ryan DR, et al Testicular cancer and genetics knowledge among familial testicular cancer family members. J Genet Couns. 2008;17:351–364.[Google Scholar]
82. Vadaparampil ST, Moser RP, Loud J, Peters JA, Greene MH, Korde LFactors associated with testicular self-examination among unaffected men from multiple-case testicular cancer families. Hered Cancer Clin Pract. 2009;7:11.[Google Scholar]