MAGE-A4 is a member of the MAGE-A gene family, which consists of at least 12 genes that are activated in various tumors, including melanoma and GCTs.6,76-79 These genes encode for tumor antigens that can be recognized by tumor-specific cytolytic T

lymphocytes, and they appear to have a role in clinical immunity in some tumors. Takahashi and colleagues demonstrated the expression of MAGE proteins in human spermatogonia and (to a lesser extent) in human primary spermatocytes.80 Aubry and colleagues6 confirmed these results and also showed that Sertoli's cells and spermatids did not express MAGE-A4 immunohistochemically. These workers showed an absence of MAGE-A4 reactivity in embryonic and fetal gonads at up to 15 weeks of gestation, weak positive staining at 17 weeks, and strong staining by 28 weeks. These data suggest that the second meiotic division may interfere with the expression of this gene.

In an extensive study, Aubry and colleagues6 reported expression of MAGE-A4 in 12 of 12 classic seminomas, 0 of 5 anaplastic seminomas, 0 of 10 NSGCTs, in the seminomatous regions of two mixed tumors (seminoma/NSGCT), and in 0 of 2 Leydig cell tumors and 0 of 1 Sertoli cell tumor. Of particular interest, they also showed expression of this gene in some elements of CIS associated with seminoma and NSGCT, but with considerable heterogeneity of expression in different regions of the testis. Others have shown greater heterogeneity of expression in seminoma.77-79 Hara and colleagues, using a polymerase chain reaction technique, reported the expression of MAGE-A4 in NSGCTs78 although this observation could reflect contamination by nonmalignant germline elements within the tumor-bearing testis. Nevertheless, Aubry and colleagues hypothesized that MAGE-A4 is expressed in premeiotic germ cells and GCTs that express classic germ cell lineage but not in tumors with embryonic, extraembryonic, or somatic differentiation, perhaps yielding important information about the differential lineage of seminoma and NSGCT.6 However, at the time of reporting, it was too early to assess whether MAGE-A4 had any functional role in the progression from the primordial germ cell to the malignant state.

Cyclin D2

The D-type cyclins (D1, D2, and D3) are important regulators of cell cycle function, particularly the G1 phase. In a series of experiments in knockout mice, Sicinski and colleagues showed that cyclin D2 defi ciency leads to sterility because of the failure of ovarian granulosa cells to proliferate normally in response to follicle-stimulating hormone (FSH).81 Males deficient in the D cyclins have testicular hypoplasia. Sicinski and colleagues showed that GCT cell lines often express high levels of cyclin D2 mRNA but very little or no cyclin D1 and D3 and that an increased copy number of the cyclin D2 gene is often present in these cell lines.81 Extra copies of the chromosomal region 12p13, which contains the cyclin D2 gene, are very common in testicular GCTs and presumably are provided by i(12p). These data suggest that the expression of a cyclin that is essential for the development of a specific tissue is particularly susceptible to being subverted during onco-genesis in the same tissue.81


The epidemiology of GCTs is reviewed in detail in Chapter 2. To some extent, what is known about the clinical epidemiology of these tumors is revealing of their histogenesis. One of the more dramatic aspects of the epidemiology of this disease is the clear evidence of increasing incidence during the past century, with a rise from around 2 to 3 new cases per 100,000 males per year to the current level of 6 to 8 new cases per 100,000 males per year in some populations. There is a definite racial predominance, with a white-to-black ratio of up to 40:1.82 The highest incidences are found in Scandinavia and New Zealand, but the basis of this is unknown. The most common traditional etiologic association is the linkage between cryptorchidism and the genesis of tes-ticular cancer. As noted previously, an unexpectedly frequent association is the concurrence of atypical cutaneous nevi and germ cell malignancies, which appears to be more common than the linkage of tes-ticular maldescent and GCTs.74 While a potential mechanism via altered signaling of c-kit offers an attractive explanation, no finite data have been reported on this issue. A possible model of relevance may again be provided by the 129 strain mouse, bearing the lethal yellow allele of the agouti locus (Ay) in this instance. This variant shows a reduced incidence of GCTs but an increased frequency of other solid tumors.55 Of particular interest is the observation that the agouti gene product may inhibit function of melanocortin receptors,83 which may provide a mechanism linking the biology of GCTs and that of pigmented skin tumors.

Most of the etiologic and epidemiologic associations appear to point to an origin in atypical germ cells. The association of testicular maldescent and the formation of testicular tumors has been known for more than 200 years,84,85 and atypical germ cells have been identified in cryptorchid testicles.22 Similarly, testicular cancer is found more commonly in patients with testicular dysgenesis, infertility, and Kleinfelter's syndrome (with expression of an XXY chromosome). Additional epidemiologic associations include reduced body muscle mass and a lower prevalence of male pattern baldness, which may imply lower circulating testosterone levels, as either a cause or an effect of testicular cancer.86 Although testicular trauma and mumps orchitis have largely been discounted as antecedents of GCTs,87,88 earlier studies suggested that both could have mechanisms of oncogenesis predicated on testicular atrophy and the consequent evolution of atypical germ cells. Similar mechanisms have been considered to be involved in studies that have suggested that the ingestion of estrogens during the first trimester of pregnancy may be associated with an increased risk of testicular cancer in the offspring.89 It thus appears that subjects with reproductive disorders associated with a relative deficiency of androgen function are at increased risk of testicular cancer. As increases in the length of a trinucleotide repeat cytidine, adenine, guanine (CAG) in the androgen receptor gene may lead to reduced transactivation of this gene, King and col-leagues90 assessed a series of 11 testicular cancer cell lines for expanded (CAG)« tracts in DNA and identified this phenomenon in five lines. In addition, they found expanded CAG repeats in 1 of 11 sporadic testicular tumors. However, when comparing the expression of this repeat in patients with testicular cancer and in control subjects, Rajpert-De Meyts and colleagues did not reveal any significant differences in prevalence of CAG repeats in the androgen receptor genes between the two populations.91 Further studies are needed to clarify this important issue.

As an extension of this concept of genetic transmission, family clustering has occasionally been reported, with a possible increased incidence in father-son and sibling pairs.68,92,93 In theory, this phenomenon could reflect a heritable pattern of CAG repeats with associated alterations in the function of the androgen receptor gene within sequential generations of affected families. This could also explain the racial differences in the incidence of tes-ticular cancer. My colleagues and I postulated the potential for genetic anticipation in germ cell malignancy about 20 years ago, based on a limited database of father-son pairs.68 Recently, Han and Peschel94 have updated the literature, identifying 52 father-son pairs with testicular germ cell tumors, and have suggested that genetic anticipation does, in fact, occur in this disease. They have dealt with the issue of case ascertainment bias to some extent, noting that fathers have tended to present later and with less aggressive disease than have their offspring. In this study, earlier presentation and the presence of NSGCT (rather than seminoma) were identified as parameters of genetic anticipation and increased aggression. However, it should be noted that semi-noma per se is not necessarily a less aggressive tumor than NSGCT and that the improved results of therapy reflect greater responsiveness to radiation therapy and, perhaps, to chemotherapy. In addition, this study did not take into consideration the potential impact of the development of effective chemotherapy for advanced disease; in the past 20 years, the potential for patients with more aggressive disease to survive and to produce children has changed dramatically. In addition, hormonal factors may confound the process, as discussed below. Thus, the real situation in regard to the impact of genetic anticipation in germ cell malignancy remains unresolved.

As noted above, several parameters of testicular dysfunction and infertility are associated with the development of GCTs. The prevalence of high circulating levels of FSH may explain some of the populations that have an increased incidence of GCTs, with one of the putative mechanisms being altered expression or function of the cyclin D proteins. Of relevance, one study found that male dizygotic twins are three times more likely to develop testicular GCTs than are male monozygotic twins although it should be noted that zygosity was determined by questionnaire in this study.95 A potential explanation of this finding may be the association of FSH hypersecretion in the mothers of dizygotic twins, a marked similarity between the geographic distribution in the occurrence of dizygotic twinning and tes-ticular cancer, the apparent linkage of high levels of cyclin D2 and FSH, and the association between Down syndrome, FSH hypersecretion, and testicular cancer.96 This leads to the hypothesis that chronic FSH hypersecretion may be causative of testicular cancer.96 This may also be a mechanism for the familial aggregation of GCTs as noted above, analogous to the putative familial hormone patterns that lead to the familial aggregation of male pattern baldness (it should not be forgotten that in patients with testicular cancer, baldness is in fact less common).

It should also be noted that a direct hormonal association of testicular dysfunction, hormonal levels, and testicular cancer is not the only putative mechanism. For example, many of the epidemio-logic observations in testicular cancer patients could be explained on the basis of a transmitted carcinogen. For example, Schwartz has hypothesized that ochratoxin A, a mycotoxin found as a contaminant of various foods, may cause testicular cancer.97 Ochratoxin A is a known genotoxic carcinogen and has been shown in animal experiments to cause adducts in testicular DNA. Thus, this is another potential mechanism for familial aggregation, given the tendency for clustering of familial dietary patterns. This association has not been proved for GCTs in human studies, but it is a reminder that much current epidemiologic information is circumstantial and that the exact origins and histogenetic mechanisms in the formation of GCTs remain unclear.

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