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Testicular germ cell tumor (TGCT) is the most common malignancy in young men. Familial clustering, epidemiologic evidence of increased risk with family or personal history, and the association of TGCT with congenital genitourinary tract anomalies suggest an underlying genetic predisposition (1-6). Unfortunately, unraveling its genetic basis through traditional linkage studies has been difficult, in part because families with many affected individuals are exceedingly rare (7-10). Several cytogenetic abnormalities have been associated with sporadic TGCT, notably somatic isochromosome 12p in tumor tissue, and the germ-line chromosome abnormality 47,XXY (Klinefelter syndrome), which is associated with an increased risk of mediastinal germ cell tumors (11). Cytogenetic abnormalities have led to the localization of several hereditary cancer syndrome genes (e.g., retinoblastoma, Wilms tumor, and familial adenomatous polyposis; refs. 12-14). Given the paucity of data about potential genetic mechanisms in hereditary TGCT (HTGCT), we did conventional karyotype analysis and spectral karyotyping (SKY) in the largest cohort of HTGCT cases studied to date, seeking clues to the location of as-yet-unidentified testicular cancer susceptibility genes. We also provide a brief summary of previously reported cases and conclude that large-scale chromosome abnormalities are likely not the cause of the majority of HTGCT cases.
The Multidisciplinary Etiologic Study of Familial Testicular Cancer was initiated in 2002 (National Cancer Institute Protocol 02-C-0178) to identify possible testicular cancer susceptibility genes and to characterize more precisely the clinical phenotype of the familial testicular cancer syndrome (15). For this analysis, the first 28 consecutive TGCT patients to enroll in this ongoing protocol were studied. This was a convenience sample, constrained in size by cost considerations and lacking a prior hypothesis to suggest a particular subset or number of cases would be statistically appropriate. Classic G-banding cytogenetic analysis and SKY were done on metaphase spreads of cultured peripheral blood lymphocytes from each subject; a minimum of 20 metaphases was analyzed for nonrandom clonal abnormalities (16). Results were reported using the International System for Human Cytogenetic Nomenclature (17). A literature review was also done via PubMed, using all languages and the search terms hereditary testicular cancer, familial testicular, and genetics and testicular cancer, to identify HTGCT cases that have previously been evaluated using these cytogenetic techniques; three reports were identified (18-20).
We studied 28 affected individuals from 17 independent families composed of 3 father-son pairs, 5 sibling pairs, 4 cousin pairs, 4 with a complex affection pattern, and 1 bilateral case (Table 1). Mean age at HTGCT diagnosis was 30 years, and the usual 50:50 mix of seminoma and nonseminomatous tumors was observed. We detected a constitutional chromosome abnormality in 1 of 28 subjects (#23), 46,XY,inv(7)(q21.2q32), with no detectable loss or gain of chromosomal material using G-banding and SKY (Fig. 1). His father (#22) had TGCT and was cytogenetically normal (46,XY). We identified the same chromosome inversion in his mother, who had neither a personal nor family history of cancer and no identifiable phenotypic abnormalities, leading us to conclude that this germ-line chromosome abnormality was not associated with TGCT risk.
Our literature review revealed 17 previously studied HTGCT cases from 14 independent families (Table 1). Seven of these cases were bilateral affecteds with no family history of TGCT. There were no detectable cytogenetic abnormalities in these 17 individuals. Based on finding one chromosome abnormality among 45 subjects studied with standard cytogenetic techniques of comparable quality, and given that the general population incidence of chromosome abnormalities is 1/160 (21), the relative risk = (1/45)/(1/160) = 3.6 (exact 95% confidence interval, 0.09-19). This association is not causal, as the one abnormality was inherited from the unaffected bloodline. With 95% confidence, the confidence interval excludes the existence of a causal abnormality with relative risk >19.
Family history is a well-known TGCT risk factor, with sons and brothers of affected individuals having 4- to 6-fold and 8- to 12-fold risk increases, respectively (1, 3-6). Other established TGCT risk factors include previous contralateral TGCT, cryptorchidism, gonadal dysgenesis, inguinal hernia, and hypospadias (11). Disorders of male urogenital differentiation have been suggested to be part of a testicular dysgenesis syndrome that includes TGCT (22). Furthermore, individuals with several genetic syndromes associated with male urogenital differentiation are also at risk of developing germ cell tumors, including Klinefelter syndrome, XY gonadal dysgenesis, and possibly Down syndrome (trisomy 21; refs. 11, 22, 23). Although these disorders do not fully explain the familial clustering of TGCT, clearly there is evidence that TGCT susceptibility genes exist (7).
The identification of constitutional cytogenetic abnormalities has led to the localization and cloning of several hereditary cancer syndrome genes. Although previous studies failed to detect constitutional chromosome abnormalities in males with HTGCT, these studies were limited in their number of familial cases. Therefore, to circumvent the linkage analysis difficulties in familial testicular cancer, we sought to identify constitutional chromosome abnormalities in 27 individuals with HTGCT and 1 with bilateral TGCT using G-banding and SKY.
We detected a chromosome 7q paracentric inversion in one TGCT case, but this abnormality did not explain the clustering of TCGT in his family. Inversions have been more widely recognized since the advent of chromosome banding techniques, with chromosome 7 paracentric inversions among the most common. Nearly 70% of paracentric inversions are inherited; the majority are identified incidentally and are not associated with clinical features of a genetic syndrome (24). There have been no reports linking this inversion, or its related breakpoints, with any phenotypic abnormalities. Therefore, we have concluded that it is not associated with an inherited predisposition to HTGCT.
In summary, we found no disease-associated germ-line cytogenetic abnormalities in either 28 HTGCT cases we studied or 17 previously reported cases. Because G-banding (5-8 Mb resolution) and SKY (2-3 Mb resolution) require direct visualization of chromosomes, small aberrations such as microdeletions or duplications would not have been detected in our patients. Therefore, higher resolution tools such as array-based comparative genomic hybridization, which has not been systematically applied to TGCT, are potentially more sensitive to identifying genomic regions containing high-penetrance HTGCT susceptibility genes.