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Other entities represented in this entry:
SNOMEDCT: 713577007; ORPHA: 363483, 363494, 363504, 842, 876, 99865; DO: 5557;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p22.3 | {Male germ cell tumor, somatic} | 273300 | 3 | BCL10 | 603517 | |
| 4p16.3 | Spermatocytic seminoma, somatic | 273300 | 3 | FGFR3 | 134934 | |
| 4q12 | Germ cell tumors, somatic | 273300 | 3 | KIT | 164920 | |
| 19p13.3 | Testicular tumor, somatic | 273300 | 3 | STK11 | 602216 |
A number sign (#) is used with this entry because testicular germ cell tumors have been associated with somatic mutation in several genes; see MOLECULAR GENETICS.
Testicular germ cell tumors (TGCTs) affect 1 in 500 men and are the most common cancer in males aged 15 to 40 in western European populations. The incidence of TGCT rose dramatically during the 20th century. Known risk factors for TGCT include a history of undescended testis (UDT), testicular dysgenesis, infertility, previously diagnosed TGCT, and a family history of the disease. Brothers of men with TGCT have an 8- to 10-fold risk of developing TGCT, whereas the relative risk to fathers and sons is 4-fold. This familial relative risk is much higher than that for most other types of cancer (summary by Rapley et al., 2000).
Genetic Heterogeneity of Testicular Germ Cell Tumors
A locus for testicular germ cell tumors (TGCT1; 300228) has been identified on chromosome Xq27.
Hutter et al. (1967) reviewed the reports of testicular tumors in brothers and in twins and reported affected brothers.
Gustavson et al. (1975) reported bilateral testicular teratoma in 2 infant brothers with XXY Klinefelter syndrome. One of them also had hydrocephalus due to stenosis of the aqueduct of Sylvius. Familial occurrence of the Klinefelter syndrome is rare. The association of the Klinefelter syndrome and testicular teratoma may be more than coincidental because they have been observed together in other cases and many testicular teratoma are both X-chromatin and Y-chromatin positive suggesting that they are XXY.
Raghavan et al. (1980) reported a father who had sequential bilateral seminomas and a son who had embryonal cell carcinoma and seminoma. The authors reviewed 5 other reports of testicular tumors in father and son, as well as 7 reports of concordant monozygotic twin pairs and 11 reports of nontwin brothers. The report of Raghavan et al. (1980) illustrates the dominant inheritance of hereditary tumors and their bilaterality (e.g., acoustic neuroma, retinoblastoma, pheochromocytoma, etc.). The sons (and other first-degree relatives) of men with bilateral tumors may be at particular risk.
Shinohara et al. (1980) reported mature testicular teratoma in 2 first cousins. Furthermore, the common grandparents were consanguineous, being related as first cousins. The parent (i.e., the parent involved in the consanguinity) of the teratoma-carrying boys was the mother in one case and the father in the other. In a 10-member sibship in a Spanish-American family, DiBella (1983) described testicular neoplasm in 3 brothers, benign ovarian neoplasms in 2 sisters, suspected benign tumors of the uterus in 2 additional sisters, and a suspected testicular mass in a fourth brother. Lynch et al. (1985) described the infantile form of embryonal carcinoma of the testis in a 5-year-old boy and in a 23-year-old man who was the maternal half brother of his mother. Copeland et al. (1986) reported testicular embryonal carcinoma in 2 brothers and a first cousin.
Von der Maase et al. (1986) found carcinoma in situ in the contralateral testis in 27 of 500 patients (5.4%) with unilateral testicular germ cell cancer. The estimated risk of developing invasive growth from the contralateral testicular cancer was 40% within 3 years and 50% within 5 years. None of the 473 patients without carcinoma in situ detected by screening biopsy developed contralateral testicular cancer after an observation time ranging from 12 to 96 months. These observations suggested to the authors that there is a subset of this type of testicular cancer that is genetic and has a bilateral predisposition. The authors suggested that all such carcinomas begin as carcinoma in situ. Von der Maase et al. (1986) recommended that all patients with unilateral testicular germ cell cancer should be offered biopsy of the contralateral testis. Of the 27 patients, 16 had a cancer that was labeled seminoma and 11 had a cancer that was considered to be nonseminoma. It would be of great interest to know the median age of the patients with contralateral carcinoma in situ as contrasted with the others. If these represent a subset who had inherited 1 of the 2 mutations according to the Knudson theory, then the patients with contralateral carcinoma in situ should have an earlier average age of development of carcinoma.
Patel et al. (1990) reported 6 cases of familial testicular cancer: 4 father-son pairs, a pair of brothers, and a 23-year-old man who had a maternal uncle with testicular cancer. In the U.K., according to Forman et al. (1992), 42 families with 2 or more cases of testicular cancer were reported to the familial testicular cancer registry. These families included 2 pairs of identical twins, 27 sets of other brothers (25 pairs, 2 triples), 9 father-son pairs, 2 pairs of first cousins, and 2 uncle-nephew pairs. In all, 91 testicular tumors were described in 86 persons. Pure seminoma was present in 46% and other germ cell tumors in 54%. The median age at diagnosis was significantly younger than in a comparable series of nonfamilial patients. The cumulative risk of developing testicular cancer by the age of 50 years for a brother of a patient was estimated to be 2.2%, which results in a relative risk of 9.8 in comparison with the general population. No significant peculiarity of class I HLA type was found in a study of 21 affected sib pairs.
Huddart et al. (1996) studied 3 families suggesting that there is a familial predisposition to both male and female germ cell tumors. In 1, the proband presented with a seminoma at the age of 51, his brother had had a testicular teratoma at the age of 28, and their cousin had an endodermal sinus tumor of the ovary diagnosed at 32 years. In the second family, the index case presented with an undifferentiated malignant teratoma at 28 years of age and his sister was diagnosed with bilateral mature teratomatous cysts at the age of 39. In the third family, the index case presented with a retroperitoneal teratoma at 26 years and his sister was diagnosed with an ovarian dysgerminoma at 45 years. Huddart et al. (1996) noted that none of these families had any features indicative of the Li-Fraumeni syndrome (151623) or any other cancer family syndrome. Trentini and Palmieri (1974) and Yule et al. (1994) reported single families with ovarian and testicular germ cell tumors and Jackson (1967) presented a family with multiple cases of dysgerminoma.
Greene et al. (2010) noted that in familial cases the most common number of affected family members was 2, that age at diagnosis was 2 to 3 years younger for familial versus sporadic cases, and that familial TGCT were more likely to be bilateral than sporadic TGCT.
Association with Testicular Microlithiasis
Coffey et al. (2007) analyzed the frequency of testicular microlithiasis (TM; 610441) in 169 patients with testicular germ cell tumor (TGCT), 58 relatives, and 101 controls and found that TM was more frequent in unaffected male relatives of TGCT cases than controls and that patients with a history of TGCT had a higher frequency of TM in their contralateral remaining testis than controls. Coffey et al. (2007) also demonstrated significant concordance of TM between relatives, raising the hypothesis that TGCT and TM have a joint etiology.
Korde et al. (2008) performed testicular ultrasound in 48 men with familial testicular cancer from 31 families with at least 2 cases of TGCT, and in 33 of their unaffected male relatives. Testicular microlithiasis (TM) was more frequent in the contralateral testicles of men with a history of TGCT than in unaffected men (48% vs 24%; p = 0.04). The association appeared stronger for men with 5 or more microliths than for those with less than 5 microliths. Testicular microlithiases were bilateral in 6 (75%) of the 8 unaffected men in whom they were detected. Among affected men, TM was not associated with histology, age at diagnosis, or cancer treatment. Korde et al. (2008) noted that TM was more prevalent among unaffected family members in this study (24%) than previously described in the general population (0.6 to 9%), and that it appeared to cluster in certain families. The findings suggested both a familial predisposition to TM and an association between TM and TGCT.
Forman et al. (1992) reported an epidemiologic study that showed an 8- to 10-fold increase in relative risk of testicular cancer to brothers of patients and a 4-fold increase in risk to fathers and sons. Families with multiple cases of testicular cancer are rare and almost all those reported have only 2 affected members.
Heimdal et al. (1996) found that 51 of 922 (5.5%) Norwegian patients with testicular cancer and 5 of 237 (2.1%) Swedish patients had a relative with confirmed testicular cancer. It was a first-degree relative who was affected in the case of 32 of the probands. Standardized incidence ratios (SIRs) were 10.2 for brothers, 4.3 for fathers, and 5.7 for sons. The estimate for the risk to brothers in the Norwegian part of the sample for development of testicular cancer by the age of 60 was 4.1%. Patients with familial testicular cancer had bilateral tumors more often than sporadic cases (9.8% bilaterality in familial vs 2.8% in sporadic cases; P = 0.02). For patients with seminoma, age of onset was lower in familial than in sporadic cases (32.9 vs 37.6 years; P = 0.06). Heimdal et al. (1996) stated that the prevalence of undescended testis did not seem to be higher in familial than in sporadic testicular cancer.
Einhorn (2002) stated that the highest worldwide incidence of germ cell tumors is in Scandinavian countries; by contrast, testicular cancer is rare in African Americans. The primary age group is 15 to 35 years for nonseminomatous tumors and a decade older for seminomas. Although cases are few, germ cell tumors are important because they represent the most common carcinoma in men aged 15 to 35 years and thus have the potential to greatly shorten productive years of life. Available serum markers such as alphafetoprotein (104150) and human chorionic gonadotropin have allowed clinicians to make important and accurate treatment-related decisions. Testicular cancer is a model for multidisciplinary care, as surgical resection of postchemotherapy radiographically persistent disease can improve the cure rate. Germ cell tumors have become an excellent testing ground for experimental drugs, a number of which were first approved by the Food and Drug Administration primarily on the basis of data in testicular cancer.
Greene et al. (2010) reviewed the genetic risk factors and clinical phenotype of familial testicular germ cell tumors in adults, noting that although linkage analyses had identified several genomic regions of modest interest, no high-penetrance cancer susceptibility gene had been mapped to date, suggesting that the combined effects of multiple common alleles, each conferring modest risk, might underlie familial testicular cancer.
L1 Methylation Status
Mirabello et al. (2010) studied global methylation at long interspersed nuclear elements-1 (L1; 151626) in DNA from 152 patients with TGCT and 314 unaffected family members from 101 multiple-case testicular cancer families. Analysis of the correlation of L1 methylation levels among parent-child pairs independent of affection status revealed a strong positive association only between mother-daughter (r = 0.48; p = 0.0002) and father-daughter (r = 0.31; p = 0.021) pairs, suggesting gender-specific inheritance of methylation. Incorporating cancer status into the analysis revealed a strong correlation in L1 methylation levels only among affected father-son pairs (r = 0.49; p = 0.03). There was a marginally significant inverse association between lower L1 methylation levels and increased risk of TGCT, compared to healthy male relatives (p = 0.049). Mirabello et al. (2010) stated that their findings suggested that heritability of L1 methylation might be gender-specific, and that transgenerational inheritance of L1 methylation levels might be associated with testicular cancer risk.
Studying direct preparations and 24-hr cultures, Atkin and Baker (1982) found an isochromosome for the short arm of chromosome 12 in all of 10 seminomas, 1 malignant teratoma, and 1 combined seminoma and teratoma of the testis. (The same workers found a possible isochromosome for 5p in 12 of 18 carcinomas of the cervix.) They also noted a relative excess of normal chromosomes 12 in 4 of 5 of the seminomas analyzed in detail. Castedo et al. (1989) found at least 1 copy of a 12p isochromosome in 8 of 10 seminomas. Thus, the authors concluded that amplification of 1 or more genes on the short arm of chromosome 12 may be important in the development of malignant testicular tumors. Chromosomal changes presumably lead to the malignant phenotype by gene loss, gene modification or gene amplification.
Samaniego et al. (1990) analyzed the karyotype of 24 male germ cell tumors from both testicular and extragonadal sites and belonging to the histologic categories seminoma, teratoma, embryonal carcinoma, choriocarcinoma, and endodermal sinus tumor. In 90% of tumors, including all histologic subtypes and both gonadal and extragonadal presentation, they found isochromosome 12p. In contrast, they found del(12)(q13-q22) exclusively in nonseminomatous GCTs, and mixed GCTs occurring in 44% of such lesions. They developed a method based on DNA analysis for detecting i(12p) as increased copy number of 12p. Furthermore, they detected cytologic evidence of gene amplification in 12p in the form of homogeneously staining regions (HSRs) and double minute chromosomes in both treated and untreated primary extragonadal and metastatic GCTs.
Suijkerbuijk et al. (1991, 1992) applied competitive in situ hybridization (CISH) techniques (Kievits et al., 1990) to show that the aberrant chromosome in testicular germ cell tumors is indeed an isochromosome 12p. Other marker chromosomes representing translocation products that involve chromosome 12 were also identified. In the studies, DNAs from 2 rodent-human somatic cell hybrids, containing either a normal chromosome 12 or the p arm of chromosome 12 as their unique human material, were used as probes. (Competitive in situ hybridization, also referred to as chromosome painting, employs large pools of cloned genomic sequences originating from a single human chromosome as probe and involves a preannealing step in the presence of an excess of sonicated total human DNA. It results in complete staining of the particular chromosome in metaphase spreads and in interphase nuclei. Kievits et al., 1990 stated that the approach permits detection of hitherto undetectable chromosomal aberrations.)
In a cytogenetic analysis of 65 consecutively ascertained GCTs with chromosomal abnormalities, Rodriguez et al. (1992) found that an isochromosome for the short arm of chromosome 12 (i(12p)), monosomy 12, and deletions in 12q occurred with frequencies of 86%, 11%, and 20% respectively.
Because a marker chromosome interpreted as isochromosome 12p is present in most testicular tumors of germ cell origin, Peltomaki et al. (1992) investigated 22 patients with testicular germ cell tumors by Southern blot hybridization to characterize changes in chromosome 12. In comparison with normal DNA, tumor DNA of 18 patients showed increased dosages of 12p accompanied by a comparable or smaller increase or no change in the dosage of centromeric sequences of chromosome 12. The interpretation offered by the authors was that most testicular tumors had one or several isochromosomes for 12p that were formed by somatic division of the centromere and that the points of breakage and reunion in the centromeric region were different in different tumors. Sex-limited parental imprinting was excluded by the fact that allelic 12p fragments showing increased intensity were paternal in 4 and maternal in 3 of 7 informative cases. Furthermore, the observed patterns of allelic fragments suggested that the marker isochromosome was formed by sister chromatids of 1 homolog number 12 rather than the result of interchange of genetic material between different homologs.
Ottesen et al. (2004) studied 3 brothers with germ cell tumors. One had an intracranial tumor in the pineal region and the other 2 had testicular tumors. No abnormalities were detected in peripheral blood with karyotyping and molecular marker analysis of selected loci. High-resolution comparative genomic hybridization (CGH) analysis of microdissected histologic components of the overt tumors and the adjacent carcinoma in situ demonstrated a pattern of genomic imbalances characteristic for sporadic GCTs, including gain of 12p.
Stadler et al. (2012) investigated germline de novo copy number variations (CNVs) in 382 genomes of 116 early-onset cancer case parent trios and unaffected sibs. Unique de novo germline CNVs were not observed in 107 breast or colon cancer trios or controls but were found in 7% of 43 testicular germ cell tumor trios; this percentage exceeded background CNV rates and suggested a rare de novo genetic paradigm for susceptibility to some human malignancies.
Genomewide Association Studies
Leahy et al. (1995) performed a sib-pair analysis on 35 families in which there were either 2 or 3 affected brothers. These families were typed for 220 autosomal microsatellite markers spaced 10-20 cM throughout the genome. Six regions that gave a lod score of more than 1.0 on formal linkage analysis or a p value of 0.05 or less using a nonparametric approach were considered as candidate regions for a susceptibility gene. Of particular interest was one region on chromosome 4. A positive lod score of 2.6 on multipoint analysis was obtained with 2 neighboring probes in the region of 4cen-q13.
Rapley et al. (2009) performed a genomewide association study involving 730 TGCT cases and 1,435 controls, with replication in 571 cases and 1,806 controls, and found the strongest evidence for association with rs995030 (OR, 2.55; p = 1.0 x 10(-31)) and rs1508595 (OR, 2.69; p = 2.6 x 10(-30)) that are both located within the same linkage disequilibrium block on chromosome 12q22. Rapley et al. (2009) noted that this region contains only 1 annotated protein-coding gene, KITLG (184745), encoding the ligand for KIT, which has previously been implicated in the pathogenesis of TGCT. There was also evidence for susceptibility loci at rs4624820 located 10-kb 3-prime of the SPRY4 gene (607984) on chromosome 5q31.3 (per-allele odds ratio, 1.37; p = 3.3 x 10(-13)) and at rs210138 located in an intron of the BAK1 gene (600516) on chromosome 6p21.3-p21.2 (OR, 1.50; p = 1.1 x 10(-13)).
In a genomewide scan involving 277 TGCT cases and 919 controls, Kanetsky et al. (2009) found 7 markers at chromosome 12q22 within the KITLG gene that reached genomewide significance (p less than 5.0 x 10(-8)); in independent replication using 371 TGCT cases and 860 controls, TGCT risk increased 3-fold per copy of the major allele at rs3782179 and rs4474514. The markers were associated with both seminoma and nonseminoma TGCT subtypes.
Turnbull et al. (2010) conducted a genomewide association study for testicular germ cell tumor, genotyping 298,782 SNPs in 979 affected individuals and 4,947 controls from the U.K. and replicating associations in a further 664 cases and 3,456 controls. Turnbull et al. (2010) identified 3 novel susceptibility loci, 2 of which include genes that are involved in telomere regulation. They identified 2 independent signals within the TERT (187270)-CLPTM1L (612585) locus on chromosome 5p15.33, which had been associated with multiple other cancers (rs4635969, OR = 1.54, P = 1.14 x 10(-23); rs2736100, OR = 1.33, P = 7.55 x 10(-15)). Turnbull et al. (2010) also identified a locus on chromosome 12 (rs2900333, OR = 1.27, P = 6.16 x 10(-10)) that contains ATF7IP, a regulator of TERT expression. Finally, Turnbull et al. (2010) identified a locus on chromosome 9p24.3 (rs755383, OR = 1.37, P = 1.12 x 10(-23)), containing the sex determination gene DMRT1 (602424), which has been linked to teratoma susceptibility in mice.
Other Mapping Studies
Lothe et al. (1989) found loss of heterozygosity (LOH) for 3p or 11p sequences in 40% of testicular cancers.
Mathew et al. (1994) analyzed chromosome 1 loss of heterozygosity in a panel of 48 GCTs and observed allelic losses in 46% of cases on 1p and in 23% of cases on 1q. There were 4 sites of frequent deletions, 3 in the short arm (1p13, 1p22, and 1p32.2-p31.3) and 1 in the long arm (1q32). Of the 11 probes on 1p that showed allelic losses, the highest frequency of LOH was observed for D1S16 at 1p22 (38.5%). Teratomas showed higher frequency of allelic losses (24.4%) compared to embryonal carcinomas (9.5%), yolk sac tumors (12.1%), or seminomas (7.6%).
Rodriguez et al. (1992) presented data strongly suggested that loss of genetic material on 12q characterizes the development of TGCTs. To define the region of common deletion in GCTs at the molecular level, Murty et al. (1992) compared germline and tumor genotypes for 8 polymorphic loci in paired normal/tumor DNA samples from 45 GCT patients. Analysis demonstrated 2 regions of loss of constitutional heterozygosity, one at 12q13 and the other at 12q22. One tumor exhibited homozygous deletion of a region of 12q22 which includes the MGF gene (184745). The MGF and KIT (164920) genes have been shown to play key roles in embryonal and postnatal development of germ cells. The MGF gene product constitutes the ligand for the receptor encoded by the KIT protooncogene. They evaluated the expression of these 2 genes by Northern blot analysis in a panel of 3 GCT cell lines and 24 fresh GCT biopsies. Deregulated expression of MGF and KIT, which was discordant between seminomatous and nonseminomatous lesions, was observed. Murty et al. (1994) refined their data on the mapping of male germ cell tumors (MGCTs). Using 5 dinucleotide repeats mapping to 12q22, they found LOH in approximately 41% of tumors; one of the loci, D12S218, showed LOH in 37% of tumors, suggesting the presence of a tumor suppressor gene in its vicinity. In this study, a panel of 66 tumor DNA samples and their corresponding normal cells were investigated.
In a detailed deletion mapping analysis of 67 normal-tumor DNA comparisons using 20 polymorphic markers mapped to 12q22-q24, Murty et al. (1996) identified the limit of the minimal region of deletion at 12q22 between D12S377 (proximal) and D12S296 (distal). They constructed a YAC contig map of a 3-cM region of this band and developed a radiation hybrid (RH) map of the region. The consensus order developed by RH mapping was in good agreement with the YAC STS-content map order. The RH map estimated the distance between the D12S101 and D12S346 to be 246 cR(8000) and the minimal region of deletion to be 141 cR(8000).
Murty and Chaganti (1998) reviewed the genetics of male germ cell tumors. A characteristic of GCTs is high sensitivity to cisplatin-based chemotherapy. Chromosomal and molecular cytogenetic studies identified multiplication of 12p, manifested in i(12p) or tandem duplication of 12p, as a unique change in GCTs which serves as a diagnostic marker. Ectopic overexpression of cyclin D2 (CCND2; 123833), which maps to 12p, as early as in carcinoma in situ, identified CCND2 as a candidate gene in germ cell transformation. Genetic alterations identified in the tumor suppressor genes DCC (120470), RB1 (614041), and nonmetastatic protein-23 (NME1; 156490) in GCTs suggested that their inactivation plays a key role in transformation or differentiation. The exquisite sensitivity of these tumors to chemotherapy is reflected in their overexpression of wildtype p53 protein and lack of TP53 mutations.
Zafarana et al. (2002) identified the DADR (609860), SOX5 (604975), and ETNK1 (609858) genes within a region of chromosome 12p amplified in testicular seminomas. Although all 3 genes were amplified to the same level in seminomas with the amplification, only DADR expression was significantly upregulated. DADR was also highly expressed in nonseminomas of various histologies and derived cell lines lacking the 12p amplification. Low DADR expression was observed in normal testicular parenchyma and in parenchyma containing carcinoma in situ. DADR overexpression in seminomas and nonseminomas correlated with invasive growth, reduced apoptosis, and earlier clinical manifestation.
In 97 patients with familial TGCT, 22 patients with sporadic bilateral TGCT, and 871 controls, Kratz et al. (2011) genotyped 106 SNPs in 4 regions, in or near BAK1 on 6p21, DMRT1 on 9p24, KITLG on 12q, and TERT-CLPTM1L on 5p15, all of which had previously been identified in genomewide association studies of TGCT. Three previously identified risk SNPs were replicated in the familial and sporadic bilateral TGCT patients: rs210138 within an intron of BAK1 (OR, 1.80; p = 7.03 x 10(-5)), rs755383 near DMRT1 (OR, 1.67; p = 6.70 x 10 (-4)), and rs4635969 near TERT-CLPTM1L (OR, 1.59; p = 4.07 x 10(-3)). Evidence for a second independent association was found for a SNP within an intron of TERT, rs4975605 (OR, 1.68; p = 1.24 x 10(-3)). In addition, an association with another SNP in KITLG, rs2046971, was identified (OR 2.33; p = 1.28 x 10(-3)); this SNP is in high linkage disequilibrium with the previously reported risk variant rs995030. Kratz et al. (2011) suggested that familial TGCT and sporadic bilateral TGCT are polygenetic diseases caused by the same spectrum of genetic risk factors.
Y-Chromosome Microdeletion
A 1.6-Mb deletion of the Y chromosome that removes part of the AZFc region--known as the gr/gr deletion (see 415000)--has been associated with infertility. In epidemiologic studies, male infertility has shown an association with testicular germ cell tumor (TGCT) that is out of proportion with what can be explained by tumor effects. Thus, Nathanson et al. (2005) hypothesized that the gr/gr deletion may be associated with TGCT. They analyzed this deletion in a large series of TGCT cases with or without a family history of TGCT. The gr/gr deletion was present in 3% of TGCT cases with a family history. 2% of TGCT cases without a family history, and 1.3% of unaffected males. The presence of the gr/gr deletion was associated with a 2-fold increased risk of TGCT and a 3-fold increased risk of TGCT among patients with a positive family history. The gr/gr deletion was more strongly associated with seminoma TGCT than with nonseminoma TGCT. Thus, the Y microdeletion gr/gr appears to be a rare, low penetrance allele that confers susceptibility to TGCT.
Variation in the BCL10 Gene and Progression to Advanced Stage TGCT
Inoue et al. (2006) analyzed 4 SNPs in the BCL10 gene on chromosome 1p22, which had previously been identified in Japanese TGCTs by Kakinuma et al. (2001), in 73 TGCT patients and 72 controls. No significant difference in any of the 4 SNPs was observed between patients and controls. However, GCT patients with metastatic disease were more likely than patients with only local disease to carry a minor allele of either of 2 SNPs in exon 1: 13G-T (A5S; adjusted odds ratio, 6.25, and p = 0.040) or 24C-G (L8L; adjusted odds ratio, 4.63 and p = 0.015). Inoue et al. (2006) concluded that these BCL10 polymorphisms in exon 1 might play a role in progression to advanced stage TGCTs.
Somatic Mutation in the BLC10 Gene on Chromosome 1p22
Willis et al. (1999) analyzed 3 male germ cell tumor lines (Tera1, Tera2, and GCT44) and identified 2, 3, and 1 mutations in the BCL10 gene (603517), respectively (see, e.g., 603517.0001, 603517.0016, and 603517.0017).
Fakruddin et al. (1999) sequenced BCL10 in the 3 GCT cell lines previously studied by Willis et al., 1999 but found no mutations. Fakruddin et al. (1999) noted that their data were at variance with the results reported by Willis et al. (1999), and concluded that BCL10 is not a target tumor suppressor gene at 1p22 in GCTs.
Van Schothorst et al. (1999) screened exons 2 and 3 of the BCL10 gene in a series of TGCT-derived and related cell lines, including the 3 GCT cell lines previously studied by Willis et al., 1999, as well as primary tumors. No aberrations were detected by SSCP on genomic DNA or restriction endonuclease digestion analysis of PCR-amplified fragments, and van Schothorst et al. (1999) concluded that inactivation of BCL10 by genomic events in TGCTs is not involved in the majority of cases, if at all.
Lee et al. (1999) analyzed the BCL10 gene by PCR-SSCP using DNA extracted from malignant and normal cells of 439 paraffin-embedded tumor tissue samples, including 78 GCTs. Enrichment and direct sequencing of aberrantly migrating bands led to the identification of somatic mutations in 2 (2.6%) of the 78 TGCTs (both were mature teratomas; see, e.g., 603517.0018). Lee et al. (1999) concluded that BCL10 may occasionally be involved in the pathogenesis of TGCTs, but that the absence or low frequency of mutation suggested that either BCL10 is inactivated by other mechanisms or that it is not the only target of chromosome 1p22 deletion in human tumors.
Kakinuma et al. (2001) found loss of heterozygosity at chromosome 1p in 21 (42%) of 49 Japanese TGCTs, including 12 (43%) of 28 seminomas and 8 (38%) of 21 nonseminomatous GCTs. No somatic mutations were identified by SSCP and direct sequencing in any of the tumors, although 4 SNPs were detected.
Somatic Mutation in the FGFR3 Gene on Chromosome 4p16
Goriely et al. (2009) screened 30 spermatocytic seminomas for oncogenic mutations in 17 genes and identified a K650E mutation in FGFR3 (134934.0004) in 2 tumors.
Somatic Mutation in the KIT Gene on Chromosome 4q12
Tian et al. (1999) identified an asp816-to-his mutation in the KIT gene (164920.0021) in primary tissue samples from patients with germ cell tumors.
Somatic Mutation in the BRAF Gene on Chromosome 7q34
Sommerer et al. (2005) analyzed the BRAF gene (164757) in 30 seminomas and 32 nonseminomatous GCTs with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma. The activating BRAF missense mutation 1796T-A (164757.0001) was identified in 3 (9%) of 32 nonseminomatous tumors, within the embryonic carcinoma component; no BRAF mutations were found in the seminomas. There was no correlation between BRAF mutation status and tumor stage or grade or other histopathologic factors.
Somatic Mutation in the HRAS Gene on Chromosome 11p15.5
Goriely et al. (2009) screened 30 spermatocytic seminomas for oncogenic mutations in 17 candidate genes and identified apparent homozygosity for 5 mutations in the HRAS gene (190020), 3 182A-G transitions and 2 181C-A transversions, all involving the Q61 codon (see, e.g., 190020.0002).
Somatic Mutation in the KRAS Gene on Chromosome 12p12
Sommerer et al. (2005) analyzed the KRAS gene (190070) in 30 seminomas and 32 nonseminomatous GCTs with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma. KRAS mutations, all involving codon 12, were identified in 2 (7%) of 30 seminomas and 3 (9%) of 32 nonseminomas. The KRAS mutations in the nonseminomas occurred within the embryonal carcinoma component in 2 and within the choriocarcinoma in 1. No correlation between KRAS mutation pattern and histopathologic variables was observed.
Somatic Mutation in the STK11 Gene on Chromosome 19p13
Avizienyte et al. (1998) identified a somatic gly163-to-asp mutation in the STK11 gene (602216.0011) in a case of sporadic testicular carcinoma.
Exclusion Studies
Murty et al. (1996) excluded 4 genes on chromosome 12q22 as candidates for familial testicular cancer: mast cell growth factor (184745), B-cell translocation gene-1 (109580), thymopoietin (188380), and neural precursor cell expressed, developmentally down-regulated-1 (600372).
In laboratory mice, testicular germ cell tumors (TGCTs) arise from primordial germ cells (PGC) in only the inbred 129 strain, and susceptibility is under multigenic control (Stevens and Hummel, 1957). The spontaneously arising mutation Ter (Stevens, 1973) on mouse chromosome 18 (Asada et al., 1994; Sakurai et al., 1994) increases TGCT frequency on a 129/Sv background.
Inbred 129 strain mice are predisposed to developing male germ cell tumors (GCTs) of the testes. GTC incidence is increased in 129 strain males that lack functional p53 protein (191170). Muller et al. (2000) used this finding to facilitate the generation of panels of GCT-bearing intercross and backcross mice for genetic mapping analysis. A 129 strain locus, designated pgct1, that segregated with the male GCT phenotype was identified on mouse chromosome 13 near D13Mit188. This region of mouse chromosome 13 may have conservation of synteny with a portion of human chromosome 5q that is implicated in male GCT susceptibility in humans.
Youngren et al. (2005) reported the positional cloning of Ter, revealing a point mutation that introduces a termination codon in the mouse Dnd1 gene (609385). PGC deficiency was corrected both with BACs containing Dnd1 and with a Dnd1-encoding transgene. Dnd1 is expressed in fetal gonads during the critical period when TGCTs originate. Dnd1 has an RNA recognition motif and is most similar to the apobec (see 600130) complementation factor, a component of the cytidine to uridine RNA editing complex. These results suggested that Ter may adversely affect essential aspects of RNA biology during PGC development. Youngren et al. (2005) stated that Dnd1 was the first protein known to have an RNA recognition motif directly implicated as a heritable cause of spontaneous tumorigenesis, and they suggested that TGCT development in the 129-Ter mouse strain models pediatric TGCTs in humans.
Collin et al. (1996), in a genome scan of tumor-bearing progeny from backcrosses between the 129/Sv-Ter/+ and MOLF/Ei strains provided modest evidence that MOLF-derived alleles on mouse chromosome 19 enhance development of bilateral TGCTs. To obtain independent evidence for linkage to the MOLF chromosome, Matin et al. (1999) made an autosomal chromosome substitution strain (a so-called consomic strain, or CSS), in which chromosome 19 of 129/Sv +/+ was replaced by its MOLF-derived homolog. The unusually high frequency of TGCTs in this CSS (even in the absence of the Ter mutation) provided evidence confirming the genome survey results, identified linkage for a naturally occurring strain variant allele that confers susceptibility to TGCTs, and illustrated the power of CSSs in complex trait analysis.
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