EMBRYONAL CELL CARCINOMA, INCLUDED
SPERMATOCYTIC SEMINOMA, INCLUDED
MALE GERM CELL TUMOR
ENDODERMAL SINUS TUMOR, INCLUDED
NONSEMINOMATOUS GERM CELL TUMORS, INCLUDED
MGCT SEMINOMA, INCLUDED
TERATOMA, TESTICULAR, INCLUDED
TGCT
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 ... 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 ... 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.
- 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 ... - 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).
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 ... 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.