Disease relevance of TGCT1

• The gene called TGCT1 is located at Xq27 and seems to be associated with a risk of bilateral disease and undescended testis [1].
• Known risk factors for TGCT include a history of undescended testis (UDT), testicular dysgenesis, infertility, previously diagnosed TGCT (ref. 7) and a family history of the disease [2].
• The gr/gr deletion was more strongly associated with seminoma (aOR 3.0; 95% CI 1.6-5.4; P = .0004) than with nonseminoma TGCT (aOR 1.5; 95% CI 0.72-3.0; P = .29) [3].
• In epidemiological studies, male infertility has shown an association with TGCT that is out of proportion with what can be explained by tumor effects [3].
• Tenosynovial giant-cell tumor (TGCT) and pigmented villonodular synovitis (PVNS) are related conditions with features of both reactive inflammatory disorders and clonal neoplastic proliferations [4].

Psychiatry related information on TGCT1

• Approximately 2.5-5% of patients with a TGCT will develop bilateral disease and require complete castration, resulting in infertility, a need for lifelong androgen replacement, and psychological stress [5].

High impact information on TGCT1

• Testicular germ-cell tumours (TGCT) affect 1 in 500 men and are the most common cancer in males aged 15-40 in Western European populations [2].
• Our results provide evidence for a TGCT susceptibility gene on chromosome Xq27 that may also predispose to UDT [2].
• The present study shows the unique gene expression profiles of each histologic subtype of TGCT from which we have identified deregulated components in selected processes operating in normal development, such as WNT signaling and DNA methylation [6].
• In the present study the role of the CD95 death pathway in cisplatin sensitivity of TGCT cells was studied in Tera and its in vitro acquired cisplatin-resistant subclone Tera-CP [7].
• In contrast, CD95L blocking had no effect on cisplatin-induced apoptosis in Tera-CP or Scha, an intrinsic resistant TGCT cell line, nor did anti-CD95 antibody induce additional apoptosis in cisplatin-treated Tera-CP or Scha cells [7].

Chemical compound and disease context of TGCT1

• We have previously shown that p53 repression in TGCT-derived human embryonal carcinoma (EC) is relieved upon treatment with all-trans retinoic acid (RA), resulting in enhanced p53 transactivation activity [8].
• All three TGCT lines developed thyroid hyperplasia independent of their thyroxine levels [9].
• The present study suggests that, at least in our panel of TGCT cell lines, hypersensitivity for cisplatin-induced apoptosis might not be necessarily correlated with the presence of wild-type p53 and is probably not associated with Bcl-2 and Bax expression [10].
• NT2D1 human embryonal carcinoma cells represent in vitro models for the stem cells of TGCT, and can be differentiated by treatment with bone morphogenetic proteins (BMP) or retinoic acid (RA) [11].

Biological context of TGCT1

• PURPOSE: An overabundance of X chromosomes in testicular germ cell tumors and the identification of the candidate testicular germ cell tumor susceptibility gene TGCT1 on Xq27 highlight the potential involvement of X chromosomes in testicular germ cell tumor pathogenesis [12].
• These findings are consistent with a multistep model for TGCT pathogenesis in which RASSF1A methylation occurs early in tumorigenesis and additional epigenetic events characterize progression from seminoma to NSTGCTs [13].
• These properties make TGCT a unique model for studying germ cell development and gametogenesis in respect of DNA reprogramming [14].
• The aim of this study was to determine whether the main TGCT subtypes (seminoma, embryonal carcinoma, yolk sac tumour, choriocarcinoma, and mature teratoma) are distinguished by their loss of heterozygosity (LOH) patterns and whether LOH typing can help to distinguish between clonal and multifocal development of different components in mixed TGCTs [15].
• The hypothesis suggested here is that the lack of cell cycle arrest following a cisplatin-containing treatment, together with the activation of the Fas death pathway and the mitochondrial death pathway, explains the rapid and efficient apoptosis of TGCT cells [16].

Anatomical context of TGCT1

• In the adult testis, positive immunohistochemistry for OCT3/4 is an absolute indicator for the presence of the TGCT precursor carcinoma in situ/intratubular germ cell neoplasia undifferentiated (CIS/ITGCNU), seminoma, and/or embryonal carcinoma [17].
• Analyses of two TGCT cell lines indicated that the tumour cells not only express IFNgamma mRNA, but also produce and secrete IFNgamma protein; tumour-derived IFNgamma provokes IP-10 expression and secretion by endothelial cells in vitro, as assessed by PCR and ELISA [18].
• Chromosome aberrations in 20 lymphocytes of 20 patients with testicular germ cell tumors (TGCT) treated with surgery alone were compared with those of 20 cells from 20 healthy controls using standard G-banding technique [19].
• CONCLUSIONS: Immunocytological semen analysis based on expression of fetal germ cell markers in exfoliated cells has auxiliary diagnostic value, as it detects some patients with CIS/incipient tumour, but a negative result does not exclude TGCT [20].
• Despite the large capacity for differentiation displayed by TGCT stem cells, little is known of the factors controlling their developmental potency [21].

Associations of TGCT1 with chemical compounds

• Human TGCT cells were implanted in the left testis of male severe combined immunodeficient mice receiving either no treatment or hormone manipulation treatment [blockade of gonadotropin-releasing hormone secretion and/or signaling using leuprolide or leuprolide plus exogenous testosterone] [22].
• Previous work has documented activating mutations in the KIT receptor tyrosine kinase in testicular germ-cell tumors (TGCT) [23].
• Impaired estrogen synthesis and/or signaling may be at least partly responsible for inhibition of TGCT growth in the animal model [22].
• The International Germ Cell Consensus Classification (IGCCC) of testicular germ cell tumors (TGCT) in 1997 included three serum tumor markers, serum lactate dehydrogenase catalytic concentration (S-LD), serum alpha fetoprotein concentration (S-AFP), and serum human chorionic gonadotropin concentration (S-hCG) [24].
• These findings provide little support to the oestrogen hypothesis, but are consistent with higher levels of testosterones and/or AFP being associated with reduced risk of TGCT; alternatively, lower oestrogen/androgen ratios may be associated with reduced risk [25].

Analytical, diagnostic and therapeutic context of TGCT1

• Since chemotherapy has been shown to activate the Fas death pathway and TGCTs co-express both Fas and its ligand FasL, TGCT cells might undergo apoptosis upon cisplatin treatment via autocrine or paracrine activation of the Fas system by FasL [16].
• RT-PCR and immunohistochemistry indicated that IP-10 was the only chemokine investigated which was constantly expressed in TGCT [18].
• Testicular germ cell tumours (TGCT) are cured in over 80% of patients by using combination chemotherapy [26].
• The identified markers were verified by reverse transcriptase-polymerase chain reaction and in situ hybridisation in a range of different TGCT samples [27].
• At least 5% of TGCT patients present with contralateral CIS; therefore, contralateral biopsy is recommended at the time of orchidectomy [28].

References