The protein encoded by this gene is found only in testicular tissue and may be involved in spermatogenesis. Many functional paralogs and pseudogenes of this gene are present in a cluster in humans, but only a single, nonfunctional orthologous gene is found in mouse. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
TSPY expression in Gonadoblastoma and Testicular GCTs Lau, 1999 and Hildenbrand et al, 1999 reported elevated TSPY expression in gonadoblastoma.
Akimoto et al,2010 reported coexpression of TSPY and the androgen receptor (AR) in testicular germ-cell tumors.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
Male and female differ genetically by their respective sex chromosome composition, that is, XY as male and XX as female. Although both X and Y chromosomes evolved from the same ancestor pair of autosomes, the Y chromosome harbors male-specific genes, which play pivotal roles in male sex determination, germ cell differentiation, and masculinization of various tissues. Deletions or translocation of the sex-determining gene, SRY, from the Y chromosome causes disorders of sex development (previously termed as an intersex condition) with dysgenic gonads. Failure of gonadal development results not only in infertility, but also in increased risks of germ cell tumor (GCT), such as gonadoblastoma and various types of testicular GCT. Recent studies demonstrate that either loss of Y chromosome or ectopic expression of Y chromosome genes is closely associated with various male-biased diseases, including selected somatic cancers. These observations suggest that the Y-linked genes are involved in male health and diseases in more frequently than expected. Although only a small number of protein-coding genes are present in the male-specific region of Y chromosome, the impacts of Y chromosome genes on human diseases are still largely unknown, due to lack of in vivo models and differences between the Y chromosomes of human and rodents. In this review, we highlight the involvement of selected Y chromosome genes in cancer development in men.
Kido T, Lo RC, Li Y, et al. The potential contributions of a Y-located protooncogene and its X homologue in sexual dimorphisms in hepatocellular carcinoma. Hum Pathol. 2014; 45(9):1847-58 [PubMed] Related Publications
There is a significant sex disparity favoring males among hepatocellular carcinoma (HCC) patients. Although various risk factors have been identified, the exact etiology of such sexual dimorphism(s) in HCC is uncertain. Previous studies showed that overexpression of the Y-located protooncogene, testis-specific protein Y encoded (TSPY), promotes cell proliferation and oncogenesis whereas its X-located homologue, TSPYhomologue X (TSPX), retards cell cycle and oncogenic progression. Furthermore, TSPX promotes proteasomal degradation of hepatitis B virus-encoded X oncoprotein and hence could serve as a tumor suppressor in virus-associated HCC. Using immunohistochemistry and reverse-transcription polymerase chain reaction analysis, we had examined the expression of TSPY and TSPX with reference to other established biomarkers in HCC and related liver cancers. Our results demonstrated that 55 (19.2%) of 287 male cases were TSPY positive in immunohistochemistry of tissue arrays, and 15 (46.9%) of 32 male cases were TSPY positive in reverse-transcription polymerase chain reaction analysis of clinical samples. TSPY expression was closely associated with the expression of HCC biomarkers, such as glypican 3. In contrast, TSPX expression was down-regulated in 54.5% of total tumor/nontumorous paired samples (18/33) and negatively associated with those of TSPY, glypican 3, and forkhead box M1 (FOXM1) and was positively associated with that of a tumor suppressor, insulin-like growth factor binding protein 3. The present findings support the hypothesis that the oncogenic events leading to an ectopic activation of the Y-located protooncogene TSPY and/or inactivating mutation/epigenetic silencing of the X-located tumor suppressor gene TSPX could collectively contribute to the sexual dimorphism(s) in HCC and related liver cancers in male-biased manners.
Ulbright TM Gonadoblastoma and hepatoid and endometrioid-like yolk sac tumor: an update. Int J Gynecol Pathol. 2014; 33(4):365-73 [PubMed] Related Publications
Dr Robert E. Scully greatly advanced our understanding of germ cell neoplasia to the extent that it is difficult to narrow the discussion of his contributions to this topic so that it can be covered in a brief article. This article accordingly focuses on some of the recent developments concerning 2 of his major contributions in this area-the gonadoblastoma (GB) and variant morphologies of yolk sac tumor. GB was defined by Dr Scully in 1953 and its features elaborated in detail by him in 1970. This neoplasm occurred in young patients who often displayed phenotypic sex ambiguities and frequently presented with primary amenorrhea. It was bilateral in 40%, and consisted of circumscribed nests of small sex cord cells and germinoma-like cells admixed with round deposits of eosinophilic, hyaline, often calcified material. These nests were set in a spindle cell gonadal stroma with Leydig-like or lutein-like cells. Because of his work we now understand that this precursor to invasive germ cell tumors occurs in patients with a specific form of disorder of sex development, namely gonadal dysgenesis, and only in those who have a particular portion of the Y chromosome, the GB locus/TSPY gene, within the gonadal tissue. An essential element to the development of GB appears to be a defect in the genetic pathway that leads to the development of Sertoli cells. Improperly formed Sertoli cells predispose to "delayed maturation" of the gonocytes of the gonad and predispose them to undergo malignant transformation. "Undifferentiated gonadal tissue" has been proposed as the precursor to the development of GB and consists of an unorganized mixture of apparently non-neoplastic germ cells, germ cells with delayed maturation, and neoplastic germ cells with sex cord cells and gonadal stroma. Two variant morphologies of yolk sac tumor were also recognized by Dr Scully. In the hepatoid variant features similar to hepatocellular carcinoma occurred, although primitive glandular foci and lack of liver involvement permitted its distinction in most cases. More recently this variant has been found to occasionally produce bile in canalicular-like structures and to stain strongly for both SALL4 and glypican 3, 2 recently described markers of yolk sac tumor. Recognition of hepatoid yolk sac tumor was followed by the description of a potential mimic, primary ovarian hepatoid carcinoma, which, however, occurred in a significantly older patient population and was occasionally associated with surface epithelial neoplasia. The endometrioid-like variant of yolk sac tumor simulated primary endometrioid adenocarcinoma. It can be suspected on routine stains because of primitive appearing nuclei, frequent subnuclear vacuoles, and in some cases association with more usual yolk sac tumor. Its recognition is now facilitated by a panel of immunohistochemical stains that are often expressed differentially in these 2 neoplasms--endometrioid-like yolk sac tumor: positive for SALL4, glypican 3, and α-fetoprotein; endometrioid adenocarcinoma: positive for cytokeratin 7 and epithelial membrane antigen. Finally, Dr Scully contributed one of the first cases in the literature of yet another nuance in the complicated world of yolk sac neoplasia, namely the development of some tumors on the background of a surface epithelial neoplasm. This is analogous to the more common development of choriocarcinoma from carcinoma and, in the case of yolk sac tumor, diagnosis is aided clinically by the usual older age of the patient and nature of the associated neoplasia.
Hepatocellular carcinoma (HCC) is a male-predominant cancer. Previous studies have focused on the sex-related disparity in HCC, but the underlying mechanism remains unclear. Here, we aimed to discover characteristic biomarkers for male HCC. Clinical samples were subjected to iTRAQ labeling followed by 2DLC-ESI-MS/MS analysis. Seventy-three differential proteins containing 16 up-regulated and 57 down-regulated proteins were screened out in the male HCC group compared to that in female HCC group. Testis-specific Protein Y-encoded 1(TSPY1) is characteristically present in male HCC and was chosen for further investigation. The data from the functional effects of TSPY1 indicated that over-expression of TSPY1 could potentiate HCC cell proliferation, increase soft agar colonization, induce higher cell invasive ability and correlate with the metastatic potential of the HCC cell lines. In addition, TSPY1 and androgen receptor (AR) were co-expressed simultaneously in HCC cell lines as well as in HCC tissue. TSPY1 up- or down-regulation could lead to a high or low level expression of AR. These results implied that TSPY1 may be included in the regulation of AR expression involved in male HCC and it may act as a novel biomarker for male HCC.
Kido T, Lau YF The Y-located gonadoblastoma gene TSPY amplifies its own expression through a positive feedback loop in prostate cancer cells. Biochem Biophys Res Commun. 2014; 446(1):206-11 [PubMed] Related Publications
The testis-specific protein Y-encoded (TSPY) is a repetitive gene located on the gonadoblastoma region of the Y chromosome, and has been considered to be the putative gene for this oncogenic locus on the male-only chromosome. It is expressed in spermatogonial cells and spermatocytes in normal human testis, but abundantly in gonadoblastoma, testicular germ cell tumors and a variety of somatic cancers, including melanoma, hepatocellular carcinoma and prostate cancer. Various studies suggest that TSPY accelerates cell proliferation and growth, and promotes tumorigenesis. In this report, we show that TSPY could bind directly to the chromatin/DNA at exon 1 of its own gene, and greatly enhance the transcriptional activities of the endogenous gene in the LNCaP prostate cancer cells. Domain mapping analyses of TSPY have localized the critical and sufficient domain to the SET/NAP-domain. These results suggest that TSPY could efficiently amplify its expression and oncogenic functions through a positive feedback loop, and contribute to the overall tumorigenic processes when it is expressed in various human cancers.
Microchimerism (MC), transplacental acquisition of allogeneic cells from the mother (maternofetal MC) or from the fetus (fetomaternal MC) has been in the focus of research recently. Amplicons using Y-chromosome specific SRY and DYS14 sequences have been used as markers to trace cells from a male fetus in the mother. The sensitivity of these markers in formaldehyde fixed paraffin embedded samples, however, is less than optimal. To study chimerism in breast cancer we took advantage of the evolutionary history of the Y chromosome and designed amplicons on gene repeats to generate additive PCR signals. The increased sensitivity detected high incidence of male chimerism in normal breast tissues. We also showed correlation with protection from cancer with unique quantitative biology. Accumulating data from biology and medicine indicate that natural chimerism is astonishingly frequent and may affect human conditions. We hypothesize that it has significant evolutionary ramifications as well.
Hersmus R, Stoop H, Turbitt E, et al. SRY mutation analysis by next generation (deep) sequencing in a cohort of chromosomal Disorders of Sex Development (DSD) patients with a mosaic karyotype. BMC Med Genet. 2012; 13:108 [PubMed] Free Access to Full ArticleRelated Publications
BACKGROUND: The presence of the Y-chromosome or Y chromosome-derived material is seen in 4-60% of Turner syndrome patients (Chromosomal Disorders of Sex Development (DSD)). DSD patients with specific Y-chromosomal material in their karyotype, the GonadoBlastoma on the Y-chromosome (GBY) region, have an increased risk of developing type II germ cell tumors/cancer (GCC), most likely related to TSPY. The Sex determining Region on the Y gene (SRY) is located on the short arm of the Y-chromosome and is the crucial switch that initiates testis determination and subsequent male development. Mutations in this gene are responsible for sex reversal in approximately 10-15% of 46,XY pure gonadal dysgenesis (46,XY DSD) cases. The majority of the mutations described are located in the central HMG domain, which is involved in the binding and bending of the DNA and harbors two nuclear localization signals. SRY mutations have also been found in a small number of patients with a 45,X/46,XY karyotype and might play a role in the maldevelopment of the gonads. METHODS: To thoroughly investigate the presence of possible SRY gene mutations in mosaic DSD patients, we performed next generation (deep) sequencing on the genomic DNA of fourteen independent patients (twelve 45,X/46,XY, one 45,X/46,XX/46,XY, and one 46,XX/46,XY). RESULTS AND CONCLUSIONS: The results demonstrate that aberrations in SRY are rare in mosaic DSD patients and therefore do not play a significant role in the etiology of the disease.
Shahsiah R, Jahanbin B, Rabiei R, et al. Malignant ovarian germ cell tumours in gonadal Y chromosome mosaicism. J Clin Pathol. 2011; 64(11):973-6 [PubMed] Related Publications
AIMS: Previous studies have shown that two partially overlapping mechanisms are responsible for the development of malignant ovarian germ cell tumours (MOGCT): either spontaneous mutations, mostly in KIT gene, or the presence of Y chromosome material, in dysgenetic gonads. While unilateral oophorectomy and preservation of fertility is favourable in most cases, presence of whole or part of Y chromosome in dysgenetic ovaries is associated with a risk of bilateral germ cell tumour development. The aim of this study was to evaluate the frequency of Y chromosome material in these tumours. METHODS: A total of 47 cases with histopathologic diagnosis of malignant germ cell tumour were selected in a period of 9 years. A relative quantitative PCR (RQ-PCR) method was designed and validated to detect testis-specific protein Y-encoded (TSPY) gene on Y chromosome. After DNA extraction, TSPY gene was sought as a surrogate of Y chromosome. RESULTS: Significant amounts of TSPY gene were found in seven cases, two of which had gonadoblastoma and one had cytogenetic proof of Y chromosome presence. CONCLUSIONS: Some MOGCTs develop on the background of gonadal mosaicism and gonadal dysgenesis. Bilateral oophorectomy may be indicated in patients with these disorders because they are at risk of developing an MOGCT on the contralateral gonad. Moreover, this chromosomal abnormality is hardly found by routine methods, and the abnormality is more easily sought in MOGCT cells by means of RQ-PCR.
Lau YF, Li Y, Kido T Role of the Y-located putative gonadoblastoma gene in human spermatogenesis. Syst Biol Reprod Med. 2011; 57(1-2):27-34 [PubMed] Related Publications
The gonadoblastoma locus on the human Y chromosome (GBY) is postulated to serve normal functions in spermatogenesis, but could exert oncogenic properties in predisposing susceptible germ cells to tumorigenesis in incompatible niches such as streaked gonads in XY sex reversed patients or dysfunctional testis in males. The testis-specific protein Y-linked (TSPY) repeat gene has recently been demonstrated to be the putative gene for GBY, based on its location on the GBY critical region, expression patterns in early and late stages of gonadoblastoma and ability to induce gonadoblastoma-like structures in the ovaries of transgenic female mice. Over-expression of TSPY accelerates G(2)/M progression in the cell cycle by enhancing the mitotic cyclin B-CDK1 kinase activities. Currently the normal functions of TSPY in spermatogenesis are uncertain. Expression studies of TSPY, and its X-homologue, TSPX, in normal human testis suggest that TSPY is co-expressed with cyclin B1 in spermatogonia and various stages of spermatocytes while TSPX is principally expressed in Sertoli cells in the human testis. The co-expression pattern of TSPY and cyclin B1 in spermatogonia and spermatocytes suggest respectively that 1) TSPY is important for male spermatogonial cell replication and renewal in the testis; and 2) TSPY could be a catalyst/meiotic factor essential for augmenting the activities of cyclin B-cyclin dependent kinases, important for the differentiation of the spermatocytes in prophase I and in preparation for consecutive rounds of meiotic divisions without an intermediate interphase during spermatogenesis.
Epping MT, Meijer LA, Krijgsman O, et al. TSPYL5 suppresses p53 levels and function by physical interaction with USP7. Nat Cell Biol. 2011; 13(1):102-8 [PubMed] Related Publications
We have previously reported a gene expression signature that is a powerful predictor of poor clinical outcome in breast cancer. Among the seventy genes in this expression profile is a gene of unknown function: TSPYL5 (TSPY-like 5, also known as KIAA1750). TSPYL5 is located within a small region at chromosome 8q22 that is frequently amplified in breast cancer, which suggests that TSPYL5 has a causal role in breast oncogenesis. Here, we report that high TSPYL5 expression is an independent marker of poor outcome in breast cancer. Mass spectrometric analysis revealed that TSPYL5 interacts with ubiquitin-specific protease 7 (USP7; also known as herpesvirus-associated ubiquitin-specific protease; HAUSP). USP7 is the deubiquitylase for the p53 tumour suppressor and TSPYL5 reduces the activity of USP7 towards p53, resulting in increased p53 ubiquitylation. We demonstrate that TSPYL5 reduces p53 protein levels and inhibits activation of p53-target genes. Furthermore, expression of TSPYL5 overrides p53-dependent proliferation arrest and oncogene-induced senescence, and contributes to oncogenic transformation in multiple cell-based assays. Our data identify TSPYL5 as a suppressor of p53 function through its interaction with USP7.
Akimoto C, Ueda T, Inoue K, et al. Testis-specific protein on Y chromosome (TSPY) represses the activity of the androgen receptor in androgen-dependent testicular germ-cell tumors. Proc Natl Acad Sci U S A. 2010; 107(46):19891-6 [PubMed] Free Access to Full ArticleRelated Publications
Testis-specific protein on Y chromosome (TSPY) is an ampliconic gene on the Y chromosome, and genetic interaction with gonadoblastoma has been clinically established. However, the function of the TSPY protein remains to be characterized in physiological and pathological settings. In the present study, we observed coexpression of TSPY and the androgen receptor (AR) in testicular germ-cell tumors (TGCTs) in patients as well as in model cell lines, but such coexpression was not seen in normal testis of humans or mice. TSPY was a repressor for androgen signaling because of its trapping of cytosolic AR even in the presence of androgen. Androgen treatment stimulated cell proliferation of a TGCT model cell line, and TSPY potently attenuated androgen-dependent cell growth. Together with the finding that TSPY expression is reduced in more malignant TGCTs in vivo, the present study suggests that TSPY serves as a repressor in androgen-induced tumor development in TGCTs and raises the possibility that TSPY could be used as a clinical marker to assess the malignancy of TGCTs.
Faller WJ, Rafferty M, Hegarty S, et al. Metallothionein 1E is methylated in malignant melanoma and increases sensitivity to cisplatin-induced apoptosis. Melanoma Res. 2010; 20(5):392-400 [PubMed] Related Publications
DNA methylation plays a major role in cancer by silencing tumour suppressor genes. In melanoma, only a discrete number of methylated genes have been identified so far. After the treatment of melanoma cells with a DNA methyltransferase inhibitor and subsequent transcriptomic profiling, we had identified earlier a cohort of melanoma progression-associated genes regulated by methylation. Here, we identified which of these genes are directly methylated in melanoma cell lines and tissues. First, we examined 16 genes by bisulphite sequencing in the WM793 isogenic cell line model series. Five of these genes (CYBA, FABP5, MT1E, TSPY1 and TAC1) displayed increased methylation in several invasive cell lines compared with the parental WM793 cells, indicating their involvement in progression. Next, we analyzed several matched primary/metastatic tumours using methylation-specific PCR, which revealed that MT1E (one of the five genes assessed) was methylated in the largest proportion of tumours. Examination of a larger cohort of samples showed that 1 of 17 (6%) of the benign naevi, 16 of 43 (37%) primary tumours and 6 of 13 (46%) of the metastases displayed MT1E methylation. In addition, ectopic over-expression of MT1E mediated sensitization to cisplatin-induced apoptosis. Overall, these studies suggest that MT1E is a potential tumour suppressor gene, whose loss may promote resistance to apoptosis-inducing therapies.
Hertel JD, Huettner PC, Dehner LP, Pfeifer JD The chromosome Y-linked testis-specific protein locus TSPY1 is characteristically present in gonadoblastoma. Hum Pathol. 2010; 41(11):1544-9 [PubMed] Related Publications
Gonadoblastoma is a rare gonadal neoplasm that occurs almost exclusively in individuals who are phenotypically females. Most cases develop in women who have an abnormal karyotype in which at least a portion of the centromeric region of the short arm of chromosome Y is present, a region often referred to as the GBY locus. Of the several genes present in the GBY locus, the TSPY1 gene (which encodes testis-specific protein, a protein thought to have a role in cell cycle regulation) appears to be the most likely to have a critical role in the pathogenesis of gonadoblastoma. To evaluate the association of TSPY1 with the tumor, we developed an interphase fluorescent in situ hybridization assay that uses probes that target the region of the GBY locus that contains TSPY1 and a commercially available chromosome X CEP probe. Using this set of probes in a dual-color approach, we evaluated 6 cases of gonadoblastoma identified from our files and found that both TSPY1 and chromosome X were present in 5 (84%) of 6 cases; in these 5 cases, the adjacent nonneoplastic gonadal parenchyma showed the same genotype as the tumor. Of 6 cases, 1 (16%) showed no evidence of TSPY1; in this case, which occurred in a gravida 2 para 2 woman, 2 X chromosomes were present in the nonneoplastic ovary, the gonadoblastoma, and associated dysgerminoma and granulosa cell tumors. From a basic science perspective, our data demonstrate that the TSPY1 gene is present in most gonadoblastomas, supporting the hypothesized role for TSPY1 in gonadoblastoma tumorigenesis; the lack of TSPY1 in a fertile woman suggests that other loci can, however, substitute for TSPY1 in the development of the tumor. From a clinical perspective, our data show that interphase fluorescence in situ hybridization targeting TSPY1 is a straightforward approach that can be used in the evaluation of Y-associated intersex disorders in women who develop gonadoblastoma.
Bianco B, Oliveira KC, Guedes AD, et al. OCT4 gonadal gene expression related to the presence of Y-chromosome sequences in Turner syndrome. Fertil Steril. 2010; 94(6):2347-9 [PubMed] Related Publications
To show that in the dysgenetic gonads of 104 Turner syndrome patients no significant difference was found regarding the expression of the genes DAX1, FOG2, GATA4, OCT4, SF1, SRY, TSPY, WT1, and STRA8 compared with controls, except for genes OCT4, SRY, and TSPY in both gonads of a patient whose chromosomal constitution was 45,X/45,X,add(15)(p11). The expression analysis of genes OCT4, SRY, and TSPY in the dysgenetic gonads of Turner syndrome patients may allow introducing modifications in the microenvironment that could contributed to a malignant transformation process.
Carvalho R, Pinheiro MF, Medeiros R Localization of candidate genes in a region of high frequency of microvariant alleles for prostate cancer susceptibility: the chromosome region Yp11.2 genetic variation. DNA Cell Biol. 2010; 29(1):3-7 [PubMed] Related Publications
The Y chromosome has been suggested to play a role in prostate cancer (PCa) because the loss of this chromosome is the most common aberration in PCa. Study of short tandem repeats (STRs) could provide a means to rapidly scan genomes at known or unknown predisposing loci for some diseases. DNA samples from 281 patients with PCa at the Portuguese Institute of Oncology, Porto, Portugal, and a population control of 175 healthy controls were analyzed for region Yp11.2 using AmpFlSTR Y-Filer kit (Applied Biosystems). The results demonstrated that microvariant alleles of DYS458 are overrepresented (p = 0.026). We found that allele 12 of DYS393 and allele 19 of DYS458 could have a protective effect (p = 0.0051; odds ratio [OR] = 0.48; 95% confidence interval [95% CI] 0.27-0.38; and p = 0.0272; OR = 0.47; 95% CI 0.22-0.98). On the other hand, patients carrying allele 13 of DYS393 presented an increased risk to PCa (p = 0.015; OR = 1.97; 95% CI 1.26-3.07). These results are in concordance with the involvement of Y chromosome in PCa development. STR allele studies may add further information from the definition of a genetic profile of PCa resistance or susceptibility. As TSPY is located at region Yp11.2, this gene could play an essential role in PCa development.
Gadi VK Fetal microchimerism in breast from women with and without breast cancer. Breast Cancer Res Treat. 2010; 121(1):241-4 [PubMed] Related Publications
A lasting legacy of a fetus to the mother is a small number of stably persistent allogeneic cells; the phenomenon known as fetal microchimerism. Prior studies demonstrated that fetal microchimerism in the peripheral blood is associated with protection from breast cancer. Whether the same association of fetal microchimerism extends to the tissue of interest, the breast, is unknown. Total genomic DNA was extracted from frozen normal breast tissue adjacent to invasive disease in women with breast cancer. Control DNA was extracted from reduction mammoplasty tissues from women with no prior history of any breast cancer. The presence of male DNA, presumably from a prior male fetus, was determined with a quantitative PCR assay for the Y chromosome gene, DYS14. Proportions of tissues harboring fetal microchimerism were compared. Thirty-eight cancer-free breast tissues from women with and without a history of breast cancer were evaluable for the presence and quantity of fetal microchimerism testing with the DYS14 assay. Breast tissue from women free of cancer harbored FMc more frequently than normal breast tissue adjacent to invasive disease in women with breast cancer (63 and 26%, respectively). The odds ratio, corrected for total DNA quantity tested, for this protective association of fetal microchimerism against breast cancer was 0.17 (95% confidence interval 0.04-0.76). Findings indicate that the protective association of fetal microchimerism against breast cancer observed previously in the peripheral blood is also reflected in breast tissue.
Patients with disorders of sex development (DSD), especially those with gonadal dysgenesis and hypovirilization, are at risk of developing the so-called type II germ cell tumors (GCTs). Both carcinoma in situ and gonadoblastoma (GB) can be the precursor lesion, resulting in a seminomatous or non-seminomatous invasive cancer. SRY mutations residing in the HMG domain are found in 10-15% of 46,XY gonadal dysgenesis cases. This domain contains two nuclear localization signals (NLSs). In this study, we report a unique case of a phenotypical normal woman, diagnosed as a patient with 46,XY gonadal dysgenesis, with an NLS missense mutation, on the basis of the histological diagnosis of a unilateral GB. The normal role of SRY in gonadal development is the upregulation of SOX9 expression. The premalignant lesion of the initially removed gonad was positive for OCT3/4, TSPY and stem cell factor in germ cells, and for FOXL2 in the stromal component (ie, granulosa cells), but not for SOX9. On the basis of these findings, prophylactical gonadectomy of the other gonad was performed, also showing a GB lesion positive for both FOXL2 (ovary) and SOX9 (testis). The identified W70L mutation in the SRY gene resulted in a 50% reduction in the nuclear accumulation of the mutant protein compared with wild type. This likely explains the diminished SOX9 expression, and therefore the lack of proper Sertoli cell differentiation during development. This case shows the value of the proper diagnosis of human GCTs in identification of patients with DSD, which allows subsequent early diagnosis and prevention of the development of an invasive cancer, likely to be treated by chemotherapy at young age.
Lau YF, Li Y, Kido T Gonadoblastoma locus and the TSPY gene on the human Y chromosome. Birth Defects Res C Embryo Today. 2009; 87(1):114-22 [PubMed] Related Publications
The gonadoblastoma (GBY) locus is the only oncogenic locus on the human Y chromosome. It is postulated to serve a normal function in the testis, but could exert oncogenic effects in dysgenetic gonads of individuals with intersex and/or dysfunctional testicular phenotypes. Recent studies establish the testis-specific protein Y-encoded (TSPY) gene to be the putative gene for GBY. TSPY serves normal functions in male stem germ cell proliferation and differentiation, but is ectopically expressed in early and late stages of gonadoblastomas, testicular carcinoma in situ (the premalignant precursor for all testicular germ cell tumors), seminomas, and selected nonseminomas. Aberrant TSPY expression stimulates protein synthetic activities, accelerates cell proliferation, and promotes tumorigenicity in athymic mice. TSPY binds to type B cyclins, enhances an activated cyclin B-CDK1 kinase activity, and propels a rapid G(2)/M transition in the cell cycle. TSPY also counteracts the normal functions of its X-homologue, TSPX, which also binds to cyclin B and modulates the cyclin B-CDK1 activity to insure a proper G(2)/M transition in the cell cycle. Hence, ectopic expression and actions of the Y-located TSPY gene in incompatible germ cells, such as those in dysgenetic or ovarian environments and dysfunctional testis, disrupt the normal cell cycle regulation and predispose the host cells to tumorigenesis. The contrasting properties of TSPY and TSPX suggest that somatic cancers, such as intracranial germ cell tumors, melanoma, and hepatocellular carcinoma, with detectable TSPY expression could exhibit sexual dimorphisms in the initiation and/or progression of the respective oncogenesis.
Bianco B, Lipay M, Guedes A, et al. SRY gene increases the risk of developing gonadoblastoma and/or nontumoral gonadal lesions in Turner syndrome. Int J Gynecol Pathol. 2009; 28(2):197-202 [PubMed] Related Publications
The presence of Y-chromosome material in patients with dysgenetic gonads increases the risk of gonadal tumors and/or nontumoral androgen-producing lesions. The patients' prognosis can vary, depending on their karyotype. The objective of this study was to investigate the presence of Y-chromosome mosaicism in Turner syndrome patients and its association with the development of gonadal tumors and/or nontumoral androgen-producing lesions. Eighty-seven Turner syndrome patients were studied. Genomic DNA was extracted from peripheral blood and genes SRY and TSPY and DYZ3 repeat of the Y chromosome were amplified by polymerase chain reaction. To the Y-positive patients, prophylactic gonadectomy was offered. The data disclosed hidden Y-chromosome mosaicism in 16 (18.5%) of the patients. SRY sequence was detected in all of the 16 patients, and 4 (4.6%) of them presented DYZ3 repeat region and TSPY gene. Eleven of the patients with Y-positive sequences agreed to undergo the prophylactic surgery. In 2 cases, bilateral gonadoblastoma was found and, in another case, the histopathologic study of the gonads revealed hilus cell hyperplasia. In a further case, there were hilus cell hyperplasia and a stromal luteoma. In conclusion, a systematic search for hidden Y-chromosome mosaicism, especially SRY, in Turner syndrome patients is justified by the possibility of preventing gonadal lesions.
Kido T, Lau YF The human Y-encoded testis-specific protein interacts functionally with eukaryotic translation elongation factor eEF1A, a putative oncoprotein. Int J Cancer. 2008; 123(7):1573-85 [PubMed] Related Publications
Testis-specific protein Y-encoded (TSPY) is the putative gene for the gonadoblastoma locus on the Y chromosome. TSPY is expressed in normal germ cells of fetal and adult testis and ectopically in tumor germ cells, including gonadoblastoma in intersex patients, testicular germ cell tumors, prostate cancer and other somatic cancers. It is a member of the TSPY/SET/NAP1 superfamily and harbors a highly conserved domain, termed SET/NAP domain. To explore its possible role(s) in tumorigenesis, we had performed a yeast two-hybrid screen of a fetal gonadal cDNA library and identified the translation elongation factor eEF1A as a binding partner for TSPY at the SET/NAP domain. TSPY and eEF1A were highly expressed and colocalized in tumor germ cells of human seminoma specimens, suggesting their possible interaction in germ cell tumors. They were colocalized in the cytoplasm and could be co-immunoprecipitated from transfected COS7 cells. Significantly, both eEF1A1 and eEF1A2 have postulated to be involved in various types of human cancer, including breast and prostate cancers. TSPY enhanced protein synthesis of a reporter gene, which was augmented by an overexpression of eEF1A. TSPY also increased the nuclear redistribution of eEF1A, resulting in a parallel increase in reporter gene transcripts. Our results suggest that TSPY could exert its oncogenic function(s) by interacting with eEF1As and stimulating gene expression via its enhancements in protein synthesis and gene transcription.
Li Y, Lau YF TSPY and its X-encoded homologue interact with cyclin B but exert contrasting functions on cyclin-dependent kinase 1 activities. Oncogene. 2008; 27(47):6141-50 [PubMed] Related Publications
Testis-specific protein Y-encoded (TSPY) is the putative gene for the gonadoblastoma locus on the Y chromosome (GBY). TSPY and an X-homologue, TSPX, harbor a conserved domain, designated as SET/NAP domain, but differ at their C termini. Ectopic expression of TSPY accelerates cell proliferation by abbreviating the G(2)/M stage, whereas overexpression of TSPX retards cells at the same stage of the cell cycle. Previous studies demonstrated that the SET oncoprotein is capable of binding to cyclin B. Using various protein interaction techniques, we demonstrated that TSPY and TSPX indeed bind competitively to cyclin B at their SET/NAP domains in vitro and in vivo. TSPY colocalizes with cyclin B1 during the cell cycle, particularly on the mitotic spindles at metaphase. TSPY enhances while TSPX represses the cyclin B1-CDK1 phosphorylation activity. The inhibitory effect of TSPX on the cyclin B1-CDK1 complex has been mapped to its carboxyl acidic domain that is absent in TSPY, suggesting that TSPX could serve a normal function in modulating cell-cycle progression at the G(2)/M stage, whereas TSPY has acquired a specialized function in germ cell renewal and differentiation. Epigenetic dysregulation of TSPY in incompatible germ or somatic cells could promote cell proliferation and predispose susceptible cells to tumorigenesis.
Hersmus R, de Leeuw BH, Wolffenbuttel KP, et al. New insights into type II germ cell tumor pathogenesis based on studies of patients with various forms of disorders of sex development (DSD). Mol Cell Endocrinol. 2008; 291(1-2):1-10 [PubMed] Related Publications
Disorders of sex development (DSD), previously known as intersex, refer to congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical. Patients with specific variants of this disorder have an elevated risk for the development of so-called type II germ cell cancers, i.e., the seminomatous and nonseminatous tumors, referred to as germ cell tumors (GCTs). Specifically DSD patients with gonadal dysgenesis or hypovirilization are at risk. A prerequisite for type II GCT formation is the presence of a specific part of the Y chromosome (referred to as the GBY region), with the TSPY gene being the most likely candidate. Also the octamer binding transcription factor OCT3/4 is consistently expressed in all type II GCTs with pluripotent potential, as well as in the precursor lesions carcinoma in situ (CIS) in case of a testis and gonadoblastoma (GB) in the DSD gonad. The actual risk for malignant transformation in individual DSD patients is hard to predict, because of confusing terminology referring to the different forms of DSD, and unclear criteria for identification of the presence of malignant germ cells, especially in young patients. This is specifically due to the phenomenon of delay of germ cell maturation, which might result in over diagnosis. This review will give novel insight into the pathogenesis of the type II GCTs through the study of patients with various forms of DSD for which the underlying molecular defect is known. To allow optimal understanding of the pathogenesis of this type of cancers, first normal gonadal development, especially regarding the germ cell lineage, will be discussed, after which type II GCTs will be introduced. Subsequently, the relationship between type II GCTs and DSD will be described, resulting in a number of new insights into the development of the precursor lesions of these tumors.
Kandalaft LE, Zudaire E, Portal-Núñez S, et al. Differentially expressed nucleolar transforming growth factor-beta1 target (DENTT) exhibits an inhibitory role on tumorigenesis. Carcinogenesis. 2008; 29(6):1282-9 [PubMed] Free Access to Full ArticleRelated Publications
Differentially expressed nucleolar transforming growth factor-beta1 target (DENTT), also known as testis-specific protein Y-encoded-like (TSPYL-2) and cell division autoantigen-1, is a member of the testis-specific protein Y-encoded (TSPY)/TSPY-L/SET/nucleosome assembly protein-1 superfamily. DENTT is expressed in various tissues including normal human lung. Here, we investigate the involvement of DENTT in cancer promotion and progression. DENTT messenger RNA (mRNA) and protein levels were shown to be markedly downregulated in human and mouse primary tumors and in human tumor cell lines. Overexpression of DENTT in human lung (A549-DENTT) and breast (MCF-7-DENTT) cancer cells resulted in diminished growth potential in anchorage-dependent growth assays and reduced capacity to form colonies under anchorage-independent culture conditions. The migratory potential of A549-DENTT and MCF-7-DENTT cells was reduced when compared with empty vector control cells. Treating human lung cell lines with demethylating agents increased DENTT expression significantly. DENTT expression pattern paralleled that of transforming growth factor-beta1 (TGF-beta1) in normal and malignant tissue and ectopic expression or treatment with TGF-beta1 in lung cancer cells was followed by increased DENTT mRNA and protein levels. Collectively, our results suggest a role for DENTT as a suppressor of the tumorigenic phenotype.
Singh AP, Bafna S, Chaudhary K, et al. Genome-wide expression profiling reveals transcriptomic variation and perturbed gene networks in androgen-dependent and androgen-independent prostate cancer cells. Cancer Lett. 2008; 259(1):28-38 [PubMed] Free Access to Full ArticleRelated Publications
Previously, we have developed a unique in vitro LNCaP cell model, which includes androgen-dependent (LNCaP-C33), androgen-independent (LNCaP-C81) and an intermediate phenotype (LNCaP-C51) cell lines resembling the stages of prostate cancer progression to hormone independence. This model is advantageous in overcoming the heterogeneity associated with the prostate cancer up to a certain extent. We characterized and compared the gene expression profiles in LNCaP-C33 (androgen-dependent) and LNCaP-C81 (androgen-independent) cells using Affymetrix GeneChip array analyses. Multiple genes were identified exhibiting differential expression during androgen-independent progression. Among the important genes upregulated in androgen-independent cells were PCDH7, TPTE, TSPY, EPHA3, HGF, MET, EGF, TEM8, etc., whereas many candidate tumor suppressor genes (HTATIP2, CDKN2A, CDKN2B, CDKN1C, TP53, TP73, ICAM1, SOCS1/2, SPRY2, PPP2CA, PPP3CA, etc.) were decreased. Pathway prediction analysis identified important gene networks associated with growth-promoting and apoptotic signaling that were perturbed during androgen-independent progression. Further investigation of one of the genes, PPP2CA, which encodes the catalytic subunit of a serine phosphatase PP2A, a potent tumor suppressor, revealed that its expression was decreased in prostate cancer compared to adjacent normal/benign tissue. Furthermore, the downregulated expression of PPP2CA was significantly correlated with tumor stage and Gleason grade. Future studies on the identified differentially expressed genes and signaling pathways may be helpful in understanding the biology of prostate cancer progression and prove useful in developing novel prognostic biomarkers and therapy for androgen-refractory prostate cancer.
Gadi VK, Nelson JL Fetal microchimerism in women with breast cancer. Cancer Res. 2007; 67(19):9035-8 [PubMed] Related Publications
Fetal microchimerism (FMc) describes long-term persistence of small numbers of fetal-derived allogeneic cells in the mother. Although FMc has been implicated as a mechanism of autoimmune disease, it may confer a beneficial effect with immune surveillance of malignant cells. We hypothesized that allogeneic FMc imparts a protective effect against breast cancer. Two observations provided a rationale for the study hypothesis. First, allogeneic cells convey risk reduction for recurrent malignancy in hematopoietic cell transplantation. Second, reduced risk of breast cancer is well recognized among parous compared with nulliparous women. As an initial test of the hypothesis, we investigated 82 women, 35 with breast cancer and 47 who were healthy, for male DNA in peripheral blood, presumed from a prior pregnancy with a male fetus. The prevalence and levels of male DNA were determined by real-time quantitative PCR for the Y chromosome-specific gene DYS14 in DNA extracted from peripheral blood mononuclear cells. FMc was found significantly more often in healthy women than women with breast cancer (43% versus 14%, respectively). Considering the absence of FMc as a risk factor, the odds ratio was 4.4 [95% confidence intervals (95% CI), 1.34-16.99; P = 0.006]. Restricting analysis to women known to had given birth to a son, the odds ratio was 5.9 (95% CI, 1.26-6.69; P = 0.01). Our findings indicate that allogeneic FMc may contribute to reduction in risk of breast cancer. Further studies are indicated and, if confirmed, extended studies to examine whether allogeneic immune surveillance from FMc is deficient in women with breast cancer.
Looijenga LH, Hersmus R, Oosterhuis JW, et al. Tumor risk in disorders of sex development (DSD). Best Pract Res Clin Endocrinol Metab. 2007; 21(3):480-95 [PubMed] Related Publications
Disorders of sex development (DSD), previously referred to as intersex disorders, comprise a variety of anomalies defined by congenital conditions in which chromosomal, gonadal, or anatomical sex is atypical. Besides issues such as gender assignment, clinical and diagnostic evaluation, surgical and psychosocial management, and sex steroid replacement, the significantly increased risk for developing specific types of malignancies is both clinically and biologically relevant. This relates to germ-cell tumors specifically in DSD patients with hypovirilization or gonadal dysgenesis. The presence of a well-defined part of the Y chromosome (known as the GBY region) is a prerequisite for malignant transformation, for which the testis-specific protein on the Y chromosome (TSPY) is a likely candidate gene. The precursor lesions of these cancers are carcinoma in situ (CIS)/intratubular germ-cell neoplasia unclassified (ITGCNU) in testicular tissue and gonadoblastoma in those without obvious testicular differentiation. Most recently, undifferentiated gonadal tissue (UGT) has been identified as the likely precursor for gonadoblastoma. The availability of markers for the different developmental stages of germ cells allows detailed investigation of the characteristics of normal and (pre)malignant germ cells. Although informative in a diagnostic setting for adult male patients, these markers - such as OCT3/4 - cannot easily distinguish (pre)malignant germ cells from germ cells showing delayed maturation. This latter phenomenon is frequently found in gonads of DSD patients, and may be related to the risk of malignant transformation. Thus, the mere application of these markers might result in over-diagnosis and unnecessary gonadectomy. It is proposed that morphological and histological evaluation of gonadal tissue, in combination with OCT3/4 and TSPY double immunohistochemistry and clinical parameters, is most informative in estimating the risk for germ-cell tumor development in the individual patient, and might in future be used to develop a decision tree for optimal management of patients with DSD.
Oosterhuis JW, Stoop H, Honecker F, Looijenga LH Why human extragonadal germ cell tumours occur in the midline of the body: old concepts, new perspectives. Int J Androl. 2007; 30(4):256-63; discussion 263-4 [PubMed] Related Publications
Hypotheses on the origin and distribution of extragonadal germ cell tumours (GCTs) and teratomas are briefly reviewed and revisited in the light of (i) new developments in the classification of GCTs, (ii) data on genomic imprinting of these neoplasms and (iii) the recent finding that germ cells can be derived from mouse and human embryonal stem (ES) cells. Only the Type I (infantile teratomas/yolk sac tumours) and Type II GCTs (seminomatous tumours and non-seminomas) occur in the gonads and extragonadal localizations. The data on genomic imprinting lend support to the hypothesis that they are derived from germ cells. These precursor cells could have differentiated from ES cells in extragonadal localizations. Their distribution along the midline of the body is still best explained by the migration of primitive germ cells during development. The narrower distribution of the Type II than the Type I GCTs is probably due to the more strict conditions for survival and proliferation of primordial germ cells (PGCs)/gonocytes from which the Type II tumours originate, when compared with the precursor cells of Type I tumours, probably primitive germ cells closer to the ES cell. The known niches in which the Type II tumours develop have in common that they contain feeder cells expressing stem cell factor (SCF) - the ligand for the SCF receptor c-KIT, involved in proliferation and survival of PGCs/gonocytes - and contain GBY including the gene TSPY.
The testis-specific protein Y-encoded (TSPY) gene is the putative gene for the gonadoblastoma locus on the Y chromosome (GBY) that predisposes dysgenetic gonads of intersex patients to gonadoblastoma development. TSPY is expressed at high levels in gonadoblastoma tissues, supporting its possible oncogenic function in this type of germ cell tumors. To explore the possibility that this Y chromosome gene is also involved in pathogenesis of the more common testicular germ cell tumors (TGCTs), we have conducted various expression studies using immunohistochemistry, Western blotting, and reverse transcription-polymerase chain reaction analysis on 171 cases of TGCTs and selected normal testis controls. Our results demonstrated that TSPY protein is abundantly expressed in the precursor, carcinoma in situ or intratubular germ cell neoplasia unclassified, and seminoma, but only minimally or not expressed in various types of nonseminomas. TSPY coexpresses with established germ cell tumor markers (such as placental-like alkaline phosphatase, c-KIT, OCT4) and proliferative markers (such as Ki-67 and cyclin B1) in the same tumor cells at both RNA and protein levels. Ectopic TSPY expression in cultured cells up-regulates progrowth genes, including those at chromosome 12p13, frequently gained/amplified in TGCTs. Our results suggest that TSPY, in combination with other markers, could be an important marker for diagnosis and subclassification of TGCTs and support its role in the pathogenesis of both gonadoblastoma and TGCTs.
Li Y, Vilain E, Conte F, et al. Testis-specific protein Y-encoded gene is expressed in early and late stages of gonadoblastoma and testicular carcinoma in situ. Urol Oncol. 2007 Mar-Apr; 25(2):141-6 [PubMed] Related Publications
The testis-specific protein Y-encoded gene (TSPY) is a tandem repeat gene located at the critical region for the gonadoblastoma locus on Y chromosome that predisposes the dysgenetic gonads of intersex individuals to oncogenesis. The expression and molecular properties of TSPY suggest that it is the putative gene for the gonadoblastoma locus on Y chromosome. In this study, we examined the expression of TSPY and other germ cell tumor markers in 4 cases of gonadoblastoma using immunostaining techniques. Our results showed that TSPY expression was closely associated with initiation and various stages of gonadoblastoma development. TSPY protein localized with established germ cell tumor markers, such as the placental alkaline phosphatase, c-KIT, and OCT3/4, in the same tumor cells of both gonadoblastoma and adjacent carcinoma in situ, the precursor for germ cell tumors. These findings support the candidacy of TSPY as the gene for the gonadoblastoma locus on Y chromosome and suggest that TSPY could be a significant marker for these types of germ cell tumors.
BACKGROUND: Ovarian germ cell tumours (OGCTs) typically arise in young females and their pathogenesis remains poorly understood. We investigated the origin of malignant OGCTs and underlying molecular events in the development of the various histological subtypes of this neoplasia. RESULTS: We examined in situ expression of stem cell-related (NANOG, OCT-3/4, KIT, AP-2gamma) and germ cell-specific proteins (MAGE-A4, NY-ESO-1, TSPY) using a tissue microarray consisting of 60 OGCT tissue samples and eight ovarian small cell carcinoma samples. Developmental pattern of expression of NANOG, TSPY, NY-ESO-1 and MAGE-A4 was determined in foetal ovaries (gestational weeks 13-40). The molecular genetic part of our study included search for the presence of Y-chromosome material by fluorescence in situ hybridisation (FISH), and mutational analysis of the KIT oncogene (exon 17, codon 816), which is often mutated in testicular GCTs, in a subset of tumour DNA samples. We detected a high expression of transcription factors related to the embryonic stem cell-like pluripotency and undifferentiated state in OGCTs, but not in small cell carcinomas, supporting the view that the latter do not arise from a germ cell progenitor. Bilateral OGCTs expressed more stem cell markers than unilateral cases. However, KIT was mutated in 5/13 unilateral dysgerminomas, whereas all bilateral dysgerminomas (n = 4) and all other histological types (n = 22) showed a wild type sequence. Furthermore, tissue from five phenotypic female patients harbouring combined dysgerminoma/gonadoblastoma expressed TSPY and contained Y-chromosome material as confirmed by FISH. CONCLUSION: This study provides new data supporting two distinct but overlapping pathways in OGCT development; one involving spontaneous KIT mutation(s) leading to increased survival and proliferation of undifferentiated oogonia, the other related to presence of Y chromosome material and ensuing gonadal dysgenesis in phenotypic females.
Hildenbrand R, Schröder W, Brude E, et al. Detection of TSPY protein in a unilateral microscopic gonadoblastoma of a Turner mosaic patient with a Y-derived marker chromosome. J Pathol. 1999; 189(4):623-6 [PubMed] Related Publications
Gonadoblastomas are seen almost exclusively in dysgenetic gonads of patients with a chromosomal mosaicism of 45,X and an additional Y-bearing cell line. This paper presents a case of a Turner mosaic patient with 45,X/46,X,+mar karyotype, who developed a unilateral microscopic gonadoblastoma. Cytogenetic and molecular analysis confirmed a Y-chromosomal origin of the marker chromosome, with a deletion of the distal Yq arm and the proposed region of a so far undefined gonadoblastoma locus (GBY) present. One of the candidate genes within the postulated GBY region is TSPY (testis-specific protein Y-encoded). To study the TSPY protein expression, an anti-fusion protein antibody was used for immunohistochemistry of the patient's gonads. In contrast to the dysgenetic gonad, an intense immunoreaction was found in gonadoblastoma tumour cells of the other gonad. These results confirm the high level of TSPY protein expression by these cells and demonstrate the value of this antibody as an additional marker to confirm the diagnosis of gonadoblastoma.