Identification of germ cells at risk for neoplastic transformation in gonadoblastoma

Kersemaekers, Anne-Marie F.; Honecker, Friedemann; Stoop, Hans; Cools, Martine; Molier, Michel; Wolffenbuttel, Katja P.; Bokemeyer, Carsten; Li, Yunmin; Lau, Yun‐Fai Chris; Oosterhuis, J. Wolter; Looijenga, Leendert H. J.

doi:10.1016/j.humpath.2005.02.016

Cited by 151 publications

(140 citation statements)

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“…19 This genomic region contains TSPY as one of the likely candidate genes. This is supported by the strong expression of TSPY in CIS and the germ cells of GB, 28 as is also the case in this patient. Normally, TSPY is expressed in spermatogonia of the adult testis and is believed to be related to mitotic proliferation.…”

Section: Discussionsupporting

confidence: 87%

A novel SRY missense mutation affecting nuclear import in a 46,XY female patient with bilateral gonadoblastoma

et al. 2009

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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 nonseminomatous 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.

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Section: Discussionsupporting

confidence: 87%

A novel SRY missense mutation affecting nuclear import in a 46,XY female patient with bilateral gonadoblastoma

et al. 2009

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“…TSPY is normally expressed in early gonocytes and prespermatogonia in fetal testis and in spermatogonia, spermatocytes and round spermatids in adult testis (Honecker et al, 2004;Kido and Lau, 2005), and has been postulated to serve normal functions in stem germ cell proliferation and meiotic division (Schnieders et al, 1996;Lau, 1999). TSPY is ectopically expressed in tumor cells in various types of germ cell tumors, including gonadoblastoma, testicular germ cell tumors and male intracranial germ cell tumors, and has been considered as a key marker that is important in the pathogenesis of these types of human tumors Kersemaekers et al, 2005;Hoei-Hansen et al, 2006;Oram et al, 2006;Li et al, 2007b). Significantly, it is also aberrantly expressed in prostate cancer and numerous somatic cancers, including hepatocellular carcinoma and melanoma of male origins (Lau and Zhang, 2000;Lau et al, 2003;Gallagher et al, 2005;Yin et al, 2005), suggesting that the TSPY tandem arrays are hot spots for epigenetic dysregulation.…”

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confidence: 99%

TSPY and its X-encoded homologue interact with cyclin B but exert contrasting functions on cyclin-dependent kinase 1 activities

Lau

2008

Oncogene

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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.

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Section: Introductionmentioning

confidence: 99%

“…This amplicon is particularly rich in genes, several of which [e.g., c-MYC [31], NOV [nephroblastoma overexpressed gene], EIF3S3 [eukaryotic translation initiation factor 3 subunit 3], HAS2 [hyaluronan synthase2] [32], KIAA0196 [33], and PSCA [34]] are expressed in prostate and have either oncogenic or tumor suppressor potential. FISH analysis has identified amplification of the 8q24 amplicon [32,[35][36][37] in a large percentage of human adenocarcinomas [38,39] and some prostate intraepithelial neoplasias (PIN) [37].…”

Section: Introductionmentioning

confidence: 99%

“…However, the precise role played by c-MYC in human prostate cancer is unclear in part due to the amplification of the 8q24 amplicon. This amplicon is particularly rich in genes, several of which [e.g., [32,[35][36][37] in a large percentage of human adenocarcinomas [38,39] and some prostate intraepithelial neoplasias (PIN) [37].Mouse models of prostatic neoplasia have been generated in which the c-MYC gene was expressed from either the probasin promoter [20] or C(3)1 promoter [22]. Two probasin promoter variants were used in one study; these promoters share the same prostate specificity but differ in promoter activity.…”

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The Role of the Y-Located TSPY Gene in Prostatic Oncongenesis

Lau¹

2006

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 5e. TASK NUMBER 5f. WORK UNIT NUMBER REPORT DATE 01-02-2006 REPORT TYPE PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERNorthern California Institute for Research and Education San Francisco, CA 94121 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTESOriginal contains colored plates: ALL DTIC reproductions will be in black and white. ABSTRACTThe TSPY gene is the only functional gene within the critical region harboring the gonadoblastoma locus on the Y chromosome (GBY). Expression studies demonstrated that it is aberrantly expressed in prostate cancer. This project is designed to address the role of this putative oncogene on the Y chromosome in this male-specific cancer. The objectives are: 1) to identify the oncogenic or tumor promoting domain in TSPY, and 2)to correlate TSPY over-expression with prostatic oncogenesis in transgenic mice. For the past year, we have examined the TSPY expression in additional 61 cases of prostate cancer and demonstrated that its expression is proportional to the degrees of malignancy of these clinical samples. Similar study of a tissue recombination model of prostate cancer demonstrated the same results, suggesting TSPY expression is intimately associated with prostate cancer. Significantly, studies of a line of transgenic mice harboring 50 copies of the human TSPY gene on their Y chromosome demonstrated that TSPYis expressed in hyperplasic regions of the prostates of old mice, resembling those of latent cancer in old men. These findings are significant, supporting the role of TSPY in the initiation of prostatic oncogenesis. For the next 12-month period, we plan to continue our characterization of our transgenic mice to confirm TSPY as an oncogene. SUBJECT TERMS INTRODUCTIONThe TSPY gene is a tandemly repeated gene on he short arm of the human Y chromosome. Genetic mapping and complet...

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Identification of germ cells at risk for neoplastic transformation in gonadoblastoma

Cited by 151 publications

References 32 publications

A novel SRY missense mutation affecting nuclear import in a 46,XY female patient with bilateral gonadoblastoma

A novel SRY missense mutation affecting nuclear import in a 46,XY female patient with bilateral gonadoblastoma

TSPY and its X-encoded homologue interact with cyclin B but exert contrasting functions on cyclin-dependent kinase 1 activities

The Role of the Y-Located TSPY Gene in Prostatic Oncongenesis

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