The Genetic Burden of Man

Y Chromosome and Human Cancers

The Y chromosome is critical for male development and physiology, such as spermatogenesis. However, dysfunctions of its genes could contribute to diseases that are male-specific, such as testicular germ cell tumors, the number one cancer among young men between the ages of 15 to 35 years, and prostate cancer, affecting primarily the elderly population, and numerous diseases that have a male-preference in their manifestation. Examples of the latter include autism, hepatocellular carcinoma and Hirschsprung's disease. Hence, although the Y chromosome is essential for normal male development and physiology, it is also a genetic burden for man.
Clues of the oncogenic role of the Y chromosome have come from observations that patients with disorders of sex development (DSD) with residual Y materials develop gonadoblastoma at extremely high frequency in thier dysgenetic gonads at early ages. A gonadoblastoma locus on the Y chromosome (GBY) has been proposed to explain such high penetrance of this type of germ cell tumors among patients harboring a mutated or dysfunctional Y chromosome. Numerous studies, by our laboratory and others, suggest that the testis-specific protein Y-encoded (TSPY) gene is the putative gene for GBY. Indeed, TSPY is abundantly expressed in gonadoblastoma and is associated with the oncogenesis of this type of tumors in XY females (Figure 3), as well as testicular germ cell tumors (TGCTs), seminomas, selected nonseminomas, intracranial germ cell tumors of male origin, and somatic cancers including prostate cancer, hepatocellular carcinoma and melanoma.

Figure 3. Expression of TSPY in early stages of gonadoblastoma of a XY sex-reversed patient (A). TSPY-positive (dark brown) tumor cells emerged from apparently emply follicles that proliferated rapidly and filled up the space (B - H).

Functions of TSPY Gene in Normal Physiology and Diseases

Our studies suggest that TSPY serves normal functions in male stem germ cell proliferation and meiotic division. It interacts with type B cyclins and affects the cyclin B-CDK1 kinase activities. Detailed studies suggest that TSPY and cyclin B1 are co-expressed tightly during spermatocyte differentiation and play key roles in mediating two rounds of meiotic division without an intermediate interphase during spermatogenesis, a unique feature for male meiosis. Ectopic expression of TSPY accelerates cell proliferation in vitro and tumorigenesis in athymic mice. It up-regulates oncogenes and progrowth genes, particularly those on chromosome 12p, and down-regulates growth inhibitors. TSPY is tandemly repeated 20-60 times and constitutes a large block (up to 1 MB of DNA) of functional gene array on the short arm of the human Y chromosome. The frequent variation of its gene-copy number suggests that its gene array is a hot spot for genetic instability on the human Y chromosome, both among normal population and in various diseases conditions.

Our efforts are focused on elucidating the molecular mechanisms responsible for TSPY dysregulation and tumor-predisposing functions in human cancers, particularly on prostate cancer and testicular germ cell tumors. Additional studies include identification of TSPY interactive partners in its onocgenic and normal functions. Successful implementation of our research should provide important insights on the role of TSPY in the pathogenesis of these two types of cancers, affecting elderly and young men respectively in the population.

TSPY and cancer stem cells. Our studies demonstrated that TSPY is expressed at high levels in the premalignant precursor, carcinoma-in-situ (CIS) or intratubular germ cell neoplasia unclassified (ITGCNU), of all testicular germ cell tumors. Its expression is closely correlated with specific germ cell tumor markers, such as placental alkaline phosphatase, c-Kit and Oct4. Since CIS has been considered to be a cancer stem cell, TSPY could potentially be important for either the maintenance or oncogenic differentiation of CIS in germ cell tumorigenesis. Recently, we have established an intratubular transplantation model for TGCT. The availbility of such model will allow us to evaluate the role of TSPY and other putative oncogenes in cancer stem cell proliferation and development of TGCTs.