Cancer genetics/epigenetics and the X chromosome: possible new links for malignant glioma pathogenesis and immune-based therapies.

Human high-grade gliomas (HGGs) are rapidly progressing heterogeneous brain tumors of unknown etiology and there are no effective treatment modalities available. The recent discovery of cancer-specific antigens has opened new doors for specific tumor-targeted treatments using passive and active immunotherapeutic strategies. In particular, SEREX (serological analysis of recombinant cDNA expression libraries) has aided in the discovery of numerous new tumor antigens. These specific tumor antigens are located on chromosome X and are expressed predominantly in the testes among normal organs, and hence termed Cancer/Testis Antigens (CTAs). We found that the vast majority of HGG patients overexpress a receptor for an immune regulatory cytokine, interleukin 13 (IL-13), which differs from the normal tissue physiological receptor. Interestingly, the HGG-associated receptor protein, IL-13R alpha, is expressed solely in the testes and its gene is localized to chromosome X, which mirror the expression pattern and genomic localization of CTAs. There is little evidence for frequent gross structural abnormalities on chromosome X in HGG. Although the mechanism that causes X chromosome-linked CTAs to be aberrantly expressed in tumors is not fully understood, evidence is beginning to point toward the DNA methylation dysregulation that occurs in tumor cells as being implicit in this process and perhaps in the oncogenic process as well. Therefore, further study of the phenomenon of CTAs may bring the dual benefit of better understanding tumorigenesis and providing new molecular tools for better management of HGGs. Also, we propose that the X chromosome may in fact be an important player in HGG oncogenesis.