Abstract IA04: ATRX mutations in human carcinogenesis

Abstract

Abstract The recent years, genome-wide analyses identified the genetic landscapes of many different tumor types. One of the most frequent class of genes found to be mutated were genes whose products regulate epigenetic mechanisms, like chromatin modification and remodeling, providing a link between genetic alterations and epigenetic changes in cancer. One of these genes is ATRX. This gene has been studied in the context of alpha thalassemia-mental retardation X-linked syndrome. In human sporadic solid tumors, it was first shown to be mutated in pancreatic neuroendocrine tumors (PanNETs). Approximately, 50% of PanNETs had mutations in either ATRX or DAXX. The proteins of these two genes form a complex that deposits H3.3 at heterochromatin and telomeres. ATRX, but not DAXX, has also been found to be mutated in certain types of central nervous system tumors. The prevalence of mutations in ATRX is different for the different types of gliomas. It is mutated more frequently in astrocytomas and oligoastrocytomas, but rarely in primary glioblastomas. Recently, we identified mutations in the promoter of TERT in the same set of glioma samples. TERT mutations were more prevalent in primary glioblastomas and oligodendrogliomas. Overall, mutations in ATRX and TERT were mutually exclusive, suggesting that these two genetic mechanisms result in equivalent growth advantages. Mutations in ATRX have almost perfect correlation with Alternative Lengthening of Telomeres (ALT) phenotype in PanNETs, CNS tumors and other cases with ATRX mutations, thus, TERT activation and ALT phenotype are mutually exclusive. This has implications for understanding the relationship between telomeres and tumorigenesis. These studies, in addition to providing clues about the underlying genetic changes that drive tumorigenesis, they also have clinical implications. Mutations in ATRX or DAXX in PanNETs associate with better prognosis. Mutations of ATRX and TERT aid in the classification and prognostication of brain tumors. Further understanding of the role of ATRX in tumorigenesis should help in uncovering new ways for therapeutic targeting of tumors with mutations in this gene. Citation Format: Nickolas E. Papadopoulos. ATRX mutations in human carcinogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr IA04.