Rhabdoid tumor is a clinically aggressive malignancy that generally presents in the first four years of life. Rhabdoid tumors of the central nervous system (atypical teratoid/rhabdoid tumor; AT/RT), kidney and soft tissues are associated with alterations of the INI1/hSNF5 tumor suppressor gene in chromosome 22q11.2. AT/RT is the only pediatric brain tumor for which the primary genetic etiology has been elucidated, and as many as 35% of children may have predisposing germline deletions or mutations of INI1. INI1 is a member of the SWI/SNF chromatin remodeling complex and functions to repress or activate gene transcription. Understanding the role of INI1 in tumor development specifically addresses the goals of the NIH Brain Tumor Progress Review Group, but has wider implications for a variety of pediatric and adult diseases that may arise as a consequence of mutations in genes involved in chromatin remodeling. A continuing goal of this program is to determine the spectrum of clinicopathologic manifestations of heterogeneous germline and somatic mutations of the INI1 gene. In aim 1, we will perform a comprehensive genomic analysis of the 22q11.2 region, including deletion analysis by FISH and MLPA, as well as direct sequencing. We will determine whether specific deletions or mutations are associated with anatomic site, as well as prognosis. In aim 2, we will define the spectrum of de novo and inherited germline deletions and mutations in patients and their families. Preliminary data suggests that there is a bias in the parent of origin of germline mutations, which will be explored in a larger patient cohort. A genome wide approach, using high density single nucleotide polymorphisms arrays, will be used in aim 3 to interrogate the region of chromosome band 22q11.2 which contains INI1, as well as to identify other chromosomal regions that may be related to rhabdoid tumor development. The characterization of potential candidate genes associated with clinical features and outcome will be explored in aim 4 using a combination of mutation and expression analyses. PUBLIC HEALTH RELEVANCE: Rhabdoid tumors of the brain, kidney and soft tissues are clinically aggressive malignancies that primarily affect children under four years of age. The INI1 gene on chromosome 22 is a key tumor suppressor inactivated in the majority of tumors. Understanding the mechanisms by which INI1 is inactivated will be important for treatment stratification, and ultimately designing biologically based therapeutic strategies for patients.