Project Summary/Abstract A small subset of pituitary adenomas demonstrates aggressive behavior as defined by rapid growth following treatment, namely hormonal therapy, surgery, and radiation. Aggressive pituitary tumors are devastating, life- limiting malignancies with two patterns of growth: (1) they can remain confined to the skull base and grow relentlessly, resulting in progressive neurologic dysfunction or (2) they can metastasize. These tumors are poorly studied and under-recognized in part because there are no validated biomarkers that predict future aggressive behavior. We hypothesize that recurrent patterns of copy number variation, including a molecular hypodiploidy phenotype, characterized by an early, clonal loss of one copy of chromosomes 1, 2, 3, 6, 8, 10, 11, 13, 15, 17, 18, 21, and 22, predict future progression following treatment with radiotherapy. Additionally, we hypothesize that aggressive pituitary adenomas and carcinomas harbor recurrent epigenetic and genetic alterations at a gene and pathway level that define a more aggressive molecular subtype. This foundational work is needed so that clinicians can prospectively identify tumors with a higher malignant potential. The identification of a biomarker of aggressive disease is critical for improving patient outcomes by preventing both over- and undertreatment, and for clinical trial development.