"DESCRIPTION (provided by applicant): The long-term goal of the Genomics of Acute Myeloid Leukemia Program Project Grant (GAML PPG) is to define all of the genetic events that contribute to the pathogenesis of AML, and to use this information to improve the risk assessment and treatment of patients with this disease. This goal will be addressed in a highly integrated and productive PPG structure that involves four projects and four cores. During the past 5 years, the members of this PPG developed the approaches (that are now widely used) to perform whole genome sequencing of AML genomes, and to validate all variants with custom capture arrays and deep digital sequencing. We have contributed 200 AML samples to The Cancer Genome Atlas for their AML project, which is led by two of our PPG members (Ley and Wilson). Although analysis of this enormous dataset is ongoing, these studies have led to the discovery of more than 200 recurrently mutated genes in AML, including DNMT3A, U2AF1, and IDH1, representing new classes of mutations that were not previously (<known to be relevant for this disease. The deep digital sequencing of all variants in these genomes has also revealed groups of mutations with similar variant allele frequencies, which represent clones of cells within the samples. We have learned that all AML samples have a founding clone, and most contain 1-3 additional subclones that are derived from the founding clone. Our data suggests that specific subclones may contain mutations that are relevant for altered growth properties and/or altered drug sensitivity, which may contribute to refractory disease or relapse. In the next funding period, we will strategically sequence selected genomes and transcriptomes of AML samples from our tumor bank (which now includes more than 1,200 fully annotated cases of AML and MDS). Samples will be selected to address critical issues in AML biology, to maximize our understanding of the genetic origins of the disease, to identify genetic variants that are associated with primary refractory disease and early relapse (associated with the worst prognosis of all patients), and to define variants associated with treatment-related AML, which is fatal in most patients who develop the disease. By defining recurring mutations that are found in different subtypes of AML, and linking them to clonal behavior, clinical behavior, and outcomes, we hope to refine risk classification for AML, and to define new genetic targets for novel therapies in high risk patients." |