Treatment-associated AML, which develops as a consequence of treatment for a primary cancer diagnosis and ensuing treatment, is emerging as a major clinical problem. This project is aimed at identifying relevant mutations that contribute to the disease’s pathogenesis.
Center Initiated Projects (CIPs) are proposed by the McDonnell Genome Institute to help fulfill the mission and strategic vision of the NHGRI and NIH. All CIP data will be released in a timely manner via appropriate databases in accordance with NHGRI and NIH guidelines.
Project Summary: Therapy-related acute myeloid leukemia/myelodysplasia (t-AML/t-MDS), which develops as a consequence of treatment for a primary cancer diagnosis and ensuing treatment (chemo- and/or radio-therapy), is emerging as a major clinical problem. It accounts for 10-20% of all cases of AML, and its incidence is rising. The prognosis in patients with t-AML/t-MDS is dismal, and has not improved substantially in the last few decades. In a review of 644 patients with t-AML/t-MDS treated with a variety of therapies, the complete response rate was only 28%, with a median survival of 6-12 months. The development of new therapeutics and strategies for risk stratification or early detection has been severely hampered by the lack of understanding of the molecular pathogenesis of t-AML/t-MDS. In fact, we argue that major improvements in the clinical management of patients with t-AML/t-MDS are unlikely without a better understanding of the genetic alterations contributing to t-AML/t-MDS susceptibility, transformation, and resistance to chemotherapy. Of note, there is accumulating evidence that the spectrum of mutations contributing to t-AML/t-MDS may be different from that in de novo AML. In fact, candidate gene sequencing studies in t-AML/t-MDS to date have identified mutations in only a minority of cases. These studies suggest that we have not yet discovered most of the relevant mutations that contribute to t-AML/t-MDS pathogenesis, highlighting the need for a discovery project specifically directed at identifying mutations in t-AML/t-MDS. The identification of somatic mutations in t-AML/t-MDS is likely to have direct and immediate clinical relevance. First, it may allow for early detection and intervention of t-AML/t-MDS in high-risk groups, such as patients undergoing autologous stem cell transplantation for relapsed lymphoma. Second, though the overall prognosis of patients with t-AML/t-MDS is poor, the pattern of genetic alterations may identify a subgroup with better (or worse) outcomes. Finally, these data will identify new genes and gene pathways to develop targeted therapeutics. In this regard, we propose a goal of sequencing the genomes of 25 paired tumor/normal samples from patients with t-AML, analyzing these data to identify genome-wide variants, and validating these by our conventional approaches. Once we have established annotated variants, we will design a solid-phase capture array that is customized to contain all suspect mutations for recurrent screening of a larger tumor repository. Status of Samples: 25 total cases (tumor:normal pairs): 50 total genomes. 7 cases in library construction. 11 cases with completed libraries. 3 cases in data generation. 4 cases in analysis. Follow-up work to include validation and extension sequencing. Collaborators: Dr. Tim Ley. IRB Status: Compliant.