Abstract SY30-03: First impressions of the multiple myeloma genome

Abstract

Abstract Multiple myeloma is a malignancy of mature B-lymphoid cells whose pathogenesis remains obscure. To address this, we undertook a large-scale effort to characterize the genomes of multiple myleoma tumor samples and their matched normal DNAs. Funded by the Multiple Myeloma Research Foundation, this sequencing effort is one of the largest cancer genome sequencing projects completed to date, representing 29 patients (22 whole genomes and 17 whole exomes) sequenced to an average of 30X coverage. Improvements in mutation-calling algorithms yielded a mutation rate of ~ 10-6, with a mutation validation rate of 97%, indicating that the false-positive rate of mutations in this dataset is extremely low. Highlights of novel and biologically important findings from this dataset will be presented, and include: 1) mutations in the transcription factor IRF4; 2) mutations in histone methyltransferases; 3) mutations in genes involved in protein translation; 4) mutations in genes involved in blood coagulation; and 5) an activating mutation in BRAF, for which small-molecule inhibitors are in clinical development. These results suggest that sequencing of the multiple myeloma genome will provide new insights into the pathogenesis of multiple myeloma, and moreover suggest that while mutations in particular genes may be rare, they may result in the aberrant activity of common pathways. This in turn suggests that the sequencing of large numbers of cancer genomes may be required to develop a full understanding of the biological consequences of somatic mutations. Citation Format: Todd R. Golub. First impressions of the multiple myeloma genome [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY30-03