Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides

• Published in: Blood Vol. 120; no. 5; pp. 1060 - 1066
• Main Authors: Egan, Jan B., Shi, Chang-Xin, Tembe, Waibhav, Christoforides, Alexis, Kurdoglu, Ahmet, Sinari, Shripad, Middha, Sumit, Asmann, Yan, Schmidt, Jessica, Braggio, Esteban, Keats, Jonathan J., Fonseca, Rafael, Bergsagel, P. Leif, Craig, David W., Carpten, John D., Stewart, A. Keith
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 02.08.2012; Americain Society of Hematology; American Society of Hematology
• Subjects: Aged; Biological and medical sciences; Cell Transformation, Neoplastic - genetics; Chromosome Aberrations; Chromosomes, Human, Pair 14; Chromosomes, Human, Pair 4; Clonal Evolution - genetics; Clonal Evolution - physiology; Comparative Genomic Hybridization; Disease Progression; Female; Follow-Up Studies; Genome, Human - genetics; Hematologic and hematopoietic diseases; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Leukemia, Plasma Cell - diagnosis; Leukemia, Plasma Cell - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoid Neoplasia; Medical sciences; Multiple Myeloma - diagnosis; Multiple Myeloma - genetics; Recurrence; Sequence Analysis, DNA - methods; Immunopathology; Clonality; Leukemia initiating cells; Hematology; Malignant hemopathy; Myeloma; Plasmocytic leukemia; Immunoglobulinopathy; Lymphoproliferative syndrome; Diagnosis; Genome; Sequencing; Cancer
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2012-01-405977

The longitudinal evolution of a myeloma genome from diagnosis to plasma cell leukemia has not previously been reported. We used whole-genome sequencing (WGS) on 4 purified tumor samples and patient germline DNA drawn over a 5-year period in a t(4;14) multiple myeloma patient. Tumor samples were acquired at diagnosis, first relapse, second relapse, and end-stage secondary plasma cell leukemia (sPCL). In addition to the t(4;14), all tumor time points also shared 10 common single-nucleotide variants (SNVs) on WGS comprising shared initiating events. Interestingly, we observed genomic sequence variants that waxed and waned with time in progressive tumors, suggesting the presence of multiple independent, yet related, clones at diagnosis that rose and fell in dominance. Five newly acquired SNVs, including truncating mutations of RB1 and ZKSCAN3, were observed only in the final sPCL sample suggesting leukemic transformation events. This longitudinal WGS characterization of the natural history of a high-risk myeloma patient demonstrated tumor heterogeneity at diagnosis with shifting dominance of tumor clones over time and has also identified potential mutations contributing to myelomagenesis as well as transformation from myeloma to overt extramedullary disease such as sPCL.