title: Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides.
abstract: 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.
authors.affiliation: Division of Hematology-Oncology, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.
authors.forename: Jan B
authors.initials: JB
authors.lastname: Egan
authors.forename: Chang-Xin
authors.initials: CX
authors.lastname: Shi
authors.forename: Waibhav
authors.initials: W
authors.lastname: Tembe
authors.forename: Alexis
authors.initials: A
authors.lastname: Christoforides
authors.forename: Ahmet
authors.initials: A
authors.lastname: Kurdoglu
authors.forename: Shripad
authors.initials: S
authors.lastname: Sinari
authors.forename: Sumit
authors.initials: S
authors.lastname: Middha
authors.forename: Yan
authors.initials: Y
authors.lastname: Asmann
authors.forename: Jessica
authors.initials: J
authors.lastname: Schmidt
authors.forename: Esteban
authors.initials: E
authors.lastname: Braggio
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Keats
authors.forename: Rafael
authors.initials: R
authors.lastname: Fonseca
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.forename: David W
authors.initials: DW
authors.lastname: Craig
authors.forename: John D
authors.initials: JD
authors.lastname: Carpten
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
mesh_terms: D000368:Aged; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002869:Chromosome Aberrations; D002883:Chromosomes, Human, Pair 14; D002894:Chromosomes, Human, Pair 4; D060965:Clonal Evolution / Q000235:genetics* / Q000502:physiology; D055028:Comparative Genomic Hybridization; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D007952:Leukemia, Plasma Cell / Q000175:diagnosis / Q000235:genetics*; D009101:Multiple Myeloma / Q000175:diagnosis / Q000235:genetics*; D012008:Recurrence; D017422:Sequence Analysis, DNA / Q000379:methods