title: Clonal competition with alternating dominance in multiple myeloma.
abstract: Emerging evidence indicates that tumors can follow several evolutionary paths over a patient's disease course. With the use of serial genomic analysis of samples collected at different points during the disease course of 28 patients with multiple myeloma, we found that the genomes of standard-risk patients show few changes over time, whereas those of cytogenetically high-risk patients show significantly more changes over time. The results indicate the existence of 3 temporal tumor types, which can either be genetically stable, linearly evolving, or heterogeneous clonal mixtures with shifting predominant clones. A detailed analysis of one high-risk patient sampled at 7 time points over the entire disease course identified 2 competing subclones that alternate in a back and forth manner for dominance with therapy until one clone underwent a dramatic linear evolution. With the use of the Vk*MYC genetically engineered mouse model of myeloma we modeled this competition between subclones for predominance occurring spontaneously and with therapeutic selection.
authors.affiliation: Comprehensive Cancer Center, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Keats
authors.forename: Marta
authors.initials: M
authors.lastname: Chesi
authors.forename: Jan B
authors.initials: JB
authors.lastname: Egan
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Garbitt
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Palmer
authors.forename: Esteban
authors.initials: E
authors.lastname: Braggio
authors.forename: Scott
authors.initials: S
authors.lastname: Van Wier
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Blackburn
authors.forename: Angela S
authors.initials: AS
authors.lastname: Baker
authors.forename: Angela
authors.initials: A
authors.lastname: Dispenzieri
authors.forename: Shaji
authors.initials: S
authors.lastname: Kumar
authors.forename: S Vincent
authors.initials: SV
authors.lastname: Rajkumar
authors.forename: John D
authors.initials: JD
authors.lastname: Carpten
authors.forename: Michael
authors.initials: M
authors.lastname: Barrett
authors.forename: Rafael
authors.initials: R
authors.lastname: Fonseca
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D060965:Clonal Evolution / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D016000:Cluster Analysis; D056915:DNA Copy Number Variations / Q000235:genetics; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046228:Microarray Analysis; D008954:Models, Biological; D009101:Multiple Myeloma / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D012008:Recurrence