title: Minor clone provides a reservoir for relapse in multiple myeloma.
abstract: Recent studies have provided direct evidence for genetic variegation in subclones for various cancer types. However, little is known about subclonal evolutionary processes according to treatment and subsequent relapse in multiple myeloma (MM). This issue was addressed in a cohort of 24 MM patients treated either with conventional chemotherapy or with the proteasome inhibitor, bortezomib. As MM is a highly heterogeneous disease associated with a large number of chromosomal abnormalities, a subset of secondary genetic events that seem to reflect progression, 1q21 gain, NF-κB-activating mutations, RB1 and TP53 deletions, was examined. By using high-resolution single-nucleotide polymorphism arrays, subclones were identified with nonlinear complex evolutionary histories. Such reordering of the spectrum of genetic lesions, identified in a third of MM patients during therapy, is likely to reflect the selection of genetically distinct subclones, not initially competitive against the dominant population but which survived chemotherapy, thrived and acquired new anomalies. In addition, the emergence of minor subclones at relapse appeared to be significantly associated with bortezomib treatment. These data support the idea that new strategies for future clinical trials in MM should combine targeted therapy and subpopulations' control to eradicate all myeloma subclones in order to obtain long-term remission.
authors.affiliation: INSERM UMR 892, CNRS UMR 6299, Université de Nantes, Nantes, France.
authors.forename: F
authors.initials: F
authors.lastname: Magrangeas
authors.forename: H
authors.initials: H
authors.lastname: Avet-Loiseau
authors.forename: W
authors.initials: W
authors.lastname: Gouraud
authors.forename: L
authors.initials: L
authors.lastname: Lodé
authors.forename: O
authors.initials: O
authors.lastname: Decaux
authors.forename: P
authors.initials: P
authors.lastname: Godmer
authors.forename: L
authors.initials: L
authors.lastname: Garderet
authors.forename: L
authors.initials: L
authors.lastname: Voillat
authors.forename: T
authors.initials: T
authors.lastname: Facon
authors.forename: A M
authors.initials: AM
authors.lastname: Stoppa
authors.forename: G
authors.initials: G
authors.lastname: Marit
authors.forename: C
authors.initials: C
authors.lastname: Hulin
authors.forename: P
authors.initials: P
authors.lastname: Casassus
authors.forename: M
authors.initials: M
authors.lastname: Tiab
authors.forename: E
authors.initials: E
authors.lastname: Voog
authors.forename: E
authors.initials: E
authors.lastname: Randriamalala
authors.forename: K C
authors.initials: KC
authors.lastname: Anderson
authors.forename: P
authors.initials: P
authors.lastname: Moreau
authors.forename: N C
authors.initials: NC
authors.lastname: Munshi
authors.forename: S
authors.initials: S
authors.lastname: Minvielle
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics*; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D002869:Chromosome Aberrations; D002999:Clone Cells; D003907:Dexamethasone / Q000008:administration & dosage; D018450:Disease Progression; D019143:Evolution, Molecular; D005260:Female; D005500:Follow-Up Studies; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000139:chemically induced* / Q000175:diagnosis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011719:Pyrazines / Q000008:administration & dosage; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016160:Retinoblastoma Protein / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000069286:Bortezomib; D003907:Dexamethasone