title: Bi-allelic inactivation is more prevalent at relapse in multiple myeloma, identifying RB1 as an independent prognostic marker.
abstract: The purpose of this study is to identify prognostic markers and treatment targets using a clinically certified sequencing panel in multiple myeloma. We performed targeted sequencing of 578 individuals with plasma cell neoplasms using the FoundationOne Heme panel and identified clinically relevant abnormalities and novel prognostic markers. Mutational burden was associated with maf and proliferation gene expression groups, and a high-mutational burden was associated with a poor prognosis. We identified homozygous deletions that were present in multiple myeloma within key genes, including CDKN2C, RB1, TRAF3, BIRC3 and TP53, and that bi-allelic inactivation was significantly enriched at relapse. Alterations in CDKN2C, TP53, RB1 and the t(4;14) were associated with poor prognosis. Alterations in RB1 were predominantly homozygous deletions and were associated with relapse and a poor prognosis which was independent of other genetic markers, including t(4;14), after multivariate analysis. Bi-allelic inactivation of key tumor suppressor genes in myeloma was enriched at relapse, especially in RB1, CDKN2C and TP53 where they have prognostic significance.
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Chavan
authors.affiliation: Foundation Medicine Inc., Cambridge, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: He
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: R
authors.initials: R
authors.lastname: Tytarenko
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: S
authors.initials: S
authors.lastname: Deshpande
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: P
authors.initials: P
authors.lastname: Patel
authors.affiliation: Foundation Medicine Inc., Cambridge, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bailey
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: C K
authors.initials: CK
authors.lastname: Stein
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: O
authors.initials: O
authors.lastname: Stephens
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: N
authors.initials: N
authors.lastname: Weinhold
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: N
authors.initials: N
authors.lastname: Petty
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: D
authors.initials: D
authors.lastname: Steward
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: L
authors.initials: L
authors.lastname: Rasche
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bauer
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: C
authors.initials: C
authors.lastname: Ashby
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: E
authors.initials: E
authors.lastname: Peterson
authors.affiliation: Foundation Medicine Inc., Cambridge, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ali
authors.affiliation: Foundation Medicine Inc., Cambridge, MA, USA.|Albany Medical College, Albany, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ross
authors.affiliation: Foundation Medicine Inc., Cambridge, MA, USA.
authors.forename: V A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Foundation Medicine Inc., Cambridge, MA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Stephens
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: S
authors.initials: S
authors.lastname: Thanendrarajan
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: C
authors.initials: C
authors.lastname: Schinke
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: M
authors.initials: M
authors.lastname: Zangari
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: F
authors.initials: F
authors.lastname: van Rhee
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.|Icahn School of Medicine at Mt. Sinai, New York, NY, USA.
authors.forename: B
authors.initials: B
authors.lastname: Barlogie
authors.affiliation: Foundation Medicine Inc., Cambridge, MA, USA.|Tufts University Medical Center, Boston, MA, USA.
authors.forename: T I
authors.initials: TI
authors.lastname: Mughal
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: F E
authors.initials: FE
authors.lastname: Davies
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Morgan
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Walker
mesh_terms: D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D056286:Retinoblastoma Binding Proteins / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: C000606393:RB1 protein, human; D056286:Retinoblastoma Binding Proteins; D016160:Retinoblastoma Protein; D044767:Ubiquitin-Protein Ligases