Evolution and structure of clinically relevant gene fusions in multiple myeloma

Nat Commun. 2020 May 29;11(1):2666. doi: 10.1038/s41467-020-16434-y.

Abstract

Multiple myeloma is a plasma cell blood cancer with frequent chromosomal translocations leading to gene fusions. To determine the clinical relevance of fusion events, we detect gene fusions from a cohort of 742 patients from the Multiple Myeloma Research Foundation CoMMpass Study. Patients with multiple clinic visits enable us to track tumor and fusion evolution, and cases with matching peripheral blood and bone marrow samples allow us to evaluate the concordance of fusion calls in patients with high tumor burden. We examine the joint upregulation of WHSC1 and FGFR3 in samples with t(4;14)-related fusions, and we illustrate a method for detecting fusions from single cell RNA-seq. We report fusions at MYC and a neighboring gene, PVT1, which are related to MYC translocations and associated with divergent progression-free survival patterns. Finally, we find that 4% of patients may be eligible for targeted fusion therapies, including three with an NTRK1 fusion.

Trial registration: ClinicalTrials.gov NCT01454297.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • DNA Copy Number Variations / genetics
  • Gene Expression Profiling / methods
  • Gene Fusion / genetics*
  • Histone-Lysine N-Methyltransferase / biosynthesis
  • Histone-Lysine N-Methyltransferase / genetics*
  • Humans
  • Immunoglobulins / genetics
  • Middle Aged
  • Multiple Myeloma / genetics*
  • Progression-Free Survival
  • Proto-Oncogene Proteins c-myc / genetics*
  • RNA, Long Noncoding / genetics
  • RNA-Seq / methods
  • Receptor, Fibroblast Growth Factor, Type 3 / biosynthesis
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics*
  • Receptor, trkA / genetics
  • Repressor Proteins / biosynthesis
  • Repressor Proteins / genetics*

Substances

  • Immunoglobulins
  • MYC protein, human
  • PVT1 long-non-coding RNA, human
  • Proto-Oncogene Proteins c-myc
  • RNA, Long Noncoding
  • Repressor Proteins
  • Histone-Lysine N-Methyltransferase
  • NSD2 protein, human
  • FGFR3 protein, human
  • Receptor, Fibroblast Growth Factor, Type 3
  • Receptor, trkA

Associated data

  • figshare/10.6084/m9.figshare.11941494
  • figshare/10.6084/m9.figshare.11941506
  • ClinicalTrials.gov/NCT01454297