Multiple myeloma immunoglobulin lambda translocations portend poor prognosis

• Type of Material: Article
• Authors: Benjamin G. Barwick, Emory University; Paola Neri, University of Calgary; Nizar J. Bahlis, University of Calgary; Ajay Nooka, Emory University; Madhav Dhodapkar, Emory University; David L. Jaye, Emory University; Craig Hofmeister, Emory University; Jonathan Kaufman, Emory University; Vikas Gupta, Emory University; Daniel Auclair, Multiple Myeloma Research Foundation; Jonathan J. Keats, Translational Genomics Research Institute; Sagar Lonial, Emory University; Paula Vertino, Emory University; Lawrence Boise, Emory University
• Language: English
• Date: 2019-04-23
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2019, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-019-09555-6
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 10
• Issue: 1
• Start Page: 1911
• End Page: 1911
• Grant/Funding Information: C.C.H. is supported by NIH/NCI award 5R01CA201382-03.; This study was supported in part by the Emory Integrated Genomics Core of Winship Cancer Institute of Emory University and NIH/NCI award number P30CA138292.; MHV is supported by NIH/NCI award 7R35CA197603-03.; This work was supported by an Answer Fund award from the MMRF.; BGB is supported by Postdoctoral Fellowship PF-17-109-1-TBG from the American Cancer Society.
• Keywords: READ ALIGNMENT; DYSREGULATION; CLASS DISCOVERY; CLASSIFICATION; BREAKPOINTS; GENETIC ABNORMALITIES; SELECTIVE-INHIBITION; LENALIDOMIDE PLUS DEXAMETHASONE; Science & Technology - Other Topics; Science & Technology; Multidisciplinary Sciences; MUTATIONS; BIOCONDUCTOR PACKAGE
• Research Categories: Health Sciences, Pathology; Health Sciences, Oncology; Biology, Genetics

Abstract

Multiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed high risk. Here we analyze structural variants from 795 newly-diagnosed patients as part of the CoMMpass study. We report translocations involving the immunoglobulin lambda (IgL) locus are present in 10% of patients, and indicative of poor prognosis. This is particularly true for IgL-MYC translocations, which coincide with focal amplifications of enhancers at both loci. Importantly, 78% of IgL-MYC translocations co-occur with hyperdiploid disease, a marker of standard risk, suggesting that IgL-MYC-translocated myeloma is being misclassified. Patients with IgL-translocations fail to benefit from IMiDs, which target IKZF1, a transcription factor that binds the IgL enhancer at some of the highest levels in the myeloma epigenome. These data implicate IgL translocation as a driver of poor prognosis which may be due to IMiD resistance.