Accelerated single cell seeding in relapsed multiple myeloma.

Abstract

Multiple myeloma (MM) progression is characterized by the seeding of cancer cells in different anatomic sites. To characterize this evolutionary process, we interrogated, by whole genome sequencing, 25 samples collected at autopsy from 4 patients with relapsed MM and an additional set of 125 whole exomes collected from 51 patients. Mutational signatures analysis showed how cytotoxic agents introduce hundreds of unique mutations in each surviving cancer cell, detectable by bulk sequencing only in cases of clonal expansion of a single cancer cell bearing the mutational signature. Thus, a unique, single-cell genomic barcode can link chemotherapy exposure to a discrete time window in a patient's life. We leveraged this concept to show that MM systemic seeding is accelerated at relapse and appears to be driven by the survival and subsequent expansion of a single myeloma cell following treatment with high-dose melphalan therapy and autologous stem cell transplant.

• Authors: Heather J Landau, Venkata Yellapantula, Benjamin T Diamond, Even H Rustad, Kylee H Maclachlan, Gunes Gundem, Juan Medina-Martinez, Juan Arango Ossa, Max F Levine, Yangyu Zhou, Rajya Kappagantula, Priscilla Baez, Marc Attiyeh, Alvin Makohon-Moore, Lance Zhang, Eileen M Boyle, Cody Ashby, Patrick Blaney, Minal Patel, Yanming Zhang, Ahmet Dogan, David J Chung, Sergio Giralt, Oscar B Lahoud, Jonathan U Peled, Michael Scordo, Gunjan Shah, Hani Hassoun, Neha S Korde, Alexander M Lesokhin, Sydney Lu, Sham Mailankody, Urvi Shah, Eric Smith, Malin L Hultcrantz, Gary A Ulaner, Frits van Rhee, Gareth J Morgan, Ola Landgren, Elli Papaemmanuil, Christine Iacobuzio-Donahue, Francesco Maura
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 3617 (07 17 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32680998 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Melphalan

Topics

• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Cell Survival (drug effects, genetics)
• Clonal Evolution (drug effects)
• Disease Progression
• Dose-Response Relationship, Drug
• Hematopoietic Stem Cell Transplantation (adverse effects)
• Humans
• Male
• Melphalan (administration & dosage, adverse effects)
• Middle Aged
• Multiple Myeloma (diagnostic imaging, genetics, pathology, therapy)
• Mutation (drug effects)
• Neoplasm Invasiveness (genetics, pathology)
• Neoplasm Recurrence, Local (diagnostic imaging, genetics, pathology, therapy)
• Positron Emission Tomography Computed Tomography
• Single-Cell Analysis
• Spatio-Temporal Analysis
• Transplantation, Autologous (adverse effects)
• Whole Genome Sequencing