Accelerated single cell seeding in relapsed multiple myeloma

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 e...

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Bibliographic Details
Published in:	Nature communications 2020-07, Vol.11 (1), p.3617-10, Article 3617
Main Authors:	Landau, Heather J, Yellapantula, Venkata, Diamond, Benjamin T, Rustad, Even H, Maclachlan, Kylee H, Gundem, Gunes, Medina-Martinez, Juan, Ossa, Juan Arango, Levine, Max F, Zhou, Yangyu, Kappagantula, Rajya, Baez, Priscilla, Attiyeh, Marc, Makohon-Moore, Alvin, Zhang, Lance, Boyle, Eileen M, Ashby, Cody, Blaney, Patrick, Patel, Minal, Zhang, Yanming, Dogan, Ahmet, Chung, David J, Giralt, Sergio, Lahoud, Oscar B, Peled, Jonathan U, Scordo, Michael, Shah, Gunjan, Hassoun, Hani, Korde, Neha S, Lesokhin, Alexander M, Lu, Sydney, Mailankody, Sham, Shah, Urvi, Smith, Eric, Hultcrantz, Malin L, Ulaner, Gary A, van Rhee, Frits, Morgan, Gareth J, Landgren, Ola, Papaemmanuil, Elli, Iacobuzio-Donahue, Christine, Maura, Francesco
Format:	Article
Language:	eng
Subjects:	Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - adverse effects Autografts Autopsies Autopsy Cancer Cancer therapies Cell Survival - drug effects Cell Survival - genetics Chemotherapy Clonal Evolution - drug effects Cytotoxic agents Cytotoxicity Disease Progression Dose-Response Relationship, Drug Expansion Gene sequencing Genomes Hematopoietic Stem Cell Transplantation - adverse effects Humans Male Melphalan Melphalan - administration & dosage Melphalan - adverse effects Middle Aged Multiple myeloma Multiple Myeloma - diagnostic imaging Multiple Myeloma - genetics Multiple Myeloma - pathology Multiple Myeloma - therapy Mutation Mutation - drug effects Neoplasm Invasiveness - genetics Neoplasm Invasiveness - pathology Neoplasm Recurrence, Local - diagnostic imaging Neoplasm Recurrence, Local - genetics Neoplasm Recurrence, Local - pathology Neoplasm Recurrence, Local - therapy Positron Emission Tomography Computed Tomography Single-Cell Analysis Spatio-Temporal Analysis Stem cells Transplantation, Autologous - adverse effects Whole Genome Sequencing Windows (intervals)
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Summary:	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.
ISSN:	2041-1723 2041-1723