Synapse - Tracking the evolution of therapy-related myeloid neoplasms using chemotherapy signatures

Tracking the evolution of therapy-related myeloid neoplasms using chemotherapy signatures Journal Article

Authors:	Diamond, B.; Ziccheddu, B.; Maclachlan, K.; Taylor, J.; Boyle, E.; Ossa, J. A.; Jahn, J.; Affer, M.; Totiger, T. M.; Coffey, D.; Chandhok, N.; Watts, J.; Cimmino, L.; Lu, S. X.; Bolli, N.; Bolton, K.; Landau, H.; Park, J. H.; Ganesh, K.; McPherson, A.; Sekeres, M. A.; Lesokhin, A.; Chung, D. J.; Zhang, Y.; Ho, C.; Roshal, M.; Tyner, J.; Nimer, S.; Papaemmanuil, E.; Usmani, S.; Morgan, G.; Landgren, O.; Maura, F.
Article Title:	Tracking the evolution of therapy-related myeloid neoplasms using chemotherapy signatures
Abstract:	Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms (tMN). Preleukemic clones (ie, clonal hematopoiesis [CH]) are detectable years before the development of these aggressive malignancies, although the genomic events leading to transformation and expansion are not well defined. Here, by leveraging distinctive chemotherapy-associated mutational signatures from whole-genome sequencing data and targeted sequencing of prechemotherapy samples, we reconstructed the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy was revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan were hypermutated and enriched for complex structural variants (ie, chromothripsis), whereas neoplasms with nonmutagenic chemotherapy exposures were genomically similar to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as temporal barcodes linked to discrete clinical exposure in each patient's life, we estimated that several complex events and genomic drivers were acquired after chemotherapy was administered. For patients with prior multiple myeloma who were treated with high-dose melphalan and autologous stem cell transplantation, we demonstrate that tMN can develop from either a reinfused CH clone that escapes melphalan exposure and is selected after reinfusion, or from TP53-mutant CH that survives direct myeloablative conditioning and acquires melphalan-induced DNA damage. Overall, we revealed a novel mode of tMN progression that is not reliant on direct mutagenesis or even exposure to chemotherapy. Conversely, for tMN that evolve under the influence of chemotherapy-induced mutagenesis, distinct chemotherapies not only select preexisting CH but also promote the acquisition of recurrent genomic drivers. © 2023 The American Society of Hematology
Keywords:	adult; cancer chemotherapy; cancer survival; controlled study; genetics; leukemia, myeloid, acute; cancer recurrence; cancer growth; antineoplastic agents; cancer patient; antineoplastic agent; dna damage; multiple myeloma; melphalan; autologous stem cell transplantation; hematopoietic stem cell transplantation; pathology; protein p53; b cell lymphoma; myeloablative conditioning; platinum; neoplasms, second primary; transplantation, autologous; mutagenesis; life history; autotransplantation; acute myeloid leukemia; bone marrow cancer; chromothripsis; humans; human; article; whole genome sequencing; malignant neoplasm; de novo acute myeloid leukemia; therapy related malignant neoplasm; second primary neoplasm
Journal Title:	Blood
Volume:	141
Issue:	19
ISSN:	0006-4971
Publisher:	American Society of Hematology
Date Published:	2023-05-11
Start Page:	2359
End Page:	2371
Language:	English
DOI:	10.1182/blood.2022018244
PUBMED:	36626250
PROVIDER:	scopus
PMCID:	PMC10273163
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85151450515&doi=10.1182%2fblood.2022018244&partnerID=40&md5=3906ba36e8a08831c762bf93dcee91d3
Notes:	Article -- Export Date: 31 May 2023 -- Source: Scopus