Chemotherapy Signatures Map Evolution of Therapy-Related Myeloid Neoplasms

Abstract

Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms1, 2. Pre-leukemic clones (i.e., clonal hematopoiesis) are detectable years before the development of these aggressive malignancies3-5, though the genomic events leading to transformation and expansion are not well-defined. Here, leveraging distinctive chemotherapy-associated mutational signatures6-12 from whole-genome sequencing data and targeted sequencing of pre-chemotherapy samples, we reconstruct the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy is revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan are relatively hypermutated and enriched for complex structural variants (i.e., chromothripsis), while neoplasms with alternative exposures bear a similar profile to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as a temporal barcode in each patient’s life, we estimate that several complex events and genomic drivers are acquired after chemotherapy exposure. In the case of treatment with high-dose melphalan and autologous stem cell transplantation, we demonstrate that the procedure allows clonal hematopoiesis to escape chemotherapy exposure entirely, and to be reinfused to expand to malignancy. This information reveals a novel mode of malignant progression for therapy-related malignancies that is not reliant on direct mutagenesis or even exposure to chemotherapy, itself, and prompts further investigation into leukemia-permissive effects of cytotoxic drugs.

Clonal Hematopoiesis: Role in Hematologic Non-Hematologic

“… 175 In a second study, using wide genome sequencing therapy-related myeloid neoplasias (tMN) samples from patients exposed to various anti-cancer drugs and pre-therapy samples, have characterized the mutational impact of chemotherapy and used chemotherapy-induced signatures (CIS) as a temporal barcode to reconstitute tumor evolution. 176 tMNs evolving without CISs display features similar to those observed in de novo AMLs. In contrast, tMNs with CIS, such as those occurring in platinum- or melphalantreated patients, are hypermutated and more frequently associated with complex genomes, including chromothripsis and copy number alterations.…”

“… 176 Interestingly the procedure of treatment involving high-dose melphalan and ASCT allows clonal hematopoiesis to escape chemotherapy exposure and to be reinfused to expand to malignancy; these patients can develop tMN bearing no evidence of melphalan-induced mutations. 176 …”

“…In contrast, tMNs with CIS, such as those occurring in platinum-or melphalantreated patients, are hypermutated and more frequently associated with complex genomes, including chromothripsis and copy number alterations. 176 Interestingly the procedure of treatment involving highdose melphalan and ASCT allows clonal hematopoiesis to escape chemotherapy exposure and to be reinfused to expand to malignancy; these patients can develop tMN bearing no evidence of melphalan-induced mutations. 176 TMNs are molecularly heterogeneous and are represented by tMDSs and tAMLs; the majority of tMNs display chromosomal abnormalities associated with MDS or KMT2A rearrangements.…”

“…176 Interestingly the procedure of treatment involving highdose melphalan and ASCT allows clonal hematopoiesis to escape chemotherapy exposure and to be reinfused to expand to malignancy; these patients can develop tMN bearing no evidence of melphalan-induced mutations. 176 TMNs are molecularly heterogeneous and are represented by tMDSs and tAMLs; the majority of tMNs display chromosomal abnormalities associated with MDS or KMT2A rearrangements. 177 At molecular level, the majority (about 80%) of these tMNs display an abnormal karyotype, while a minority (about 20%) is associated with a normal karyotype; TMNs with normal karyotype compared to those with abnormal karyotype are enriched for mutations in TET2, NPM1, ASXL1, SRSF2, RUNX1 and STAG2, many genes frequently mutated in CHIP.…”