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Clonal hematopoiesis and therapy-related myeloid neoplasms following neuroblastoma treatment.

Accepted version
Peer-reviewed

Type

Article

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Authors

Lu, Wanhua 
Mitchell, Emily 
Ijaz, Jannat 

Abstract

Therapy-related myeloid neoplasms (TMN) constitute one of the most challengingcomplications of cancer treatment.1 Whilst understanding of TMN pathogenesis remains fragmentary, genomic studies in adults have thus far refuted the notion that TMN simply result from cytotoxin-induced DNA damage.2–4 Analysis of the preclinical evolution of a limited number of adult TMN have retraced the majority of cases to clonal haematopoiesis (CH) that predates cytotoxic treatment and lacks the mutational footprint of genotoxic therapies.2–6 Balanced translocations, generally attributed to treatment with topoisomerase II inhibitors, are implicated in a minority of TMN.1 TMN is a leading cause of premature death in childhood cancer survivors, and affects 7-11% of children treated for high-risk neuroblastoma and sarcoma.7,8 However, the origin of pediatric TMN remains unclear. Targeted sequencing of known cancer genes detects CH in ~4% of children following cytotoxic treatment,6,9 whereas CH is vanishingly rare in young individuals in the general population.10,11 Moreover, to our knowledge, no cases of childhood TMN have been retraced to pretreatment CH. In light of these observations, we asked whether a broader driver landscape had eluded targeted CH screens in pediatric cancer patients and/or whether therapy-induced mutagenesis may be an under-recognised catalyst of CH and TMN in this patient group.

Description

Keywords

Antineoplastic Combined Chemotherapy Protocols, Child, Child, Preschool, Clonal Evolution, Clonal Hematopoiesis, Combined Modality Therapy, Female, Hematopoietic Stem Cell Transplantation, Humans, Leukemia, Myeloid, Acute, Mutation, Myeloablative Agonists, Myelodysplastic Syndromes, Neoplasms, Second Primary, Neuroblastoma, Preleukemia, Transplantation Conditioning, Transplantation, Autologous

Journal Title

Blood

Conference Name

Journal ISSN

0006-4971
1528-0020

Volume Title

137

Publisher

American Society of Hematology

Rights

All rights reserved
Sponsorship
Cancer Research UK (23917)