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Role of Germline Predisposition to Therapy-Related Myeloid Neoplasms

  • Germline Predisposition to Myeloid Neoplasms (M Patnaik, Section Editor)
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Abstract

Purpose of Review

Therapy-related myeloid neoplasms (t-MNs) are aggressive leukemias that develop following exposure to DNA-damaging agents. A subset of patients developing t-MN may have an inherited susceptibility to develop myeloid neoplasia. Herein, we review studies reporting t-MN and their association with a germline or inherited predisposition.

Recent Findings

Emerging evidence suggests that development of t-MN is the result of complex interactions including generation of somatic variants in hematopoietic stem cells and/or clonal selection pressure exerted by the DNA-damaging agents, and immune evasion on top of any inherited genetic susceptibility. Conventionally, alkylating agents, topoisomerase inhibitors, and radiation have been associated with t-MN. Recently, newer modalities including poly (ADP-ribose) polymerase inhibitors (PARPi) and peptide receptor radionucleotide therapy (PRRT) are associated with t-MN. At the same time, the role of pathogenic germline variants (PGVs) in genes such as BRCA1/2, BARD1, or TP53 on the risk of t-MN is being explored. Moreover, studies have shown that while cytotoxic therapy increases the risk of developing myeloid neoplasia, it may be exposing the vulnerability of an underlying germline predisposition.

Summary

t-MN remains a disease with poor prognosis. Studies are needed to better define an individual’s inherited neoplastic susceptibility which will help predict the risk of myeloid neoplasia in the future. Understanding the genes driving the inherited neoplastic susceptibility will lead to better patient- and cancer-specific management including choice of therapeutic regimen to prevent, or at least delay, development of myeloid neoplasia after treatment of a prior malignancy.

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Acknowledgements

The authors would like to thank Ms. Monika Kutyna (University of Adelaide) for assistance with generating Fig. 1. Figures 2 and 3 were created using Biorender.com.

Funding

MVS was supported by Leukemia Research Foundation New Investigator Award and Eagles 5th District Cancer Telethon Funds for Cancer Research.

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Authors and Affiliations

  1. Division of Hematology, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55906, USA

    Anmol Baranwal & Mithun Vinod Shah

  2. Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia

    Christopher N. Hahn

  3. Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia

    Christopher N. Hahn

  4. Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia

    Christopher N. Hahn & Devendra K. Hiwase

  5. Royal Adelaide Hospital, Central Adelaide Local Health Network, Adelaide, SA, Australia

    Devendra K. Hiwase

  6. South Australian Health and Medical Research Institute, Adelaide, SA, Australia

    Devendra K. Hiwase

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  1. Anmol Baranwal
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Correspondence to Mithun Vinod Shah or Devendra K. Hiwase.

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Baranwal, A., Hahn, C.N., Shah, M.V. et al. Role of Germline Predisposition to Therapy-Related Myeloid Neoplasms. Curr Hematol Malig Rep 17, 254–265 (2022). https://doi.org/10.1007/s11899-022-00676-2

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