TY - JOUR
T1 - Role of Germline Predisposition to Therapy-Related Myeloid Neoplasms
AU - Baranwal, Anmol
AU - Hahn, Christopher N.
AU - Shah, Mithun Vinod
AU - Hiwase, Devendra K.
N1 - Funding Information:
MVS was supported by Leukemia Research Foundation New Investigator Award and Eagles 5th District Cancer Telethon Funds for Cancer Research.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Clonal hematopoiesis
KW - DNA damage
KW - Genetic predisposition to disease
KW - Germ-line mutation
KW - Poly (ADP-ribose) polymerase inhibitors
KW - Therapy-associated neoplasms
UR - http://www.scopus.com/inward/record.url?scp=85136587069&partnerID=8YFLogxK
U2 - 10.1007/s11899-022-00676-2
DO - 10.1007/s11899-022-00676-2
M3 - Review article
C2 - 35986863
AN - SCOPUS:85136587069
SN - 1558-8211
JO - Current Hematologic Malignancy Reports
JF - Current Hematologic Malignancy Reports
ER -