Abstract
Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies (carriers-without HM). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For example, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germ line variants for the acquisition of somatic variants in BCOR, PHF6, and TET2 and second hits in RUNX1 are warranted.
| Original language | English |
|---|---|
| Pages (from-to) | 6092-6107 |
| Number of pages | 16 |
| Journal | Blood Advances |
| Volume | 7 |
| Issue number | 20 |
| Early online date | 5 Jul 2023 |
| DOIs | |
| Publication status | Published - 24 Oct 2023 |
Bibliographical note
Acknowledgments:The authors thank the patients and their family members for participating in this research program. This work is supported by a grant from the RUNX1 Research Program. This project is also proudly supported by funding from the Leukemia Foundation of Australia and project grants APP1145278 and APP1164601 from the National Health and Medical Research Council of Australia. This work was produced with the financial and other support of Cancer Council SA’s Beat Cancer Project on behalf of its donors and the State Government of South Australia through the Department of Health (PRF Fellowship to H.S.S.). This work was supported by a Damon Runyon Cancer Research Foundation Physician Scientist Training Award (M.W.D.), the Edward P. Evans Foundation Young Investigator Award (M.W.D.), the Cancer Research Foundation (M.W.D.), and a National Institutes of Health (NIH) K12 Paul Calabresi award (M.W.D.). P.A. was supported by a fellowship from The Hospital Research Foundation. Part of this project was undertaken while P.A. was holding a Royal Adelaide Hospital Mary Overton Early Career Fellowship. L.M is supported by the Associazione Italiana per la Ricerca sul Cancro (Accelerator Award Project 22796; 5x1000 Project 21267; Investigator Grant 2017 Project 20125). L.C.F and P.V. are supported by Maddie Riewoldt’s Vision. L.A.G was supported by the Cancer Research Foundation. K.Y. and P.L. are supported by the Division of Intramural Research, National Human Genome Research Institute, NIH. T.R. is supported by a grant of the European Hematology Association and Federal Ministry of Education and Research (BMBF) MyPred (01GM1911B). C.B. is supported by the European Union’s Horizon 2020 Research and Innovation Program under grant agreement number 739593 and by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, financed under the ED-18-1-2019 to 001, TKP2021-EGA-24 and TKP2021-NVA-15 funding schemes. NIH Intramural Sequencing Center Comparative Sequencing Program was involved in the generation of sequencing data from the NIH.
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