Somatic mutational landscape of hereditary hematopoietic malignancies caused by germ line RUNX1, GATA2, and DDX41 variants

Homan, CC; Drazer, MW; Yu, K; Lawrence, DM; Feng, J; Arriola-Martinez, LA; Pozsgai, MJ; McNeely, KE; Ha, TT; Venugopal, P; Arts, P; King-Smith, S; Cheah, JJ; Armstrong, M; Wang, P; Bodor, C; Cantor, AB; Cazzola, M; Degelman, ES; DiNardo, CD; Duployez, N; Favier, R; Frohling, S; Rio-Machin, A; Klco, JM; Kramer, A; Kurokawa, M; Lee, J; Malcovati, L; Morgan, NV; Georges, N; Owen, C; Patel, KP; Preudhomme, C; Raslova, H; Rienhoff, HY; Ripperger, T; Schulte, RR; Tawana, K; Velloso, E; Benedict, Y; Kim, EMK; Sood, R; Hsu, AP; Holland, SM; Phillips, K; Poplawski, N; Babic, M; Wei, AH; Forsyth, CJ; Mar Fan, H; Lewis, I; Cooney, JP; Susman, R; Fox, LC; Blombery, P; Singhal, D; Hiwase, DK; Phipson, B; Schreiber, AW; Hahn, CN; Scott, HS; Liu, PP; Godley, LA; Brown, AL

Author(s): Homan, CC; Drazer, MW; Yu, K; Lawrence, DM; Feng, J; Arriola-Martinez, LA; Pozsgai, MJ; McNeely, KE; Ha, TT; Venugopal, P; Arts, P; King-Smith, S; Cheah, JJ; Armstrong, M; Wang, P; Bodor, C; Cantor, AB; Cazzola, M; Degelman, ES; DiNardo, CD; Duployez, N; Favier, R; Frohling, S; Rio-Machin, A; Klco, JM; Kramer, A; Kurokawa, M; Lee, J; Malcovati, L; Morgan, NV; Georges, N; Owen, C; Patel, KP; Preudhomme, C; Raslova, H; Rienhoff, HY; Ripperger, T; Schulte, RR; Tawana, K; Velloso, E; Benedict, Y; Kim, EMK; Sood, R; Hsu, AP; Holland, SM; Phillips, K; Poplawski, N; Babic, M; Wei, AH; Forsyth, CJ; Mar Fan, H; Lewis, I; Cooney, JP; Susman, R; Fox, LC; Blombery, P; Singhal, D; Hiwase, DK; Phipson, B; Schreiber, AW; Hahn, CN; Scott, HS; Liu, PP; Godley, LA; Brown, AL;
Details: Publication Year 2023-07-05,Volume 7,Issue #20,Page 6092-6107
Journal Title: Blood Advances
Abstract: Individuals with germline variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of pre-malignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized pre-emptive treatments and inform appropriate counselling 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 germline variants for the acquisition of somatic variants in BCOR, PHF6, TET2, and second hits in RUNX1 are warranted.
Publisher: ASH
Keywords: Humans; Core Binding Factor Alpha 2 Subunit/genetics; *Hematologic Neoplasms/genetics; Germ-Line Mutation; *Leukemia; DEAD-box RNA Helicases/genetics; Carcinogenesis; Germ Cells; GATA2 Transcription Factor/genetics
Research Division(s): Blood Cells And Blood Cancer
PubMed ID: 37406166
Publisher's Version: https://doi.org/10.1182/bloodadvances.2023010045
Open Access at Publisher's Site: https://doi.org/10.1182/bloodadvances.2023010045
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-07-12 08:04:56

Last Modified: 2023-11-20 03:24:06