Dataset Information

Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41.

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.

SUBMITTER: Homan CC

PROVIDER: S-EPMC10582382 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Publications

Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41.

Homan Claire C CC Drazer Michael W MW Yu Kai K Lawrence David M DM Feng Jinghua J Arriola-Martinez Luis L Pozsgai Matthew J MJ McNeely Kelsey E KE Ha Thuong T Venugopal Parvathy P Arts Peer P King-Smith Sarah L SL Cheah Jesse J Armstrong Mark M Wang Paul P Bödör Csaba C Cantor Alan B AB Cazzola Mario M Degelman Erin E DiNardo Courtney D CD Duployez Nicolas N Favier Remi R Fröhling Stefan S Rio-Machin Ana A Klco Jeffery M JM Krämer Alwin A Kurokawa Mineo M Lee Joanne J Malcovati Luca L Morgan Neil V NV Natsoulis Georges G Owen Carolyn C Patel Keyur P KP Preudhomme Claude C Raslova Hana H Rienhoff Hugh H Ripperger Tim T Schulte Rachael R Tawana Kiran K Velloso Elvira E Yan Benedict B Kim Erika E Sood Raman R Hsu Amy P AP Holland Steven M SM Phillips Kerry K Poplawski Nicola K NK Babic Milena M Wei Andrew H AH Forsyth Cecily C Mar Fan Helen H Lewis Ian D ID Cooney Julian J Susman Rachel R Fox Lucy C LC Blombery Piers P Singhal Deepak D Hiwase Devendra D Phipson Belinda B Schreiber Andreas W AW Hahn Christopher N CN Scott Hamish S HS Liu Paul P Godley Lucy A LA Brown Anna L AL

Blood advances 20231001 20

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 hema ...[more]

PMID: 37406166

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Project description:BackgroundThe mutational profile of cancer reflects the activity of the mutagenic processes which have been operative throughout the lineage of the cancer cell. These processes leave characteristic profiles of somatic mutations called mutational signatures. Mutational signatures, including single-base substitution (SBS) signatures, may reflect the effects of exogenous or endogenous exposures.MethodsWe used polygenic risk scores (PRS) to summarize common germline variation associated with cancer risk and other cancer-related traits and examined the association between somatic mutational profiles and germline PRS in 12 cancer types from The Cancer Genome Atlas. Somatic mutational profiles were constructed from whole-exome sequencing data of primary tumors. PRS were calculated for the 12 selected cancer types and 9 non-cancer traits, including cancer risk determinants, hormonal factors, and immune-mediated inflammatory diseases, using germline genetic data and published summary statistics from genome-wide association studies.ResultsWe found 17 statistically significant associations between somatic mutational profiles and germline PRS after Bonferroni correction (p < 3.15 × 10-5), including positive associations between germline inflammatory bowel disease PRS and number of somatic mutations attributed to signature SBS1 in prostate cancer and APOBEC-related signatures in breast cancer. Positive associations were also found between age at menarche PRS and mutation counts of SBS1 in overall and estrogen receptor-positive breast cancer. Consistent with prior studies that found an inverse association between the pubertal development PRS and risk of prostate cancer, likely reflecting hormone-related mechanisms, we found an inverse association between age at menarche PRS and mutation counts of SBS1 in prostate cancer. Inverse associations were also found between several cancer PRS and tumor mutation counts.ConclusionsOur analysis suggests that there are robust associations between tumor somatic mutational profiles and germline PRS. These may reflect the mechanisms through hormone regulation and immune responses that contribute to cancer etiology and drive cancer progression.

Dataset Information

Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41.

Publications

Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41.

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