| Title: | Overall cancer risk in people with deleterious germline DDX41 variants |
| Journal: | Haematologica |
| Published: | 13 Feb 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39945023/ |
| DOI: | https://doi.org/10.3324/haematol.2024.286887 |
Publication 16448
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Abstract
Germline loss-of-function (LoF) DDX41 variants predispose to late-onset hematopoietic malignancies (HM), predominantly of myeloid lineage. Among 43 families with germline DDX41LoF variants, bone marrow (BM) biopsies in those without (N=8) or with malignancies (N=21) revealed mild dysplasia in peripheral blood (57%) and BM (88%), long before the average age of DDX41-related HM onset. Therefore, we recommend baseline BM biopsies in people with germline DDX41LoF alleles to avoid over-diagnosis of myelodysplastic syndromes. A variety of solid tumors were also observed in our cohort, with 24% penetrance by age 75. Although acquired DDX41 mutations are common in HM, we failed to identify such alleles in solid tumors arising in those with germline DDX41LoF variants (N=15), suggesting an alternative mechanism driving solid tumor development. Furthermore, 33% of pedigrees in which ≥15% of first-degree relatives including the proband were diagnosed with a solid tumor had second germline deleterious variants in other cancer-predisposition genes, likely serving as primary cancer drivers. Finally, both lymphoblastoid cell lines and primary peripheral blood from individuals with germline DDX41LoF variants exhibited differential levels of inflammation-associated proteins. These data provide evidence of inflammatory dysfunction mediated by germline DDX41LoF alleles that may contribute to solid tumor growth in the context of additional germline cancer- associated variants. For those with HM and personal/family histories of solid tumors, we recommend broad germline testing. DDX41 may be an indirect modifier of solid tumor pathogenesis compared to its tumor suppressor function within hematopoietic tissues, a hypothesis that can be addressed in future work.</p>
13 Keywords
- Adult
- Aged
- Aged, 80 and over
- DEAD-box RNA Helicases
- Female
- Genetic Predisposition to Disease
- Germ-Line Mutation
- Hematologic Neoplasms
- Humans
- Male
- Middle Aged
- Neoplasms
- Pedigree
27 Authors
- Sophia C. Korotev
- Jason X. Cheng
- Yogameenakshi Haribabu
- Joshua Strauss
- Salina Dominguez
- Ashwin Koppayi
- Melody Perpich
- Madeline Pies
- Luke Moma
- Aelin Kim
- Hatice Basdag
- Courtnee Rodgers
- Satyajit Kosuri
- Ryunosuke Saiki
- Hideki Makishima
- Sanjukta Tawde
- Shelly Galasinski
- Priscilla Kandikatla
- Hari Prasanna Subramanian
- Kehan Ren
- Honghao Bi
- Mona Mohammadhosseini
- Seishi Ogawa
- Peng Ji
- Anupriya Agarwal
- Soma Das
- Lucy A. Godley
1 Application
| Application ID | Title |
|---|---|
| 83200 | Germline predisposition to hematopoietic malignancies |
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