Study of Individuals and Families With Aberrations in DDX41 or Similar Cancer Predisposition Variants

Background:

• Growing awareness of germline predisposition syndromes raises questions about how to best identify, test, and manage individuals carrying germline variants with 1.5%-6.1% of individuals with hematologic malignancies carrying an identified aberration.
• Germline mutations in DEAD-box helicase 41 (DDX41) were first identified as a susceptibility to myeloid neoplasms in 2015 and have been described in up to 6.1% in myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) patients.
• Germline DDX41 variants are associated with a distinct subtype of myeloid neoplasms, marked by familial predisposition, male predominance, and several commonly commutated somatic genes such as AXL1, EZH2, SRSF2, CUX1 and TP53, and a few underrepresented mutations such as TET2, SF3B1 and NPM1.
• Somatic deleterious variants of the second allele in patients with DDX41 germline variants leads to the onset of multiple lineage cytopenias at a mean age of 66 years (range 50-85 years), followed by the development of a hematologic malignancy.
• The myeloid malignancy associated with DDX41 variants is generally responsive to standard upfront chemotherapy. However, relapses are common and the median survival for individuals with MDS/AML secondary to germline DDX41 variants is consistent with de novo AML at approximately 5.2 years.
• In cases of familial MDS/AML associated with DDX41, the family history may appear negative due to failure to recognize the disorder in family members, reduced penetrance, or late onset of disease.
• Other germline variants in genes such as, but not limited to, CEBPA, CHEK2, ETV6, Fanconi genes, GATA2, RUNX1, and short telomere syndrome associated genes also confer hereditary hematopoietic malignancy (HHM) risk and may induce downstream effects on DDX41. Combinations of variants may exhibit variable clinical presentations, phenotypic associations, therapy responses, and treatment outcomes.
• Currently there are no biomarkers or assays to predict which patients with known HHM variants will progress to a malignancy, and many patients present with a myeloid malignancy as their initial manifestation of a germline syndrome.

Objective:

-To estimate the event free survival (EFS) in individuals with DEAD-box helicase 41 (DDX41) aberrations

Eligibility:

• Age > 1 month old
• Must have confirmed aberrations that affect the DDX41 gene, DDX41 RNA, or DDX41 protein or confirmed aberrations in another HHM variant or must have confirmed absence of HHM variants and have first or second degree relative with confirmed or suspected HHM variant(s)

-Must have an identified medical provider outside NIH who manages care, and any diagnostic findings provided by this study.

Design:

• This is a natural history and biospecimen analysis protocol for participants with aberrations in DDX41 or other HHMs and relatives of individuals with aberrations in DDX41 or other HHMs.
• We will perform comprehensive research analysis to understand the biology of HHM variants that contributes to dysregulation in hematopoietic differentiation and maturation blocks leading to dysplasia, cytopenia, and disease progression, so that these may be exploited for novel therapeutic targeting strategies.
• Diagnostic testing will be performed as is routine for these participants in addition to planned research correlative analyses. Follow-up will occur approximately annually to assess status and survival.