Myeloid neoplasms with familial predisposition

While the majority of myeloid neoplasms occur sporadically, a genetic predisposition underlies at least 5-10% (Schlegelberger et al. 2021). Numerous germline mutations in different predisposition genes are now known, which differ in penetrance, clinical disease pattern, and age of onset. This heterogeneity and the fact that somatic disease-associated mutations also occur in most predisposition genes contribute to the fact that the presence of a predisposition is often misrecognized. This is especially true for manifestations of myeloid neoplasms in adulthood.

According to current WHO classification, myeloid neoplasms with germline predisposition are divided into three groups associated with different predisposition genes (see Figure).

In particular, germline mutations in the DDX41 gene, which are detected in various patient cohorts in the literature and also in routine diagnostics at MLL in up to 4% of adult patient:ing with acute myeloid leukemia and with myelodysplastic neoplasia, have gained importance in recent years. DDX41 germline mutations are frequently identified in patients without a family history of hematologic neoplasms.

In addition, the average age of onset of the disease in patients with DDX41 germline mutation is about 68 years and thus not reduced. The age of onset should therefore not be a decisive criterion for the suspicion of the presence of a germline mutation (Kim et al. 2023; Makishima et al. 2023).

The following criteria should be considered when selecting patients for testing for genetic predisposition (Godley 2023):

• Clinical features associated with predisposition syndromes.
• Personal history of multiple primary cancers
• early age of onset (but test should be considered regardless of age)
• conspicuous family history
• Detection of cyto- and molecular genetic aberrations associated with predisposition (e.g., detection of a mutation with variant allele frequency >30% in a predisposition gene).
• Occurrence of excessive toxicity after chemotherapy or radiotherapy.

Confirmation of the presence of a germline mutation can be obtained by examination of normal tissue (e.g. oral mucosa, fingernail, CD3+ T cells from peripheral blood). This requires a declaration of consent in accordance with the Gene Diagnostics Act (https://www.mll.com/einverstaendniserklaerung-nach-gendg/mll_gendg.pdf).

If a germline mutation is confirmed, human genetic counseling of patients and their families is recommended.

The detection of a familial predisposition plays a role in the therapy and follow-up of patients as well as in potential predictive testing and improved screening for family members. The detection of a germline mutation could, for example, be crucial for early allogeneic stem cell transplantation. Consideration should be given to whether potential family donors also carry the germline mutation, as germline mutations may promote donor cell leukemias.

Godley LA. Prioritization of patients for germline testing based on tumor profiling of hematopoietic malignancies. Frontiers in Oncology 2023; 13:1084736.

Khoury JD et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia 2022; 36:1703–1719.

Kim K et al. Current Understanding of DDX41 Mutations in Myeloid Neoplasms. Cancers (Basel) 2023; 15(2):344.

Makishima H et al. Germ line DDX41 mutations define a unique subtype of myeloid neoplasms. Blood 2023; 141(5):534-549.

Schlegelberger B et al. Review of guidelines for the identification and clinical care of patients with genetic predisposition for hematological malignancies. Familial Cancer 2021; 20:295–303.