Location matters: topography of germline CEBPA variants predicts variable outcomes in familial acute myeloid leukaemia-a rare disease perspective

Germline CEBPA variant topography, TAD2 domain linked to unfavorable prognosis and therapeutic resistance

Analysis of 56 patients with germline CEBPA familial AML from 40 families demonstrates that variant localization in the TAD2 domain is a significant prognostic marker. TAD2 variants are associated with higher mortality (41% vs 15% for non-TAD2) and treatment resistance. A new de novo TAD2 variant (p.C133Ter) is identified in an additional family. These data constitute the largest single-center series published for germline CEBPA and enrich genotype-phenotype correlations for this rare entity.

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Variant topography in germline CEBPA was only partially correlated with prognosis until now. These data are actionable in oncogenetics consultation: they allow risk stratification in CEBPA families and argue for enhanced surveillance — and potentially preemptive transplantation — in TAD2 variant carriers.

Clinical impact: 2/3 · Evidence strength: 2/3 · Novelty: 1/2 · Sample size: 1/1 · Publication status: 1/1 → Total: 7/10