GERMLINE PREDISPOSITION TO MYELOID MALIGNANCIES: A COMPREHENSIVE ANALYSIS OF CEBPA, DDX41 AND RUNX1
Notice bibliographique
Résumé
Myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are typically sporadic, but germline predisposition involving genes like CEBPA, DDX41, and RUNX1 is increasingly recognized. However, the interplay between germline and somatic events in these genes remains incompletely understood. To investigate the prevalence, co-variant patterns, and clonality of pathogenic and likely pathogenic variants in CEBPA, DDX41, and RUNX1 in patients with myeloid malignancies. We analyzed 2,437 patients diagnosed with AML, MDS, MDS/AML, or myeloproliferative neoplasms (MPN). DNA from peripheral blood or bone marrow was sequenced using targeted NGS, covering 63 genes. Variants were processed using validated bioinformatic pipelines and classified per CAP/AMP/ASCO guidelines. Among the cohort, AMP/ASCO Tier-1 and Tier-2 variants were most frequently detected in RUNX1 (9.97%, n = 243), followed by CEBPA (3.94%, n = 96) and DDX41 (2.63%, n = 64). RUNX1 mutations were commonly associated with co-occurring variants in ASXL1 and SRSF2, particularly in cases with double RUNX1 hits (37.5%). VAF distribution in double-mutated RUNX1 (RUNX1 highest hit: minimum: 10.9, maximum: 47.2, median: 38.5) with variants in ASXL1 (ASXL1 highest hit: min.: 4.3, max.: 49.5, median: 32.6 and/or SRSF2 (min.: 37.5, max.: 49.5, median: 46.1) were frequently consistent suggestive of a clonal process. CEBPA alterations with bi-allelic CEBPA variants (bZIP domain in-frame variant + an N-terminal loss-of-function variant). Co-occurring variants in GATA2 and WT1 were enriched in bi-allelic cases (60%) and were often seen at similar VAF (CEBPA bi-allelic highest hit: min.: 6, max.: 59.2, median: 41.9, GATA2 highest hit: min.: 5, max.: 50, median: 42,6; WT1 highest hit: min.: 5, max.: 94.1, median: 46.8), supporting a shared clonal origin and suggesting a distinct molecular signature potentially driving leukemogenesis. DDX41 variants showed a bimodal VAF distribution in double-mutated cases, with clusters likely suggestive of acquired (min.: 3, max.: 47, median: 6) or inherited (min.: 7, max.: 93, median: 49) variants. Unlike CEBPA and RUNX1, DDX41 variants were not associated with consistent co-variant patterns, suggestive of a different pathobiology. Of note biallelic disruptive DDX41 variants have been associated with hematologic malignancies with unique AML/MDS like features. Our findings reveal distinct mutational patterns in CEBPA, DDX41, and RUNX1, genes linked to hereditary hematologic cancers. Bi-allelic CEBPA mutations, formed a molecularly coherent subgroup frequently co-mutated with GATA2 and WT1 at similar VAFs, suggesting a shared clonal origin. Similarly, RUNX1 variants often co-occurred with ASXL1 and SRSF2 mutations, also showing consistent VAFs, though RUNX1 mutations were distributed across the gene. In contrast, DDX41 cases lacked co-variant patterns but exhibited a bimodal VAF distribution, with higher VAFs (>35%) suggestive of germline variants and lower VAFs (<20%) likely representing secondary somatic events. This study highlights the distinct biological and clinical profiles of germline and somatic variants in CEBPA, DDX41, and RUNX1, underscoring the need for further research into germline predisposition and its role in the pathogenesis of myeloid neoplasms.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,002 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,001 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».