SOMATIC MUTATIONS and DNA METHYLATION IDENTIFY A SUBGROUP of POOR PROGNOSIS WITHIN LOWER RISK MYELODYSPLASTIC SYNDROMES.

Rombaut, D.; Sandmann, S.; Tekath, T.; Crouch, S.; De Graaf, A.; Kosmider, O.; Tobiasson, M.; Lennartsson, A.; Van Der Reijden, B.; Park, S.; D'Aveni, M.; Slama, B.; Clappier, E.; Fenaux, P.; Ades, L.; Van De Loosdrecht, A.; Langemeijer, S.; Symeonidis, A.; Cermak, J.; Preudhomme, C.; Savic, A.; Germing, U.; Stauder, R.; Bowen, D.; Van Marrewijk, C.; Bernard, E.; Smith, A.; Painter, D.; De Witte, T.; Varghese, J.; Hellstrom-Lindberg, E.; Dugas, M.; Martens, J.; Malcovati, L.; Jansen, J.H.; Fontenay, M.

SOMATIC MUTATIONS and DNA METHYLATION IDENTIFY A SUBGROUP of POOR PROGNOSIS WITHIN LOWER RISK MYELODYSPLASTIC SYNDROMES.

All Authors

Rombaut, D.

Sandmann, S.

Tekath, T.

Crouch, S.

De Graaf, A.

Kosmider, O.

Tobiasson, M.

Lennartsson, A.

Van Der Reijden, B.

Park, S.

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LTHT Author

Bowen, David

LTHT Department

Oncology
Haematology

Publication Date

2024

Item Type

Conference Abstract

Subject

LEUKAEMIA, MYELOID, ACUTE , BONE MARROW , CELL DIFFERENTIATION , COHORT STUDIES , CONTROLLED CLINICAL TRIALS AS TOPIC , DIAGNOSIS , WOMEN , GENES , MUTATION , MYELODYSPLASTIC SYNDROMES , SURVIVAL RATE , PROGNOSIS

Abstract

Background: Lower-risk (LR) myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem and progenitor disorders caused by early accumulation of somatic mutations in epigenetic factors and non-epigenetic factors that may produce convergent DNA methylation patterns driving specific gene expression profiles. Aim(s): The integration of genomic, epigenomic and transcriptomic profiling has the potential to spotlight distinct LR-MDS categories on the basis of pathophysiological mechanisms. Method(s): We performed a comprehensive study of somatic mutations and DNA methylation in a large and clinically well-annotated cohort of treatment-naive patients with LR-MDS at diagnosis (n=543 for mutational analysis and a subset of n=175 for additional DNA-methylation using InfiniumEPIC 850K array and gene expression profiling by RNA-sequencing). Differentially methylated regions (DMR) with differentially methylated CpG sites between cases and controls were defined by a minimum of 2 probes, an adjusted P-value <0.05, and a mean Db-value >20% at CpG sites. Consensus motifs for transcription factors were identified using Homer. Result(s): Unsupervised clustering analyses identified six clusters on the basis of genetic profiling that concentrate into four clusters on the basis of epigenetic and genetic profiling with significant overlap between the two clustering modes. The four methylation clusters showed distinct global methylation level, and distinct genetic patterns, transcriptomic profiles, and clinical and hematological features. DMR were enriched at enhancers and promoters. The clusters shared hypermethylated enhancers enriched in binding motifs for ETS and bZIP (C/EBP) transcription factor families, involved in the regulation of myeloid cell differentiation. Importantly, we identified a specific pattern of hypomethylated enhancers enriched in motifs for transcription factors FOS and JUNB, and of heavily hypermethylated promoters in one cluster gathering patients having the worst overall survival and the highest risk of AML evolution compared to the three others. (Figure present) Summary/Conclusion: Altogether, our study identified a subset of LR-MDS patients of poor prognosis on its distinctive methylation profile at early stages, therefore offering the frame for a precocious therapeutic intervention.