This study aims at prospectively enrolling a cohort of 400 incident cases of myelodysplastic syndromes (MDS) at diagnosis, to evaluate the impact of recurrent mutations on overall survival and event-free survival, using next generation sequencing. Patients are affected by ineffective hematopoiesis and a propensity to leukemia in the elderly with a global incidence of 10/100,000/year.

Myelodysplastic syndromes (MDS) are a heterogeneous group of stem cell disorders characterized by ineffective hematopoiesis with dysplasia and a propensity to acute myeloid leukemia. Patients are affected in the elderly with a global incidence of 10/100,000/year.

During the past 3 years, a significant progress has been made in the understanding of molecular pathogenesis through identification of mutations in epigenetic genes like TET2, ASXL1, EZH2, RUNX1, DNMT3A, IDH1/2, transcription factors, signalling molecules, cohesion and splicing regulators. Inactivating mutations targeting the hematopoietic stem cell may alter its gene expression pattern and could be an early mechanism of clonal selection. However, a single genetic alteration does not readily recapitulate the apoptotic and dysplastic phenotype. Several clones may co-exist, but their architecture is still unclear.

This study aims at prospectively enrolling a cohort of 350 incident cases at diagnosis, to identify evaluate the impact of recurrent mutations on overall survival and event-free survival, using next generation sequencing.

Considering the current knowledge, investigators propose to:

• perform whole exome sequencing to identify new mutations in a subset of 30 patients at diagnosis and in 10/30 samples at follow-up, and validate the recurrence of the new mutations in a training set.
• validate a high throughput technology for extensive genotyping to determine the mutational status of 54 target genes in the entire prospective cohort.
• analyze the frequency and impact on phenotype, OS and EFS of the most frequent mutations including SF3B1, SRSF2, ZRSR2, U2AF1, TET2, ASXL1, EZH2, IDH1/2, DNMT3A, NRAS, TP53, and RUNX1 and possibly of the newly discovered new mutations. Individual follow-up will be 36 months.

As ancillary studies, the evolution of mutation profiles after leukemic transformation in 10/30 MDS tested by WES, or after evaluation of the response to treatments in 100 MDS included in clinical trials of the "Groupe Francophone des Myélodysplasies" will be analyzed.

Understanding clonal architecture at diagnosis and after leukemic transformation is crucial for the knowledge of the pathophysiology of MDS. Better knowledge could help to adapt the therapeutic strategy. The study will help to delineate the pattern of genes which mutations with independent prognostic value modify the natural course of the disease. Then, investigators will apply for a grant to support a medico-economic evaluation of the molecular diagnosis in MDS.

Inclusion Criteria:

Myelodysplastic syndromes, mixed myelodysplastic/myeloproliferative disorders or secondary acute myeloid leukemia at diagnosis:

• De novo MDS subtype according to the WHO classification: RCMD and RA with or without ring sideroblasts, RAEB 1, or MDS-U, RAEB 2, therapy-related MDS or sAML, MDS/MPD.
• IPSS
• Documented chromosome 5 and 7 abnormality (del(5q) or -5, del(7q) or -7) by FISH analysis, if possible AND
• ECOG performance status ≤ 2
• Age ≥ 18 years
• Life expectancy ≥ 3 months
• Adequate renal and liver function (transaminases serum levels ≤ 3N; calculated creatinine clearance > 40 ml/min)
• Signed informed consent prior to start of any study-specific procedures
• Ability to participate to a clinical trial and adhere to study procedures

Exclusion Criteria:

• Active serious infection not controlled by oral or intravenous antibiotics
• Treatment with any investigational antileukemic agent or chemotherapy at least 6 weeks prior to study entry and lack of full recovery from side effects due to prior therapy independent of when that therapy were given
• Rapidly progressive disease with compromised organ function judged to be life-threatening by the Investigator
• Pregnant or lactating female
• Known human immunodeficiency virus (HIV) infection
• Known active hepatitis B and/or C virus infection
• ECOG performance status > 2
• Age < 18 years