Impact of Epigenetic Age on Clinic-biological Presentation and Prognosis in Myeloproliferative Neoplasms Epigenetic Age in Myeloproliferative Neoplasms (EpiC)
- Conditions
- Myeloproliferative Neoplasm
- Interventions
- Biological: Assessment of the epigenetic age
- Registration Number
- NCT06022328
- Lead Sponsor
- University Hospital, Bordeaux
- Brief Summary
Myeloproliferative Neoplasms (MPN) are hematological malignancies characterized by the excessive production of myeloid cells. MPN can be complicated by thrombosis and evolution into more aggressive diseases (myelofibrosis and acute leukemia). Aging remains the principal factor determining patients' survival in MPN. In recent years, DNA methylation has appeared as a mean to measure aging via the development of epigenetic clocks that have also been associated with the occurrence of thrombosis and cancer. The epiC project aims at determining epigenetic age of MPN patients and search for an association between this parameter and thrombotic/hematological complications.
- Detailed Description
Myeloproliferative Neoplasia (MPN) are hematological malignancies characterized by the excessive production of myeloid cells. They include Essential Thrombocythemia (ET), Polycythemia Vera (VP) and Primary Myelofibrosis (PMF). Thrombosis are the most frequent complications and are largely responsible for the morbidity and mortality observed in ET and PV patients. The most feared complications are hematological transformations (into myelofibrosis for PV and ET, into acute myeloid leukemia for PV, ET and PMF). The prognostic assessment of MPN patients is mainly based on clinical data. Although recent studies have shown that certain mutations are associated with a poorer prognosis, age remains the main risk factor affecting survival in MPN patients. Recent studies have shown that DNA methylation can be used to determine an "epigenetic age". Interestingly, this epigenetic age is associated with the development of cardiovascular disease and cancer.
In this project, the epigenetic age of MPN patients will be determined by studying the DNA methylation at diagnosis using the Infinium Human MethylationEPIC kit (Illumina). Epigenetic age will be determined with the most commonly used epigenetic clocks (DNAmAge, DNAmHannum, DNAmPhenoAge, DNAmSkinClock, DNAmGrimAge, intrinsic epigenetic age acceleration, extrinsic epigenetic age acceleration). It will be searched for an association between accelerated epigenetic aging (as assessed by the difference between epigenetic age and chronological age) and the type of MPN, the clinical and biological presentation at diagnosis (including the mutational profile of patients) and the occurrence of thrombosis and hematological evolution into myelofibrosis and/or acute leukemia.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 120
For the 110 patients with MPN:
- Patients with PV, ET or PMF
- DNA extracted from purified granulocytes at time of diagnosis
- No treatment likely to impact DNA methylation (chemotherapy, immunosuppressants in particular)
For the 10 subjects without MPN:
- Absence of hematological malignancy
- Search for JAK2V617F mutation in the context of reactive thrombocytosis or secondary polycythemia
- Absence of treatment likely to impact DNA methylation (chemotherapy, immunosuppressants in particular)
For the 110 patients with MPN:
- Patients without PV, ET or PMF
- Patients without purified granulocytes DNA available at time of diagnosis
- Patients treated by cytoreductive drug, demethylating agent, chemotherapy or immunosuppressive therapy at the time of DNA sampling
- Patients with less than 2 years' follow-up
For the 10 subjects in NMP :
- Patients with hematological malignancy and/or solid cancer
- Patients treated by cytoreductive drug, demethylating agent, chemotherapy or immunosuppressive therapy at the time of DNA sampling
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description Patients with ET Assessment of the epigenetic age 45 patients with ET: * 15 without thrombotic event (neither at diagnosis nor during follow-up) * 15 with thrombotic events (thrombosis at diagnosis or within 2 years of diagnosis) * 15 who progressed to myelofibrosis or AML during follow-up Patients with PMF Assessment of the epigenetic age 20 patients with PMF: * 10 without transformation into AML * 10 patients who progressed to AML Patients with PV Assessment of the epigenetic age 45 patients with PV * 15 without thrombotic event (neither at diagnosis nor during follow-up) * 15 with thrombotic event (thrombosis at diagnosis or within 2 years of diagnosis) * 15 who progressed to myelofibrosis or AML during follow-up Patients without MPN Assessment of the epigenetic age 10 patients without MPN
- Primary Outcome Measures
Name Time Method Accelerated ageing of patients At inclusion, up to 1 year after diagnosis Accelerated ageing will be defined as an increased difference between the epigenetic age (calculated from DNA methylation data with the different molecular clocks described: DNAmAge, DNAmHannum, DNAmPhenoAge, DNAmSkinClock, DNAmGrimAge, intrinsic epigenetic age acceleration, extrinsic epigenetic age acceleration) and the chronological age
- Secondary Outcome Measures
Name Time Method Additional somatic mutation At inclusion, up to 1 year after diagnosis In up to 50% of MPN patients, genetic variants can be detected in genes such as DNMT3A, TET2, ASXL1, SRSF2, SF3B1, U2AF1, EZH2 or TP53. We will determine which somatic genetic variant is detected by high throughput sequencing
Type of MPN (ET, PV or PMF) at diagnosis At inclusion, up to 1 year after diagnosis We will study patients with a diagnosis of ET, PV or PMF as defined by the WHO classification of hematological malignancies
Transformation into secondary myelofibrosis or acute leukemia From date of inclusion until documentation of the event, assessed up to 5 years Evolution toward secondary myelofibrosis or acute leukemia will be defined according to the WHO classification of hematological malignancies
Occurrence of thrombosis prior to diagnosis or during follow-up of the disease Between 1 year before and 2 years after MPN diagnosis Occurrence of myocardial infarction, ischemic stroke, deep vein thrombosis, pulmonary embolism, splanchnic thrombosis or any other significant thrombosis. Tinnitus, vertigo, headaches, erythromelalgia as well as superficial vein thrombosis will not be considered as thrombotic events
Leukocytes At inclusion, up to 1 year after diagnosis Leukocytes level on blood count in G/L
Platelets At inclusion, up to 1 year after diagnosis Platelet level on blood count in G/L
Hemoglobin At inclusion, up to 1 year after diagnosis Hemoglobin level on blood count in g/dL
Granulocytes At inclusion, up to 1 year after diagnosis Granulocytes level on blood count in G/L
Monocytes At inclusion, up to 1 year after diagnosis Monocytes level on blood count in G/L
Hematocrit At inclusion, up to 1 year after diagnosis Hematocrit level on blood count in %
Trial Locations
- Locations (1)
CHU de Bordeaux, service Hématologie Biologique
🇫🇷Bordeaux, France