Impact of Epigenetic Age on Clinic-biological Presentation and Prognosis in Myeloproliferative Neoplasms Epigenetic Age in Myeloproliferative Neoplasms (EpiC)

Study Overview
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Brief Summary
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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
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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.

Official Title
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Impact of Epigenetic Age on Clinic-biological Presentation and Prognosis in Myeloproliferative Neoplasms Epigenetic Age in Myeloproliferative Neoplasms (EpiC)

Conditions
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Myeloproliferative Neoplasm

Intervention / Treatment
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* Biological: Assessment of the epigenetic age


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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) Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with ET<br>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 | Biological: Assessment of the epigenetic age<br>* Retrospective assessment of the epigenetic age on DNA samples obtained at diagnosis<br>|
| Patients with PV<br>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 | Biological: Assessment of the epigenetic age<br>* Retrospective assessment of the epigenetic age on DNA samples obtained at diagnosis<br>|
| Patients with PMF<br>20 patients with PMF: 10 without transformation into AML 10 patients who progressed to AML | Biological: Assessment of the epigenetic age<br>* Retrospective assessment of the epigenetic age on DNA samples obtained at diagnosis<br>|
| Patients without MPN<br>10 patients without MPN | Biological: Assessment of the epigenetic age<br>* Retrospective assessment of the epigenetic age on DNA samples obtained at diagnosis<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Accelerated ageing of patients | 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 | At inclusion, up to 1 year after diagnosis | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Type of MPN (ET, PV or PMF) at diagnosis | We will study patients with a diagnosis of ET, PV or PMF as defined by the WHO classification of hematological malignancies | At inclusion, up to 1 year after diagnosis | 
| Transformation into secondary myelofibrosis or acute leukemia | Evolution toward secondary myelofibrosis or acute leukemia will be defined according to the WHO classification of hematological malignancies | From date of inclusion until documentation of the event, assessed up to 5 years | 
| Occurrence of thrombosis prior to diagnosis or during follow-up of the disease | 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 | Between 1 year before and 2 years after MPN diagnosis | 
| Leukocytes | Leukocytes level on blood count in G/L | At inclusion, up to 1 year after diagnosis | 
| Platelets | Platelet level on blood count in G/L | At inclusion, up to 1 year after diagnosis | 
| Granulocytes | Granulocytes level on blood count in G/L | At inclusion, up to 1 year after diagnosis | 
| Monocytes | Monocytes level on blood count in G/L | At inclusion, up to 1 year after diagnosis | 
| Hemoglobin | Hemoglobin level on blood count in g/dL | At inclusion, up to 1 year after diagnosis | 
| Hematocrit | Hematocrit level on blood count in % | At inclusion, up to 1 year after diagnosis | 
| Additional somatic mutation | 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 | At inclusion, up to 1 year after diagnosis | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myeloproliferative Neoplasm, Epigenetic age, Thrombosis, Myelofibrosis, Leukemia