Multiple myeloma (MM) is a malignant proliferation of bone marrow plasma cells and one of the most frequently occurring hematological cancer. A wide spectrum of genetic and epigenetic changes has been observed in MM, but the molecular mechanisms underlying the genetic instability are poorly understood. Global genomic hypomethylation leading to the repetitive elements destabilization has been associated with chromosomal instability, which is commonly seen in solid tumors and multiple myeloma. About 55% of the human genome consists of repetitive elements, which are for the most part made up of approximately 500,000 long interspersed nucleotide elements (LINE elements) and 1.4 million Alu repetitive elements, which are normally heavily methylated. In humans, LINEs are the major source of insertional mutagenesis, being involved in both germinal and somatic mutant phenotypes. Alu retrotransposition has also been associated with human disease. However, the LINE/Alu methylation pattern in MM and its association with the different molecular and clinical subtypes of the disease has not been addressed so far. In this study, we analyzed changes in Alu and LINE-1 methylation of 66 patients with MM at diagnosis, including 7 cases of plasma cell leukemia (PCL) which represent the most aggressive form of plasma cell dyscrasias. DNA, extracted from bone marrow samples, was bisulfite treated and the methylation status was analysed by bisulfite-PCR and Pyrosequencing. DNA methylation of LINE-1 and Alu elements has shown to correlate with total 5mC content and thus used to estimate global DNA methylation. MMs exhibited low methylation in Alu (Average=19,8%) and LINE-1 sequences (Average=62,1%) compared to the standard results of Pyrosequencing analysis for both Alu (around 30%) and LINE-1 (around 80%). PCLs methylation levels were lower than MMs. Alu measured in MM was 20,0% while in PCL, was 16,8%. LINE-1 in MM was 64,0% versus 44,0% measured in PCL. Our data suggest that repetitive DNA hypomethylation is a feature of MM and, particularly, of the subtypes with poorer prognosis. Methylation results will be also compared with chromosomal abnormalities and clinico-pathological characteristics of MM patients. Our integrated approach may help provide a more exhaustive stratification of this disease, potentially leading to a more effective patients management.

Repetitive DNA hypomethylation in multiple myeloma / V. Bollati, D. Ronchetti, L. Mosca, G. Lambertenghi Deliliers, P.A. Bertazzi, A. Baccarelli, A. Neri - In: AACR Annual Meeting : Apr 12-16, 2008, San Diego, CA[s.l] : null, 2008 Apr. (( Intervento presentato al 99. convegno Annual Meeting of the American Association for Cancer Research (AACR) tenutosi a San Diego, CA nel 2008.

Repetitive DNA hypomethylation in multiple myeloma

V. Bollati;P.A. Bertazzi;A. Baccarelli;A. Neri
2008

Abstract

Multiple myeloma (MM) is a malignant proliferation of bone marrow plasma cells and one of the most frequently occurring hematological cancer. A wide spectrum of genetic and epigenetic changes has been observed in MM, but the molecular mechanisms underlying the genetic instability are poorly understood. Global genomic hypomethylation leading to the repetitive elements destabilization has been associated with chromosomal instability, which is commonly seen in solid tumors and multiple myeloma. About 55% of the human genome consists of repetitive elements, which are for the most part made up of approximately 500,000 long interspersed nucleotide elements (LINE elements) and 1.4 million Alu repetitive elements, which are normally heavily methylated. In humans, LINEs are the major source of insertional mutagenesis, being involved in both germinal and somatic mutant phenotypes. Alu retrotransposition has also been associated with human disease. However, the LINE/Alu methylation pattern in MM and its association with the different molecular and clinical subtypes of the disease has not been addressed so far. In this study, we analyzed changes in Alu and LINE-1 methylation of 66 patients with MM at diagnosis, including 7 cases of plasma cell leukemia (PCL) which represent the most aggressive form of plasma cell dyscrasias. DNA, extracted from bone marrow samples, was bisulfite treated and the methylation status was analysed by bisulfite-PCR and Pyrosequencing. DNA methylation of LINE-1 and Alu elements has shown to correlate with total 5mC content and thus used to estimate global DNA methylation. MMs exhibited low methylation in Alu (Average=19,8%) and LINE-1 sequences (Average=62,1%) compared to the standard results of Pyrosequencing analysis for both Alu (around 30%) and LINE-1 (around 80%). PCLs methylation levels were lower than MMs. Alu measured in MM was 20,0% while in PCL, was 16,8%. LINE-1 in MM was 64,0% versus 44,0% measured in PCL. Our data suggest that repetitive DNA hypomethylation is a feature of MM and, particularly, of the subtypes with poorer prognosis. Methylation results will be also compared with chromosomal abnormalities and clinico-pathological characteristics of MM patients. Our integrated approach may help provide a more exhaustive stratification of this disease, potentially leading to a more effective patients management.
Settore MED/44 - Medicina del Lavoro
apr-2008
http://www.aacrmeetingabstracts.org/content/vol2008/1_Annual_Meeting/index.dtl
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/59524
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