Differential repetitive DNA methylation in multiple myeloma molecular subgroups

Valentina Bollati, Sonia Fabris, Valeria Pegoraro, Domenica Ronchetti, Laura Mosca, Giorgio Lambertenghi Deliliers, Valeria Motta, Pier Alberto Bertazzi, Andrea Baccarelli, Antonino Neri

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Abstract

Multiple myeloma (MM) is characterized by a wide spectrum of genetic changes. Global hypomethylation of repetitive genomic sequences such as long interspersed nuclear element 1 (LINE-1), Alu and satellite alpha (SAT-α) sequences has been associated with chromosomal instability in cancer. Methylation status of repetitive elements in MM has never been investigated. In the present study, we used a quantitative bisulfite-polymerase chain reaction pyrosequencing method to evaluate the methylation patterns of LINE-1, Alu and SAT-α in 23 human myeloma cell lines (HMCLs) and purified bone marrow plasma cells from 53 newly diagnosed MM patients representative of different molecular subtypes, 7 plasma cell leukemias (PCLs) and 11 healthy controls. MMs showed a decrease of Alu [median: 21.1 %5-methylated cytosine (%5mC)], LINE-1 (70.0%5mC) and SAT-α (77.9%5mC) methylation levels compared with controls (25.2, 79.5and 89.5%5mC, respectively). Methylation levels were lower in PCLs and HMCLs compared with MMs (16.7 and 14.8%5mC for Alu, 45.5 and 42.4%5mC for LINE-1 and 33.3 and 43.3%5mC for SAT-α, respectively). Notably, LINE-1 and SAT-α methylation was significantly lower in the non-hyperdiploid versus hyperdiploid MMs (P = 0.01 and 0.02, respectively), whereas Alu and SAT-α methylation was significantly lower in MMs with t(4;14) (P = -0.02 and 0.004, respectively). Finally, we correlated methylation patterns with DNA methyltransferases (DNMTs) messenger RNA levels showing in particular a progressive and significant increase of DNMT1 expression from controls to MMs, PCLs and HMCLs (P = 0.001). Our results indicate that global hypomethylation of repetitive elements is significantly associated with tumor progression in MM and may contribute toward a more extensive stratification of the disease.

Original languageEnglish
Pages (from-to)1330-1335
Number of pages6
JournalCarcinogenesis
Volume30
Issue number8
DOIs
Publication statusPublished - 2009

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DNA Methylation
Multiple Myeloma
Methylation
Plasma Cell Leukemia
Alu Elements
Cell Line
Patient Advocacy
Chromosomal Instability
Polyploidy
Nucleic Acid Repetitive Sequences
Cytosine
Methyltransferases
Plasma Cells
Bone Marrow Cells
Neoplasms
Polymerase Chain Reaction
Messenger RNA
DNA

ASJC Scopus subject areas

  • Cancer Research

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Differential repetitive DNA methylation in multiple myeloma molecular subgroups. / Bollati, Valentina; Fabris, Sonia; Pegoraro, Valeria; Ronchetti, Domenica; Mosca, Laura; Deliliers, Giorgio Lambertenghi; Motta, Valeria; Bertazzi, Pier Alberto; Baccarelli, Andrea; Neri, Antonino.

In: Carcinogenesis, Vol. 30, No. 8, 2009, p. 1330-1335.

Research output: Contribution to journalArticle

Bollati, V, Fabris, S, Pegoraro, V, Ronchetti, D, Mosca, L, Deliliers, GL, Motta, V, Bertazzi, PA, Baccarelli, A & Neri, A 2009, 'Differential repetitive DNA methylation in multiple myeloma molecular subgroups', Carcinogenesis, vol. 30, no. 8, pp. 1330-1335. https://doi.org/10.1093/carcin/bgp149
Bollati, Valentina ; Fabris, Sonia ; Pegoraro, Valeria ; Ronchetti, Domenica ; Mosca, Laura ; Deliliers, Giorgio Lambertenghi ; Motta, Valeria ; Bertazzi, Pier Alberto ; Baccarelli, Andrea ; Neri, Antonino. / Differential repetitive DNA methylation in multiple myeloma molecular subgroups. In: Carcinogenesis. 2009 ; Vol. 30, No. 8. pp. 1330-1335.
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abstract = "Multiple myeloma (MM) is characterized by a wide spectrum of genetic changes. Global hypomethylation of repetitive genomic sequences such as long interspersed nuclear element 1 (LINE-1), Alu and satellite alpha (SAT-α) sequences has been associated with chromosomal instability in cancer. Methylation status of repetitive elements in MM has never been investigated. In the present study, we used a quantitative bisulfite-polymerase chain reaction pyrosequencing method to evaluate the methylation patterns of LINE-1, Alu and SAT-α in 23 human myeloma cell lines (HMCLs) and purified bone marrow plasma cells from 53 newly diagnosed MM patients representative of different molecular subtypes, 7 plasma cell leukemias (PCLs) and 11 healthy controls. MMs showed a decrease of Alu [median: 21.1 {\%}5-methylated cytosine ({\%}5mC)], LINE-1 (70.0{\%}5mC) and SAT-α (77.9{\%}5mC) methylation levels compared with controls (25.2, 79.5and 89.5{\%}5mC, respectively). Methylation levels were lower in PCLs and HMCLs compared with MMs (16.7 and 14.8{\%}5mC for Alu, 45.5 and 42.4{\%}5mC for LINE-1 and 33.3 and 43.3{\%}5mC for SAT-α, respectively). Notably, LINE-1 and SAT-α methylation was significantly lower in the non-hyperdiploid versus hyperdiploid MMs (P = 0.01 and 0.02, respectively), whereas Alu and SAT-α methylation was significantly lower in MMs with t(4;14) (P = -0.02 and 0.004, respectively). Finally, we correlated methylation patterns with DNA methyltransferases (DNMTs) messenger RNA levels showing in particular a progressive and significant increase of DNMT1 expression from controls to MMs, PCLs and HMCLs (P = 0.001). Our results indicate that global hypomethylation of repetitive elements is significantly associated with tumor progression in MM and may contribute toward a more extensive stratification of the disease.",
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AU - Bollati, Valentina

AU - Fabris, Sonia

AU - Pegoraro, Valeria

AU - Ronchetti, Domenica

AU - Mosca, Laura

AU - Deliliers, Giorgio Lambertenghi

AU - Motta, Valeria

AU - Bertazzi, Pier Alberto

AU - Baccarelli, Andrea

AU - Neri, Antonino

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N2 - Multiple myeloma (MM) is characterized by a wide spectrum of genetic changes. Global hypomethylation of repetitive genomic sequences such as long interspersed nuclear element 1 (LINE-1), Alu and satellite alpha (SAT-α) sequences has been associated with chromosomal instability in cancer. Methylation status of repetitive elements in MM has never been investigated. In the present study, we used a quantitative bisulfite-polymerase chain reaction pyrosequencing method to evaluate the methylation patterns of LINE-1, Alu and SAT-α in 23 human myeloma cell lines (HMCLs) and purified bone marrow plasma cells from 53 newly diagnosed MM patients representative of different molecular subtypes, 7 plasma cell leukemias (PCLs) and 11 healthy controls. MMs showed a decrease of Alu [median: 21.1 %5-methylated cytosine (%5mC)], LINE-1 (70.0%5mC) and SAT-α (77.9%5mC) methylation levels compared with controls (25.2, 79.5and 89.5%5mC, respectively). Methylation levels were lower in PCLs and HMCLs compared with MMs (16.7 and 14.8%5mC for Alu, 45.5 and 42.4%5mC for LINE-1 and 33.3 and 43.3%5mC for SAT-α, respectively). Notably, LINE-1 and SAT-α methylation was significantly lower in the non-hyperdiploid versus hyperdiploid MMs (P = 0.01 and 0.02, respectively), whereas Alu and SAT-α methylation was significantly lower in MMs with t(4;14) (P = -0.02 and 0.004, respectively). Finally, we correlated methylation patterns with DNA methyltransferases (DNMTs) messenger RNA levels showing in particular a progressive and significant increase of DNMT1 expression from controls to MMs, PCLs and HMCLs (P = 0.001). Our results indicate that global hypomethylation of repetitive elements is significantly associated with tumor progression in MM and may contribute toward a more extensive stratification of the disease.

AB - Multiple myeloma (MM) is characterized by a wide spectrum of genetic changes. Global hypomethylation of repetitive genomic sequences such as long interspersed nuclear element 1 (LINE-1), Alu and satellite alpha (SAT-α) sequences has been associated with chromosomal instability in cancer. Methylation status of repetitive elements in MM has never been investigated. In the present study, we used a quantitative bisulfite-polymerase chain reaction pyrosequencing method to evaluate the methylation patterns of LINE-1, Alu and SAT-α in 23 human myeloma cell lines (HMCLs) and purified bone marrow plasma cells from 53 newly diagnosed MM patients representative of different molecular subtypes, 7 plasma cell leukemias (PCLs) and 11 healthy controls. MMs showed a decrease of Alu [median: 21.1 %5-methylated cytosine (%5mC)], LINE-1 (70.0%5mC) and SAT-α (77.9%5mC) methylation levels compared with controls (25.2, 79.5and 89.5%5mC, respectively). Methylation levels were lower in PCLs and HMCLs compared with MMs (16.7 and 14.8%5mC for Alu, 45.5 and 42.4%5mC for LINE-1 and 33.3 and 43.3%5mC for SAT-α, respectively). Notably, LINE-1 and SAT-α methylation was significantly lower in the non-hyperdiploid versus hyperdiploid MMs (P = 0.01 and 0.02, respectively), whereas Alu and SAT-α methylation was significantly lower in MMs with t(4;14) (P = -0.02 and 0.004, respectively). Finally, we correlated methylation patterns with DNA methyltransferases (DNMTs) messenger RNA levels showing in particular a progressive and significant increase of DNMT1 expression from controls to MMs, PCLs and HMCLs (P = 0.001). Our results indicate that global hypomethylation of repetitive elements is significantly associated with tumor progression in MM and may contribute toward a more extensive stratification of the disease.

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