DNA methylation of multiple promoter-associated CpG islands in meningiomas: relationship with the allelic status at 1p and 22q

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ID: 116613
2004
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Abstract
The purpose of this research was to examine the DNA methylation profile of meningiomas. Accordingly, we examined the DNA methylation status of ten tumor-related genes (RB1, p16 INK4a , p73, MGMT, ER, DAPK, TIMP-3, p14 ARF , THBS1, and Caspase-8) in 98 meningiomas (68 grade I; 27 grade II; and 3 grade III samples) using methylation-specific PCR and sequencing. The most frequently methylated genes were THBS1 (30%), TIMP-3 (24%), p16 INK4a (17%), MGMT (16%), p73 (15%), ER (15%), and p14 ARF (13%), whereas methylation was relatively rare in the other genes (<10%). Methylation occurred in at least one gene in 77.5% of the cases and in three or more genes in 25.5%. Methylation was tumor specific since it was absent in the controls: two non-neoplastic meningeal samples and two non-neoplastic brain samples. The frequency of aberrant gene methylation in grade I versus grade II–III tumors showed some differences for TIMP-3, THBS1, MGMT, p16 INK4a and p73; these differences reached statistical significance for TIMP-3: 18% in grade I versus 40% in grade II–III (P<0.02). Our previous loss of heterozygosity studies provided the allelic constitution at 1p and 22q for 60 of the 98 meningiomas included in this report. The level of aberrant promoter methylation increased in tumors (30 samples) displaying 1p loss (either isolated or as concurrent deletion at 1p/22q; P=0.014). These meningiomas primarily accumulated the epigenetic changes of THBS1 (14/30; 47%; P<0.005), TIMP-3 (12/30; 40%; P<0.05), p73 (10/30; 26%; P<0.02) and p14 ARF /p16 INK4a (7/30 each one; 23%; not significant). Our findings indicate that aberrant DNA methylation of promoter-associated CpG islands in meningiomas contributes to the development of these tumors.
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Authors M. Josefa Bello;Cinthia Amiñoso;Isabel Lopez-Marin;Dolores Arjona;Pilar Gonzalez-Gomez;M. Eva Alonso;Jesus Lomas;Jose M. de Campos;M. Elena Kusak;Jesus Vaquero;Alberto Isla;Manuel Gutierrez;Jose L. Sarasa;Juan A. Rey;M. Josefa Bello;Cinthia Amiñoso;Isabel Lopez-Marin;Dolores Arjona;Pilar Gonzalez-Gomez;M. Eva Alonso;Jesus Lomas;Jose M. de Campos;M. Elena Kusak;Jesus Vaquero;Alberto Isla;Manuel Gutierrez;Jose L. Sarasa;Juan A. Rey;
Journal acta neuropathologica
Year 2004
DOI
doi:10.1007/s00401-004-0911-6
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