Hypermethylation and Transcriptional Downregulation of the <i>TIMP3</i> Gene is Associated with Allelic Loss on 22q12.3 and Malignancy in Meningiomas

<jats:title>Abstract</jats:title><jats:p>The gene for the tissue inhibitor of metalloproteinase 3 (<jats:italic>TIMP3</jats:italic>) on 22q12.3 had been reported to be inactivated by promoter methylation in various types of cancers, with controversial findings in meningiomas. We performed direct sodium bisulfite sequencing in a series of 50 meningiomas, including 27 benign meningiomas [World Health Organization (WHO) grade I], 11 atypical meningiomas (WHO grade II) and 12 anaplastic meningiomas (WHO grade III), and found hypermethylation of <jats:italic>TIMP3</jats:italic> in 67% of anaplastic meningiomas, but only 22% of atypical and 17% of benign meningiomas. Moreover, <jats:italic>TIMP3</jats:italic> methylation scores were significantly inversely correlated with <jats:italic>TIMP3</jats:italic> mRNA expression levels (<jats:italic>P</jats:italic> = 0.0123), and treatment of the meningioma cell line Ben‐Men‐1 with demethylating agents induced an increased <jats:italic>TIMP3</jats:italic> mRNA expression. <jats:italic>TIMP3</jats:italic> is located in the chromosomal band 22q12, the allelic loss of which occurs early in meningioma tumorigenesis and preferentially targets the <jats:italic>NF2</jats:italic> tumor suppressor gene. In our tumor panel, all meningiomas with <jats:italic>TIMP3</jats:italic> hypermethylation—except for a single case—exhibited allelic losses on 22q12.3. Thus, <jats:italic>TIMP3</jats:italic> inactivation by methylation seems fairly exclusive to meningiomas with allelic losses on 22q12 but—in contrast to <jats:italic>NF2</jats:italic> mutation—appears to be involved in meningioma progression as it is associated with a more aggressive, high‐grade meningioma phenotype.</jats:p>