HOXA7, 9, and 10 are methylation targets associated with aggressive behavior in meningiomas

Meningioma is one of the most common intracranial tumors and is graded according to the World Health Organization (WHO) classification system. Although these tumors are often surgically curable, a malignant behavior also may occur in meningiomas with benign histologic profiles (WHO I). Thus, it is mandatory to identify biomolecular parameters useful to improve the classification of these tumors. HOXA genes belong to the HOX gene family that encodes homeodomain-containing transcription factors known to be key regulators of embryonic development, involved in cell growth and differentiation and in the development of the central nervous system. Moreover, altered HOXA gene methylation and expression have prognostic value in many tumors. The purpose of this study was to determine whether the level of HOXA3, 7, 9, and 10 methylation in meningioma could be a biomarker linked to the pathologic characteristics of the tumor. We found that methylation levels of HOXA7, 9, and 10 in 131 meningioma samples were significantly higher in WHO II/III tumors compared with WHO I tumors. Moreover, in newly diagnosed WHO I meningiomas, HOXA7, 9, and 10 methylation was significantly lower than in WHO I samples derived from recurring tumors, and multiple meningiomas presented significantly higher HOXA 10 methylation with respect to solitary meningiomas. This study demonstrates that HOXA7, 9, and 10 are methylation targets in meningioma, associated with histopathology and clinical aggressiveness parameters. Our findings suggest the possibility of detecting the malignancy potential of meningioma by assessing the HOXA methylation level and identifying patients at higher risk who could benefit from closer follow-up or postoperative adjuvant treatments.