Elsevier

Translational Research

Volume 160, Issue 5, November 2012, Pages 355-362
Translational Research

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

https://doi.org/10.1016/j.trsl.2012.05.007Get rights and content

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.

Section snippets

Tumor specimens and DNA/RNA preparation

DNA was extracted from 131 consecutive frozen meningioma and 7 meningeal samples, microscopically free of disease, excised from patients who underwent operation at the Neurosurgery Branch of the IRCCS AOU San Martino – IST between 2006 and 2009. Informed consent was obtained from all patients.

Tumors, classified according to the WHO classification, included 100 WHO I, 28 WHO II, and 3 WHO III samples. Ninety-three samples were solitary meningiomas at the onset, 14 samples were recurrence of

Results and Discussion

Epigenetics, and in particular DNA methylation, is one of the mechanisms through which cancer-related genes are inappropriately silenced or reactivated. In recent years, the interest on epigenetic alterations as cancer biomarkers independent of the functional effects has steadily increased.25

To identify biomolecular parameters that are potentially useful to improve the accuracy of the diagnosis and prognosis in meningioma, we have evaluated the methylation level of HOXA3, 7, 9, and 10 by

Conclusions

The identification of biomolecular parameters that are useful to improve the classification of meningioma may optimize the indications for possible adjuvant therapies and closer follow-up. We have conducted our study on HOXA genes, whose expression or methylation is altered in central nervous system tumors, and it has been put in relation with phenotype and resistance to treatment.17, 18, 19 Our results indicate that HOXA7, 9, and 10 are methylation targets in meningioma that are able to

References (29)

  • C. Marosi et al.

    Meningioma

    Crit Rev Oncol Hematol

    (2008)
  • G.A. Alexiou et al.

    Genetic and molecular alterations in meningiomas

    Clin Neurol Neurosurg

    (2011)
  • Y. Liu et al.

    Aberrant CpG island hypermethylation profile is associated with atypical and anaplastic meningiomas

    Hum Pathol

    (2005)
  • M. Kallio et al.

    Factors affecting operative and excess long-term mortality in 935 patients with intracranial meningioma

    Neurosurgery

    (1992)
  • H.W. Jung et al.

    Long-term outcome and growth rate of subtotally resected petroclival meningiomas: experience with 38 cases

    Neurosurgery

    (2000)
  • G. Kleinpeter et al.

    Invasion of the cavernous sinus by medial sphenoid meningioma—“radical” surgery and recurrence

    Acta Neurochir (Wien)

    (1990)
  • M.J. Puchner et al.

    Suprasellar meningiomas–neurological and visual outcome at long-term follow-up in a homogeneous series of patients treated microsurgically

    Acta Neurochir (Wien)

    (1998)
  • J. Antinheimo et al.

    Population-based analysis of sporadic and type 2 neurofibromatosis-associated meningiomas and schwannomas

    Neurology

    (2000)
  • R.H. Lekanne Deprez et al.

    Cloning and characterization of MN1, a gene from chromosome 22q11, which is disrupted by a balanced translocation in a meningioma

    Oncogene

    (1995)
  • D. Barski et al.

    Hypermethylation and transcriptional downregulation of the TIMP3 gene is associated with allelic loss on 22q12.3 and malignancy in meningiomas

    Brain Pathol

    (2010)
  • P. Jun et al.

    Epigenetic silencing of the kinase tumor suppressor WNK2 is tumor-type and tumor-grade specific

    Neuro Oncol

    (2009)
  • J.A. Kandenwein et al.

    uPA/PAI-1 expression and uPA promoter methylation in meningiomas

    J Neurooncol

    (2011)
  • Y. Nakane et al.

    Malignant transformation-related genes in meningiomas: allelic loss on 1p36 and methylation status of p73 and RASSF1A

    J Neurosurg

    (2007)
  • Y. Kishida et al.

    Epigenetic subclassification of meningiomas based on genome-wide DNA methylation analyses

    Carcinogenesis

    (2012)
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    B. B. is the recipient of a Young Investigators Grant from the Italian Ministry of Health. This work was supported by the Italian Ministry of Health and the Regione Liguria Grant “Genetic and Epigenetic Alterations in Brain Tumors.”

    The authors have read and approved the Journal policy on conflicts of interest, and they declare there are no potential conflicts of interest that could have biased the work.

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