Recurrence and Progression in Meningiomas: The Clonal Cytogenetic Evolution of a Benign Human Tumour

European Association of NeuroOncology Magazine 2013; 3 (3): 105-111

PDF    Summary   




Keywords: chromosome,  deletion of 1p,  genetic progression,  meningioma,  recurrence

Meningiomas are mostly benign tumours that originate from the coverings of brain and spinal cord. Only a minority of cases show progression to an anaplastic tumour (WHO grades II and III). Multiple and familial cases are rare and mostly associated with (hereditary) neurofibromatosis 2 (NF2). Meningiomas show an unexpectedly high recurrence rate. Also, completely removed low-grade tumours can recur. On a cytogenetic level, meningiomas are the best-studied tumours in humans. The majority of high-grade but only a minority of low-grade meningiomas show loss of merlin, a cytoskeleton-cytoplasm-linker protein. Merlin is the product of the NF2 gene located on chromosome 22. A second tumour suppressor gene on chromosome 22 on 22q12.3 is the gene for the tissue inhibitor of metalloproteinase 3 (TIMP3), which appears to be involved in meningioma progression and a high-grade meningioma phenotype. In contrast to other solid tumours, progression of meningiomas is correlated with increasing hypodiploidy, showing characteristic clonal evolutions that mostly include chromosomes 14, 18, and 19 and, more rarely, 6 and 10. Structural aberrations are rare, except for the loss of the short arm of one chromosome 1, which appears to be the decisive step for anaplastic growth. A biostatistical approach has been proposed, using an oncogenetic tree model that estimates the most likely cytogenetic pathways of meningioma patients in terms of accumulation of chromosome changes in tumour cells. The genetic progression score (GPS) estimates the genetic status of a tumour as progression in the corresponding tumour cells along this model. High GPS values are highly correlated with early recurrence of meningiomas (p < 10–4). This correlation holds true even when patients are stratified by WHO grade. Tumour location also has an impact on genetic progression. Clinical relevance of the GPS is demonstrated with respect to origin, WHO grade, and recurrence of the tumour. As a quantitative measure, the GPS allows a more precise assessment of the prognosis of meningiomas than categorical cytogenetic markers based on single chromosomal aberrations. Comparative histochemical and molecular cytogenetic studies point to the alkaline phosphatase gene (ALPL, liver-bone-kidney type) located on 1p36.1–p34 as a candidate tumour suppressor gene