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Meningioma: a cytogenetic model of a complex benign human tumor, including data on 394 karyotyped cases
1Institut für Humangenetik, Universität des Saarlandes, Homburg, Germany. hgkzan@med-rz.uni-saarland.de
Abstract:
Meningioma is the most frequent tumor of neuroectodermal origin in humans. It is usually benign. Only a minority of cases shows progression to an anaplastic tumor (WHO grade II and III). Meningioma is generally a sporadic tumor. 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 tumors can recur. Recurrence and multiplicity are correlated with the formation of a peritumoral edema. On the cytogenetic level, meningioma is the best-studied tumor in humans. Grade I tumors show either uniform monosomy 22 or a diploid karyotype. 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 tumor suppressor gene on chromosome 22 has not yet been detected. In contrast to other solid tumors, 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 infrequent, except for the loss of the short arm of chromosome 1, which appears to be the decisive step for anaplastic growth. 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 tumor suppressor gene. A model is proposed that tries to explain - with a minimum number of essential steps - the origin, progression, infiltration, and recurrence of meningiomas.
Insights
Meningiomas, common brain tumors, often recur even after removal. Genetic changes, particularly on chromosome 22 involving the NF2 gene and merlin protein, are key to tumor progression and recurrence.
Area of Science:
- Neuro-oncology
- Human Genetics
- Tumor Biology
Background:
- Meningioma is the most common neuroectodermal tumor, typically benign but with a significant recurrence rate.
- Familial cases are rare, often linked to neurofibromatosis 2 (NF2).
- Recurrence and multiplicity correlate with peritumoral edema.
Purpose of the Study:
- To elucidate the genetic underpinnings of meningioma origin, progression, and recurrence.
- To identify key genetic alterations associated with different tumor grades and clinical behaviors.
- To propose a model explaining meningioma development.
Main Methods:
- Cytogenetic analysis of meningioma tumors.
- Molecular cytogenetic studies.
- Comparative histochemical analysis.
Main Results:
- Grade I meningiomas show monosomy 22 or diploidy; high-grade tumors often lose merlin (NF2 gene product).
- Tumor progression correlates with increasing hypodiploidy and specific chromosomal gains/losses (e.g., chr 14, 18, 19).
- Loss of chromosome 1p is linked to anaplastic growth; ALPL gene on 1p is a candidate tumor suppressor.
Conclusions:
- Meningioma development involves specific genetic alterations, including NF2 gene mutations and chromosomal instability.
- Tumor suppressor genes on chromosomes 1 and 22 play critical roles in meningioma progression.
- A model is proposed to explain the multi-step process of meningioma tumorigenesis and recurrence.